Genetics of Colorectal Cancer (PDQ®)–Health Professional Version
Colon Cancer Genes
Major Genes
Major genes are defined as those that are necessary and sufficient for disease causation, with important pathogenic variants (e.g., nonsense, missense, frameshift) of the gene as causal mechanisms. Major genes are typically considered those that are involved in single-gene disorders, and the diseases caused by major genes are often relatively rare. Most pathogenic variants in major genes lead to a very high risk of disease, and environmental contributions are often difficult to recognize.[1] Historically, most major colon cancer susceptibility genes have been identified by linkage analysis using high-risk families; thus, these criteria were fulfilled by definition, as a consequence of the study design.
The functions of the major colon cancer genes have been reasonably well characterized over the past decade. Three proposed classes of colon cancer genes are tumor suppressor genes, oncogenes, and DNA repair genes.[2] Tumor suppressor genes constitute the most important class of genes responsible for hereditary cancer syndromes and represent the class of genes responsible for both familial adenomatous polyposis (FAP) and juvenile polyposis syndrome (JPS), among others. Germline pathogenic variants in oncogenes are not an important cause of inherited susceptibility to colorectal cancer (CRC), even though somatic variants in oncogenes are ubiquitous in virtually all forms of gastrointestinal cancers. Stability genes, especially the mismatch repair (MMR) genes responsible for Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC]), account for a substantial fraction of hereditary CRC, as noted below. (Refer to the Lynch Syndromesection in the Major Genetic Syndromes section of this summary for more information).MUTYH is another important example of a stability gene that confers risk of CRC based on defective base excision repair. Table 2 summarizes the genes that confer a substantial risk of CRC, with their corresponding diseases.
De Novo Pathogenic Variant Rate
Until the 1990s, the diagnosis of genetically inherited polyposis syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous pathogenic variant rate (de novo pathogenic variant rate) in these populations. Interestingly, FAP, JPS, Peutz-Jeghers syndrome, Cowden syndrome, and Bannayan-Riley-Ruvalcaba syndrome are all thought to have high rates of spontaneous pathogenic variants, in the 25% to 30% range,[3-5] while estimates of de novo pathogenic variants in the MMR genes associated with Lynch syndrome are thought to be low, in the 0.9% to 5% range.[6-8] These estimates of spontaneous pathogenic variant rates in Lynch syndrome seem to overlap with the estimates of nonpaternity rates in various populations (0.6% to 3.3%),[9-11] making the de novo pathogenic variant rate for Lynch syndrome seem quite low in contrast to the relatively high rates in the other polyposis syndromes.
Next-Generation Sequencing and Novel CRC Susceptibility Genes
Next-generation sequencing (NGS) involves technological advances over the traditional capillary-based Sanger DNA sequencing that was used in the Human Genome Project to sequence the human genome. NGS dramatically decreases the time required for genomic sequencing by utilizing massively parallel multiplexing techniques. Comparisons of genomic sequencing results between individuals with and without CRC affords yet another method to identify CRC susceptibility genes.
Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are currently being used to assess somatic alterations in tumors to inform prognosis and/or targeted therapeutics and to assess the germline to identify cancer risk alleles. (Refer to the Clinical Sequencing section in the PDQ Cancer Genetics Overview summary for more information.)
An example of the success of NGS in identifying CRC susceptibility genes is the discovery of POLE/POLD1 germline pathogenic variants in patients with adenomatous polyposis but no germline variants in known CRC genes. (Refer to the Oligopolyposis section in the Major Genetic Syndromes section of this summary for more information about POLE/POLD1.)
WES has also been used to identify new potential CRC predisposition variants. In one 2016 study, exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls were analyzed.[12] Highly penetrant rare pathogenic variants were identified in 16% of familial CRC cases, of which the majority were known colon cancer genes while POT1, POLE2, and MRE11 were identified as candidate CRC genes. The authors concluded that these findings probably discount the existence of further major high-penetrance susceptibility CRC genes.
Genetic Polymorphisms and CRC Risk
It is widely acknowledged that the familial clustering of colon cancer also occurs outside of the setting of well-characterized colon cancer family syndromes.[13] Based on epidemiological studies, the risk of colon cancer in a first-degree relative of an affectedindividual can increase an individual’s lifetime risk of colon cancer 2-fold to 4.3-fold.[14] The relative risk (RR) and absolute risk of CRC for different family history categories is estimated in Table 1. In addition, the lifetime risk of colon cancer also increases in first-degree relatives of individuals with colon adenomas.[15] The magnitude of risk depends on the age at diagnosis of the index case, the degree of relatedness of the index case to the at-risk case, and the number of affected relatives. It is currently believed that many of the moderate- and low-risk cases are influenced by alterations in single low-penetrance genes or combinations of low-penetrance genes. Given the public health impact of identifying the etiology of this increased risk, an intense search for the responsible genes is under way.
Each locus would be expected to have a relatively small effect on CRC risk and would not produce the dramatic familial aggregation seen in Lynch syndrome or FAP. However, in combination with other common genetic loci and/or environmental factors, variants of this kind might significantly alter CRC risk. These types of genetic variations are often referred to as polymorphisms. Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed disease-associated polymorphisms or functionally relevant polymorphisms. When such variation involves changes in single nucleotides of DNA they are referred to as single nucleotide polymorphisms (SNPs).
Polymorphisms underlying polygenic susceptibility to CRC are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to high-penetrance variants or alleles that are typically associated with more severe phenotypes, for example those APC or MMR gene pathogenic variants leading to an autosomal dominant inheritance pattern in a family. The definition of a moderate risk of cancer is arbitrary, but it is usually considered to be in the range of an RR of 1.5 to 2.0. Because these types of sequence variants are relatively common in the population, their contribution to total cancer risk is estimated to be much higher than the attributable risk in the population from the relatively rare syndromes such as FAP or Lynch syndrome. Additionally, polymorphisms in genes distinct from the MMR genes can modify phenotype (e.g., average age of CRC) in individuals with Lynch syndrome.
Low-penetrance variants have been identified in a number of strategies. Earlier studies focused on candidates genes chosen because of biologic relevance to cancer pathogenesis. More recently, genome-wide association studies (GWAS) have been used much more extensively to identify potential CRC susceptibility genes. (Refer to the GWASsection of this summary for more information.) Another approach is to use meta-analyses of existing GWAS datasets to discover additional novel CRC susceptibility genes.
Polymorphism-modifying risk in average-risk populations
Low-penetrance candidate genes
Several candidate genes have been identified and their potential use for clinical genetic testing is being determined. Candidate alleles that have been shown to associate with modest increased frequencies of colon cancer include heterozygous BLMAsh (the allele that is a founder pathogenic variant in Ashkenazi Jewish individuals with Bloom syndrome), the GH1 1663 T→A polymorphism (a polymorphism of the growth hormone gene associated with low levels of growth hormone and IGF-1), and the APC I1307K polymorphism.[16-18]
Of these, the variant that has been most extensively studied is APC I1307K. Yet, neither it nor any of the other variants mentioned above are routinely used in clinical practice. (Refer to the APC I1307K section of this summary for more information.)
GWAS
Although the major genes for polyposis and nonpolyposis inherited CRC syndromes have been identified, between 20% and 50% of cases from any given series of suspected FAP or Lynch syndrome cases fail to have a pathogenic variant detected by currently available technologies. It is estimated that heredity is responsible for approximately one-third of the susceptibility to CRC,[19] and causative germline pathogenic variants account for less than 6% of all CRC cases.[20] This suggests that there may be other major genes with pathogenic variants that may predispose to CRC with or without polyposis. A few such genes have been detected (e.g., MUTYH, EPCAM) but the probability for discovery of other such genes is fairly low. More recent measures for new gene discovery have taken a genome-wide approach. Several GWAS have been conducted with relatively large, unselected series of CRC patients that have been evaluated for patterns of polymorphisms in candidate and anonymous genes throughout the genome. These SNPs are chosen to capture a large portion of common variation within the genome, based on the International HapMap Project.[21,22] The goal is to identify alleles that, while not pathogenic variants, may confer an increase (or potential decrease) in CRC risk. Identification of yet unknown aberrant CRC alleles would permit further stratification of at-risk individuals on a genetic basis. Such risk stratification would potentially enhance CRC screening. The use of genome-wide scans in thousands of CRC cases and controls has led to the discovery of multiple common low-risk CRC SNPs, which can be found in the National Human Genome Research Institute GWAS catalog. A thorough discussion of GWAS can be found in the Cancer Genetics Overview PDQ summary. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes are governed by many alleles, each conferring modest risk. It is very unlikely that an allele with high frequency in the population by itself contributes substantially to cancer risk. This, coupled with the polygenic nature of tumorigenesis, means that the contribution by any single variant identified by GWAS to date is quite small, generally with an odds ratio (OR) for disease risk of less than 1.5.
Meta-analysis of GWAS has allowed for the identification of novel CRC-associated SNPs by combining data from previous GWAS.[23,23-26] These SNPs are provided in the GWAS catalog referenced above. The same considerations for GWAS mentioned above apply to the meta-analysis approach.
Genetic variation in 8q24 and SMAD7
Three separate studies showed that genetic variation at 8q24.21 is associated with increased risk of colon cancer, with RR ranging from 1.17 to 1.27.[27-29] Although the RR is modest for the risk alleles in 8q24, the prevalence (and population-attributable fraction) of these risk alleles is high. The genes responsible for this association have not yet been identified. In addition, common alleles of SMAD7 have also been shown to be associated with an approximately 35% increase in risk of colon cancer.[30]
Other candidate alleles that have been identified on multiple (>3) genetic association studies include the GSTM1 null allele and the NAT2 G/G allele.[31] None of these alleles has been characterized enough to currently support its routine use in a clinical setting. Family history remains the most valuable tool for establishing risk of colon cancer in these families. Similar to what has been reported in prostate cancer, a combination of susceptibility loci may yet hold promise in profiling individual risk.[32,33]
Variants of uncertain significance in major cancer susceptibility genes
APC I1307K
Polymorphisms in APC are the most extensively studied polymorphisms with regard to cancer association. The APC I1307K polymorphism is associated with an increased risk of colon cancer but does not cause colonic polyposis. The I1307K polymorphism occurs almost exclusively in people of Ashkenazi Jewish descent and results in a twofold increased risk of colonic adenomas and adenocarcinomas compared with the general population.[18,34] The I1307K polymorphism results from a transition from T to A at nucleotide 3920 in the APC gene and appears to create a region of hypermutability.[18] Although clinical assays to assess for the APC I1307K polymorphism are currently available, the associated colon cancer risk is not high enough to support routine use. On the basis of currently available data, it is not yet known whether the I1307K carrier state should guide decisions regarding the age to initiate screening, the frequency of screening, or the choice of screening strategy.
Clinical implications of low-penetrance alleles
Although the statistical evidence for an association between genetic variation at these loci and CRC risk is convincing, the biologically relevant variants and the mechanisms by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk, with ORs for developing CRC in heterozygous carriers usually from 1.1 to 1.3. More risk variants will likely be identified. Risks in this range do not appear to confer enough increase in age-specific risk as to warrant modification of otherwise clinically prudent screening. Until their collective influence is prospectively evaluated, their use cannot be recommended in clinical practice.
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Major Genetic Syndromes
Introduction
Originally described in the 1800s and 1900s by their clinical findings, the colon cancer susceptibility syndrome names often reflected the physician or patient and family associated with the syndrome (e.g., Gardner syndrome, Turcot syndrome, Muir-Torre syndrome, Lynch syndrome, Peutz-Jeghers syndrome [PJS], Bannayan-Riley-Ruvalcaba syndrome, and Cowden syndrome). These syndromes were associated with an increased lifetime risk of colorectal adenocarcinoma. They were mostly thought to have autosomal dominant inheritance patterns. Adenomatous colonic polyps were characteristic of the first four, while hamartomas were found to be characteristic in the last three.
With the development of the Human Genome Project and the identification in 1990 of the adenomatous polyposis coli (APC) gene on chromosome 5q, overlap and differences between these familial syndromes became apparent. Gardner syndrome and familial adenomatous polyposis (FAP) were shown to be synonymous, both caused by pathogenic variants in the APC gene. Attenuated FAP (AFAP) was recognized as a syndrome with less adenomas and extraintestinal manifestations due to an APC pathogenic variant at the 3’ or 5’ ends of the gene. MUTYH-associated polyposis (MAP) was recognized as a separate adenomatous polyp syndrome with autosomal recessive inheritance. Once the pathogenic variants were identified, the absolute risk of colorectal cancer (CRC) could be better assessed for carriers of pathogenic variants (refer to Table 3).
With these discoveries genetic testing and risk management became possible. Genetic testing refers to searching for variants in known cancer susceptibility genes using a variety of techniques. Comprehensive genetic testing includes sequencing the entire coding region of a gene, the intron -exon boundaries (splice sites), and assessment of rearrangements, deletions, or other changes in copy number (with techniques such as multiplex ligation-dependent probe amplification [MLPA] or Southern blot). Despite extensive accumulated experience that helps distinguish pathogenic variants from benign variants and polymorphisms, genetic testing sometimes identifies variants of uncertain significance (VUS) that cannot be used for predictive purposes.
Familial Adenomatous Polyposis (FAP)
By 1900, several reports had demonstrated that patients with multiple polyps (only later subclassified as adenomas and other histologies) were at very high risk of CRC and that the pattern of occurrence in families was autosomal dominant. In the 20th century, the adenoma-to-carcinoma progression was confirmed, and FAP was recognized as one human model for this progression.[11] Various complications of FAP came to be described, including upper gastrointestinal (GI) tract adenomas; fundic gland stomach polyps; nonepithelial benign tumors (osteomas, epidermal cysts, dental abnormalities [this triad is known collectively as Gardner syndrome]); desmoid tumors; congenital hypertrophy of retinal pigment epithelium (CHRPE); and malignant tumors (thyroid and brain tumors, hepatoblastoma).
FAP is one of the most clearly defined and well understood of the inherited colon cancer syndromes.[1,12,13] It is an autosomal dominant condition, and the reported incidence varies from 1 in 7,000 to 1 in 22,000 live births, with the syndrome being more common in Western countries.[14] Autosomal dominant inheritance means that affected persons are genetically heterozygous, such that each offspring of a patient with FAP has a 50% chance of inheriting the disease gene. Males and females are equally likely to be affected.
Classically, FAP is characterized by multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life (refer to Figure 3).
FAP features in addition to the colonic polyps may include polyps in the upper GI tract, extraintestinal manifestations such as CHRPE, osteomas and epidermoid cysts, supernumerary teeth, desmoid tumor formation, and other malignant changes such as thyroid tumors, small bowel cancer, hepatoblastoma, and brain tumors, particularly medulloblastoma (refer to Table 4).
FAP is also known as familial polyposis coli, adenomatous polyposis coli (APC), or Gardner syndrome (colorectal polyposis, osteomas, and soft tissue tumors). Gardner syndrome has sometimes been used to designate FAP patients who manifest these extracolonic features. However, Gardner syndrome has been shown molecularly to be a variant of FAP, and thus the term Gardner syndrome is essentially obsolete in clinical practice.[22]
Most cases of FAP result from pathogenic variants in the APC gene on chromosome 5q21. Individuals who inherit a pathogenic variant in the APC gene have a very high likelihood of developing colonic adenomas; the risk has been estimated to be more than 90%.[1,12,13] The age at onset of adenomas in the colon is variable: By age 10 years, only 15% of carriers of the APC germline variant manifest adenomas; by age 20 years, the probability rises to 75%; and by age 30 years, 90% will have presented with FAP.[1,12,13,23,24] Without any intervention, most persons with FAP will develop colon or rectal cancer by the fourth decade of life.[1,12,13] Thus, surveillance and intervention for carriers of an APC gene pathogenic variant and at-risk persons have conventionally consisted of annual sigmoidoscopy beginning around puberty. The objective of this regimen is early detection of colonic polyps in those who have FAP, leading to preventive colectomy.[25,26]
The early appearance of clinical features of FAP and the subsequent recommendations for surveillance beginning at puberty raise special considerations relating to the genetic testing of children for susceptibility genes.[27] Some proponents feel that the genetic testing of children for FAP presents an example in which possible medical benefit justifies genetic testing of minors, especially for the anticipated 50% of children who will be found not to be carriers of pathogenic variants and who can thus be spared the necessity of unpleasant and costly annual sigmoidoscopy. The psychological impact of such testing is currently under investigation and is addressed in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary.
A number of different APC pathogenic variants have been described in a series of FAP patients. The clinical features of FAP appear to be generally associated with the location of the variant in the APC gene and the type of variant (i.e., frameshift variant vs. missense variant). Two features of particular clinical interest that are apparently associated with APCvariants are (1) the density of colonic polyposis and (2) the development of extracolonic tumors.
Adenomatous polyposis coli (APC)
The APC gene on chromosome 5q21 encodes a 2,843-amino acid protein that is important in cell adhesion and signal transduction; beta-catenin is its major downstream target. APCis a tumor suppressor gene, and the loss of APC is among the earliest events in the chromosomal instability colorectal tumor pathway. The important role of APC in predisposition to colorectal tumors is supported by the association of APC germlinepathogenic variants with FAP and AFAP. Both conditions can be diagnosed genetically by testing for germline pathogenic variants in the APC gene in DNA from peripheral blood leukocytes. Most FAP pedigrees have APC alterations that produce truncating pathogenic variants, primarily in the first half of the gene.[28,29] AFAP is associated with truncating pathogenic variants primarily in the 5’ and 3’ ends of the gene and possibly missense variants elsewhere.[30-33]
More than 300 different disease-associated pathogenic variants of the APC gene have been reported.[29] The vast majority of these changes are insertions, deletions, and nonsense variants that lead to frameshifts and/or premature stop codons in the resulting transcript of the gene. The most common APC pathogenic variant (10% of FAP patients) is a deletion of AAAAG in codon 1309; no other pathogenic variants appear to predominate. Variants that reduce rather than eliminate production of the APC protein may also lead to FAP.[34]
Most APC pathogenic variants that occur between codon 169 and codon 1393 result in the classic FAP phenotype.[30-32] There has been much interest in correlating the location of the pathogenic variant within the gene with the clinical phenotype, including the distribution of extracolonic tumors, polyposis severity, and congenital hypertrophy of the retinal pigment epithelium. The most consistent observations are that attenuated polyposis and the less classic forms of FAP are associated with pathogenic variants that occur in or before exon 4 and in the latter two-thirds of exon 15,[31] and that retinal lesions are rarely associated with pathogenic variants that occur before exon 9.[32,35] Exon 9 pathogenic variants have also been associated with attenuated polyposis. Additionally, individuals with exon 9 variants tend not to have duodenal adenomas.[36]
Density of colonic polyposis
Researchers have found that dense carpeting of colonic polyps, a feature of classic FAP, is seen in most patients with APC pathogenic variants, particularly those variants that occur between codons 169 and 1393. At the other end of the spectrum, sparse polyps are features of patients with pathogenic variants occurring at the extreme ends of the APCgene or in exon 9. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section of this summary for more information.)
Extracolonic tumors
Desmoid tumors
Desmoid tumors are proliferative, locally invasive, nonmetastasizing, fibromatous tumors in a collagen matrix. Although they do not metastasize, they can grow very aggressively and be life threatening.[37] Desmoids may occur sporadically, as part of classical FAP, or in a hereditary manner without the colon findings of FAP.[18,38] Desmoids have been associated with hereditary APC gene pathogenic variants even when not associated with typical adenomatous polyposis of the colon.[38,39]
Most studies have found that 10% of FAP patients develop desmoids, with reported ranges of 8% to 38%. The incidence varies with the means of ascertainment and the location of the pathogenic variant in the APC gene.[38,40,41] APC pathogenic variants occurring between codons 1445 and 1578 have been associated with an increased incidence of desmoid tumors in FAP patients.[35,39,42,43] Desmoid tumors with a late onset and a milder intestinal polyposis phenotype (hereditary desmoid disease) have been described in patients with pathogenic variants at codon 1924.[38]
A desmoid risk factor scale has been described in an attempt to identify patients who are likely to develop desmoid tumors.[44] The desmoid risk factor scale was based on gender, presence or absence of extracolonic manifestations, family history of desmoids, and genotype, if available. By utilizing this scale, it was possible to stratify FAP patients into low-, medium-, and high-risk groups for developing desmoid tumors. The authors concluded that the desmoid risk factor scale could be used for surgical planning. Validation of the risk factors comprising this scale were supported by a large, multiregistry, retrospective study from Europe.[45]
The natural history of desmoids is variable. Some authors have proposed a model for desmoid tumor formation whereby abnormal fibroblast function leads to mesenteric plaque-like desmoid precursor lesions, which in some cases occur before surgery and progress to mesenteric fibromatosis after surgical trauma, ultimately giving rise to desmoid tumors.[46] It is estimated that 10% of desmoids resolve, 50% remain stable for prolonged periods, 30% fluctuate, and 10% grow rapidly.[47] Desmoids often occur after surgical or physiological trauma, and both endocrine and genetic factors have been implicated. Approximately 80% of intra-abdominal desmoids in FAP occur after surgical trauma.[48,49]
The desmoids in FAP are often intra-abdominal, may present early, and can lead to intestinal obstruction or infarction and/or obstruction of the ureters.[41] In some series, desmoids are the second most common cause of death after CRC in FAP patients.[50,51] A staging system has been proposed to facilitate the stratification of intra-abdominal desmoids by disease severity.[52] The proposed staging system for intra-abdominal desmoids is as follows: stage I for asymptomatic, nongrowing desmoids; stage II for symptomatic, nongrowing desmoids of 10 cm or less in maximum diameter; stage III for symptomatic desmoids of 11 to 20 cm or for asymptomatic, slow-growing desmoids; and stage IV for desmoids larger than 20 cm, or rapidly growing, or with life-threatening complications.[52]
These data suggest that genetic testing could be of value in the medical management of patients with FAP and/or multiple desmoid tumors. Those with APC genotypes, especially those predisposing to desmoid formation (e.g., at the 3’ end of APC codon 1445), appear to be at high risk of developing desmoids after any surgery, including risk-reducing colectomy and surgical surveillance procedures such as laparoscopy.[40,47,53]
The management of desmoids in FAP can be challenging and can complicate prevention efforts. Currently, there is no accepted standard treatment for desmoid tumors. Multiple medical treatments have generally been unsuccessful in the management of desmoids. Treatments have included antiestrogens, nonsteroidal anti-inflammatory drugs (NSAIDs), chemotherapy, and radiation therapy, among others. Studies have evaluated the use of raloxifene alone, tamoxifen or raloxifene combined with sulindac, and pirfenidone alone.[54-56] There are anecdotal reports of using imatinib mesylate to treat desmoid tumors in FAP patients; however, further studies are needed.[57] Significant desmoid tumor regression was reported in seven patients who had symptomatic, unresectable, intra-abdominal desmoid tumors and failed hormonal therapy when treated with chemotherapy (doxorubicin and dacarbazine) followed by meloxicam.[58]
Thirteen patients with intra-abdominal desmoids and/or unfavorable response to other medical treatments, who had expression of estrogen alpha receptors in their desmoid tissues, were included in a prospective study of raloxifene, given in doses of 120 mg daily.[54] Six of the patients had been on tamoxifen or sulindac before treatment with raloxifene, and seven patients were previously untreated. All 13 patients with intra-abdominal desmoid disease had either a partial or a complete response 7 months to 35 months after starting treatment, and most desmoids decreased in size at 4.7 ± 1.8 months after treatment. Response occurred in patients with desmoid plaques and with distinct lesions. Study limitations include small sample size, and the clinical evaluation of response was not consistent in all patients. Several questions remain concerning patients with desmoid tumors not expressing estrogen alpha receptors who have received raloxifene and their outcome and which patients may benefit from this potential treatment.
A second study of 13 patients with FAP-associated desmoids, who were treated with tamoxifen 120 mg/day or raloxifene 120 mg/day in combination with sulindac 300 mg/day, reported that ten patients had either stable disease (n = 6) or a partial or complete response (n = 4) for more than 6 months and that three patients had stable disease for more than 30 months.[55] These results suggest that the combination of these agents may be effective in at least slowing the growth of desmoid tumors. However, the natural history of desmoids is variable, with both spontaneous regression and variable growth rates.
A third study reported mixed results in 14 patients with FAP-associated desmoid tumors treated with pirfenidone for 2 years.[56] In this study, some patients had regression, some patients had progression, and some patients had stable disease.
These three studies illustrate some of the problems encountered in the study of desmoid disease in FAP patients:
- The definition of desmoid disease is used inconsistently.
- In some patients, desmoid tumors do not progress or are very slow growing and may not need therapy.
- There is no consistent, systematic way to evaluate the response to therapy.
- There is no single institution that will enroll enough patients to perform a randomized trial.
No randomized clinical trials using these agents have been performed and their use in clinical practice is based on anecdotal experience only.
Because of the high rates of morbidity and recurrence, in general, surgical resection is not recommended in the treatment of intra-abdominal desmoid tumors. However, some have advocated a role for surgery given the ineffectiveness of medical therapy, even when the potential hazards of surgery are considered, and recognizing that not all desmoids are resectable.[59] A recent review of one hospital's experience suggested that surgical outcomes with intra-abdominal desmoids may be better than previously believed.[59,60] Issues of subject selection are critical in evaluating surgical outcome data.[60] Abdominal wall desmoids can be treated with surgical resection, but the recurrence rate is high.
Stomach tumors
The most common FAP-related gastric polyps are fundic gland polyps (FGPs). FGPs are often diffuse and not amenable to endoscopic removal. The incidence of FGPs has been estimated to be as high as 60% in patients with FAP, compared with 0.8% to 1.9% in the general population.[19,21,61-65] These polyps consist of distorted fundic glands containing microcysts lined with fundic-type epithelial cells or foveolar mucous cells.[66,67]
The hyperplastic surface epithelium is, by definition, nonneoplastic. Accordingly, FGPs have not been considered precancerous; in Western FAP patients the risk of stomach cancer is minimally increased, if at all. However, case reports of stomach cancer appearing to arise from FGPs have led to a reexamination of this issue.[21,68] In one FAP series, focal dysplasia was evident in the surface epithelium of FGPs in 25% of patients versus 1% of sporadic FGPs.[67] In a prospective study of patients with FAP undergoing surveillance with esophagogastroduodenoscopy, FGPs were detected in 88% of the patients. Low-grade dysplasia was detected in 38% of these patients, whereas high-grade dysplasia was detected in 3% of these patients. In the author's view, if a polyp with high-grade dysplasia is identified, polypectomy can be considered with repeat endoscopic surveillance in 3 to 6 months. Consideration for treatment with daily proton-pump inhibitors (PPIs) also may be given.[69]
Complicating the issue of differential diagnosis, FGPs have been increasingly recognized in non-FAP patients consuming PPIs.[67,70] FGPs in this setting commonly show a “PPI effect” consisting of congestion of secretory granules in parietal cells, leading to irregular bulging of individual cells into the lumen of glands. To the trained eye, the presence of dysplasia and the concomitant absence of a characteristic PPI effect can be considered highly suggestive of the presence of underlying FAP. The number of FGPs tends to be greater in FAP than that seen in patients consuming PPIs, although there is some overlap.
Gastric adenomas also occur in FAP patients. The incidence of gastric adenomas in Western patients has been reported to be between 2% and 12%, whereas in Japan, it has been reported to be between 39% and 50%.[71-74] These adenomas can progress to carcinoma. FAP patients in Korea and Japan are reported to have a threefold to fourfold increased gastric cancer risk compared with their general population, a finding not observed in Western populations.[75-78] The recommended management for gastric adenomas is endoscopic polypectomy. The management of adenomas in the stomach is usually individualized based on the size of the adenoma and the degree of dysplasia.
Duodenum/small bowel tumors
Whereas the incidence of duodenal adenomas is only 0.4% in patients undergoing upper GI endoscopy,[79] duodenal adenomas are found in 80% to 100% of FAP patients. The vast majority are located in the first and second portions of the duodenum, especially in the periampullary region.[61,62,80] There is a 4% to 12% lifetime incidence of duodenal adenocarcinoma in FAP patients.[16,77,81,82] In a prospective multicenter surveillance study of duodenal adenomas in 368 northern Europeans with FAP, 65% had adenomas at baseline evaluation (mean age, 38 y), with cumulative prevalence reaching 90% by age 70 years. In contrast to earlier beliefs regarding an indolent clinical course, the adenomas increased in size and degree of dysplasia during the 8 years of average surveillance, although only 4.5% developed cancer while under prospective surveillance.[19] While this study is the largest to date, it is limited by the use of forward-viewing rather than side-viewing endoscopy and the large number of investigators involved in the study. Intestinal polyps can also be assessed in FAP patients using capsule endoscopy.[83-85] One study of computed tomography (CT) duodenography found that larger adenoma size could be accurately measured but smaller, flatter adenomas could not be accurately counted.[86]
A retrospective review of FAP patients suggested that the adenoma-carcinoma sequence occurred in a temporal fashion for periampullary adenocarcinomas with a diagnosis of adenoma at a mean age of 39 years, high-grade dysplasia at a mean age of 47 years, and adenocarcinoma at a mean age of 54 years.[87] A decision analysis of 601 FAP patients suggested that the benefit of periodic surveillance starting at age 30 years led to an increased life expectancy of 7 months.[81] Although polyps in the duodenum can be difficult to treat, small series suggest that they can be managed successfully with endoscopy but with potential morbidity—primarily from pancreatitis, bleeding, and duodenal perforation.[88,89]
FAP patients with particularly severe duodenal polyposis, sometimes called dense polyposis, or with histologically advanced duodenal adenomas appear to be at the highest risk of developing duodenal adenocarcinoma.[19,82,90,91] Because the risk of duodenal adenocarcinoma is correlated with the number and size of polyps, and the severity of dysplasia of the polyps, a stratification system based on these features was developed to attempt to identify those individuals with FAP at highest risk of developing duodenal adenocarcinoma.[91] According to this system, known as the Spigelman Classification (refer to Table 5), 36% of patients with the most advanced stage will develop carcinoma.[82]
A baseline upper endoscopy, including side-viewing duodenoscopy, is typically performed between ages 25 and 30 years in FAP patients.[78] The subsequent intervals between endoscopy vary according to the findings of the previous endoscopy, often, based on Spigelman stage. Recommended intervals are based on expert opinion although the relatively liberal intervals for stage 0-II disease are based in part on the natural history data generated by the Dutch/Scandinavian duodenal surveillance trial (refer to Table 6).[19]
The main advantages of the Spigelman Classification are its long-standing familiarity to and usage by those in the field, which allows reasonable standardization of outcome comparisons across studies.[74,92] However, the following are limitations on attempted application of the Spigelman Classification:
- Most pathologists do not currently employ the term moderate dysplasia, preferring a simpler low- versus high-grade dysplasia system.
- Because of the villous nature of normal duodenal epithelium, pathologists commonly disagree over the classification of “tubular,” “tubulovillous,” and “villous.”
- Spigelman staging requires biopsy, which is not always essential when only a few small plaques are present; conversely, for larger adenomas, sampling variation leads to understaging.[93,94]
The results of long-term duodenal adenoma surveillance of FAP patients in Nordic countries and the Netherlands revealed significant duodenal cancer risk in FAP patients.[96] Per protocol, biennial frontal-viewing endoscopy was performed from 1990 through 2000. Subsequently, patients were followed up with surveillance according to international guidelines. The 261 of 304 patients (86%) who had more than one endoscopy comprised the study group. Median follow-up was 14 years (range, 9–17 y). The lifetime risk of duodenal adenomatosis was 88%. Forty-four percent of patients had worsening Spigelman stage over time, whereas 12% improved and 34% remained unchanged. Twenty patients (7%) developed duodenal cancer at a median age of 56 years (range, 44–82 y). The cumulative cancer incidence was 18% at age 75 years (95% confidence interval [CI], 8%–28%). Survival in patients with symptomatic cancers was worse than those diagnosed at surveillance endoscopy.
Many factors, including severity of polyposis, comorbidities of the patient, patient preferences, and availability of adequately trained physicians, determine whether surgical or endoscopic therapy is selected for polyp management. Endoscopic resection or ablation of large or histologically advanced adenomas appears to be safe and effective in reducing the short-term risk of developing duodenal adenocarcinoma;[88,89,97] however, patients managed with endoscopic resection of adenomas remain at substantial risk of developing recurrent adenomas in the duodenum.[93] The most definitive procedure for reducing the risk of adenocarcinoma is surgical resection of the ampulla and duodenum, although these procedures also have higher morbidity and mortality associated with them than do endoscopic treatments. Duodenotomy and local resection of duodenal polyps or mucosectomy have been reported, but invariably, the polyps recur after these procedures.[98] In a series of 47 patients with FAP and Spigelman stage III or stage IV disease who underwent definitive radical surgery, the local recurrence rate was reported to be 9% at a mean follow-up of 44 months. This local recurrence rate is dramatically lower than any local endoscopic or surgical approach from the same study.[93] Pancreaticoduodenectomy and pancreas-sparing duodenectomy are appropriate surgical therapies that are believed to substantially reduce the risk of developing periampullary adenocarcinoma.[94,98-100] If such surgical options are considered, preservation of the pylorus is of particular benefit in this group of patients because most will have undergone a subtotal colectomy with ileorectal anastomosis or total colectomy with ileal pouch–anal anastomosis (IPAA). As noted in a Northern European study,[19] and others,[101,102] the vast majority of patients with duodenal adenomas will not develop cancer and can be followed with endoscopy. However, individuals with advanced adenomas (Spigelman stage III or stage IV disease) generally require endoscopic or surgical treatment of the polyps. Chemoprevention studies for duodenal adenomas in FAP patients are currently under way and may offer an alternate strategy in the future.
The endoscopic approach to larger and/or flatter adenomas of the duodenum depends on whether the ampulla is involved. Endoscopic mucosal resection (EMR) after submucosal injection of saline, with or without epinephrine and/or dye, such as indigo carmine, can be employed for nonampullary lesions. Ampullary lesions require even greater care including endoscopic ultrasound evaluation for evidence of bile or pancreatic duct involvement. Stenting of the pancreatic duct is commonly performed to prevent stricturing and pancreatitis. The stents require endoscopic removal at an interval of 1 to 4 weeks. Because the ampulla is tethered at the ductal orifices, it typically does not uniformly “lift” with injection, so injection is commonly not used. Any consideration of EMR or ampullectomy requires great experience and judgment, with careful consideration of the natural history of untreated lesions and an appreciation of the high rate of adenoma recurrence despite aggressive endoscopic intervention.[89,93,94,99,103-106] The literature uniformly supports duodenectomy for Spigelman stage IV disease. For Spigelman stage II and III disease, there is a role for endoscopic treatment invariably focusing on the one or two worst lesions that are present.
Reluctance to consider surgical resection has to do with short-term morbidity and mortality and long-term complications related to surgery. Although these concerns are likely overstated,[93,94,100,103,107-113] fear of surgical intervention can lead to aggressive and somewhat ill-advised endoscopic interventions. In some circumstances, endoscopic resection of ampullary and/or other duodenal adenomas cannot be accomplished completely or safely by endoscopic means, and duodenectomy cannot be accomplished without risking a short-gut syndrome or cannot be done at all because of mesenteric fibrosis. In such cases, surgical transduodenal ampullectomy/polypectomy can be performed. This is, however, associated with a high risk of local recurrence similar to that of endoscopic treatment.
Other tumors
The spectrum of tumors arising in FAP is summarized in Table 4.
Papillary thyroid cancer has been reported to affect 1% to 2% of patients with FAP.[114] However, a recent study [115] of papillary thyroid cancers in six females with FAP failed to demonstrate loss of heterozygosity (LOH) or pathogenic variants of the wild-type allele in codons 545 and 1061 to 1678 of the six tumors. In addition, four of five of these patients had detectable somatic RET/PTC chimeric genes. This pathogenic variant is generally restricted to sporadic papillary thyroid carcinomas, suggesting the involvement of genetic factors other than APC pathogenic variants. Further studies are needed to show whether other genetic factors such as the RET/PTC chimeric gene are independently responsible for or cooperative with APC variants in causing papillary thyroid cancers in FAP patients. Although level 1 evidence is lacking, a consensus opinion recommends annual thyroid examinations beginning in the late teenage years to screen for papillary thyroid cancer in patients with FAP. The same panel suggests clinicians could consider the addition of annual thyroid ultrasounds to this screening routine.[95,116,117]
Adrenal tumors have been reported in FAP patients, and one study demonstrated LOH in an adrenocortical carcinoma (ACC) in an FAP patient.[118] In a study of 162 FAP patients who underwent abdominal CT for evaluation of intra-abdominal desmoid tumors, 15 patients (11 females) were found to have adrenal tumors.[119] Of these, two had symptoms attributable to cortisol hypersecretion. Three of these patients underwent subsequent surgery and were found to have ACC, bilateral nodular hyperplasia, or adrenocortical adenoma. The prevalence of an unexpected adrenal neoplasia in this cohort was 7.4%, which compares with a prevalence of 0.6% to 3.4% (P < .001) in non-FAP patients.[119] No molecular genetic analyses were provided for the tumors resected in this series. A subsequent study identified adrenal lesions in 26% (23 of 90) of patients with FAP, 18% (2 of 11) of patients with AFAP, and 24% (5 of 21) of patients with MUTYH-associated polyposis. Most lesions in this series followed a benign and slowly progressive course; no cases of ACC were reported.[120]
Hepatoblastoma is a rare, rapidly progressive, and usually fatal childhood malignancy that, if confined to the liver, can be cured by radical surgical resection. Multiple cases of hepatoblastoma have been described in children with an APC pathogenic variant.[121-130] Some series have also demonstrated LOH of APC in these tumors.[122,124,131] No specific genotype-phenotype correlations have been identified in FAP patients with hepatoblastoma.[132] Although lacking level 1 evidence, a consensus panel has suggested that liver palpation, abdominal ultrasound, and measurement of serum alpha fetoprotein every 3 to 6 months for the first 5 years of life in children with a predisposition to FAP be considered.[95,133]
The constellation of CRC and brain tumors has been referred to as Turcot syndrome; however, Turcot syndrome is molecularly heterogeneous. Molecular studies have demonstrated that colon polyposis and medulloblastoma are associated with pathogenic variants in APC, while colon cancer and glioblastoma are associated with pathogenic variants in mismatch repair (MMR) genes.[134]
There are several reports of other extracolonic tumors associated with FAP, but whether these are simply coincidence or actually share a common molecular genetic origin with the colonic tumors is not always evident. Some of these reports have demonstrated LOH or a variant of the wild-type APC allele in extracolonic tumors in FAP patients, which strengthens the argument for their inclusion in the FAP syndrome.
Genetic testing for FAP
APC gene testing is now commercially available and has led to changes in management guidelines, particularly for those whose tests indicate they are not carriers of pathogenic variants. Presymptomatic genetic diagnosis of FAP in at-risk individuals has been feasible with linkage [24] and direct detection [135] of APC pathogenic variants. These tests require a small sample (<10 cc) of blood in which the lymphocyte DNA is tested. If one were to use linkage analysis to identify gene carriers, ancillary family members, including more than one affected individual, would need to be studied. With direct detection, fewer family members’ blood samples are required than for linkage analysis, but the specific pathogenic variant must be identified in at least one affected person by DNA variant analysis or sequencing. The detection rate is approximately 80% using sequencing alone.[136]
Studies have reported whole exon deletions in 12% of FAP patients with previously negative APC testing.[137,138] For this reason, deletion testing has been added as an optional adjunct to sequencing of APC. Furthermore, pathogenic variant detection assays that use MLPA are being developed and appear to be accurate for detecting intragenic deletions.[139] MUTYH gene testing may be considered in APC pathogenic variant–negative affected individuals.[140] (Refer to the Adenomatous polyposis coli [APC] section of this summary for more information.)
Patients who develop fewer than 100 colorectal adenomatous polyps are a diagnostic challenge. The differential diagnosis includes AFAP and MUTYH-associated colorectal neoplasia (also reported as MUTYH-associated polyposis or MAP).[141] AFAP can be diagnosed by testing for germline APC gene pathogenic variants. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section in the Major Genetic Syndromes section of this summary for more information.) MUTYH-associated neoplasia is caused by germline homozygous recessive pathogenic variants in the MUTYH gene.[142]
Presymptomatic genetic testing removes the necessity of annual screening of at-risk individuals who do not have the familial gene pathogenic variant. For at-risk individuals who have been found to be definitively pathogenic variant–negative by genetic testing, there is no clear consensus on the need for or frequency of colon screening,[23] although all experts agree that at least one flexible sigmoidoscopy or colonoscopy examination should be performed in early adulthood (by age 18–25 y).[23,24] Colon adenomas will develop in nearly 100% of persons who are APC pathogenic variant–positive; risk-reducing surgery comprises the standard of care to prevent colon cancer after polyps have appeared and are too numerous or histologically advanced to monitor safely using endoscopic resection.
Interventions for FAP
Individuals at risk of FAP, because of a known APC pathogenic variant in either the family or themselves, are evaluated for onset of polyposis by flexible sigmoidoscopy or colonoscopy. Once an FAP family member is found to manifest polyps, the only effective management to prevent CRC is eventual colectomy. Prophylactic surgery has been shown to improve survival in patients with FAP.[143] If feasible, the patient and his/her family members should be included in a registry because it has been shown retrospectively that registration and surveillance reduce CRC incidence and mortality.[144] In patients with classic FAP identified very early in their course, the surgeon, endoscopist, and family may choose to delay surgery for several years in the interest of achieving social milestones. In addition, in carefully selected patients with AFAP (those with minimal polyp burden and advanced age), deferring a decision about colectomy may be reasonable with surgery performed only in the face of advancing polyp burden or dysplasia.
A Finnish nationwide population-based retrospective study evaluating whether surveillance of family members with FAP reduced overall mortality and improved survival demonstrated that call-up patients (family members of a proband who were recruited to the screening program) had equivalent survival to the general population up to 20 years after diagnosis of FAP.[145] The study included 154 families with at least one family member clinically diagnosed with FAP from 1963 to 2015. There were 194 probands and 225 call-ups (83 diagnosed by genetic testing and 142 by endoscopy) with a median time of follow-up of 11.8 years. In this study, the survival analysis of members of FAP families was calculated using the relative survival estimate.[146] This estimation compares survival among FAP probands and call-ups with the survival expected in the absence of FAP among individuals of the same gender and age in each calendar year. The relative survival after 10 and 20 years of follow-up for probands was 67% (95% CI, 60%–75%) and 66% (95% CI, 58%–76%), respectively. For call-ups, the 10- and 20-year relative survival was 98% (95% CI, 95%–101%) and 94% (95% CI, 88%–100%), respectively. At 25 years of follow-up, the relative survival for call-ups was lower than the general population at 87% (95% CI, 79%–96%). The relative survival for probands was significantly lower than for call-ups (P < .001). In terms of mortality, the standardized mortality ratio was elevated in probands in both the 0- to 5-year and 5- to 10-year periods of follow-up whereas it remained stable for call-ups until 20 years of follow-up. This difference was more marked in the beginning of follow-up for probands taking into account the fact that probably most were symptomatic, and most likely had CRC at the diagnosis. The authors pointed out that if the CRC was treated successfully without recurrence, the survival of the probands approached that of the call-ups.
The recommended age at which surveillance for polyposis should begin involves a trade-off. Someone who waits until the late teens to begin surveillance faces a remote possibility that a cancer will have developed at an earlier age. Although it is rare, CRC can develop in a teenager who carries an APC pathogenic variant. However, it is preferable to allow people at risk to develop emotionally before they are faced with a major surgical decision regarding the timing of colectomy. Therefore, surveillance usually begins early (age 10–15 y). Surveillance has consisted of either flexible sigmoidoscopy or colonoscopy every year.[95,147,148] If flexible sigmoidoscopy is utilized and polyps are found, colonoscopy is performed. Historically, sigmoidoscopy may have been a reasonable approach in identifying early adenomas in most patients. However, colonoscopy is the tool of choice in light of (a) improved instrumentation for full colonoscopy; (b) sedation; (c) recognition of AFAP, in which the disease is typically most manifest in the right colon; and (d) the growing tendency to defer surgery for a number of years. Individuals who have tested negative for an otherwise known family pathogenic variant do not need FAP-oriented surveillance at all. They are recommended to undergo average-risk population screening. In the case of families in which no family variant has been identified in an affected person, clinical surveillance is warranted. Colon surveillance is not stopped in persons who are known to carry an APC pathogenic variant but who do not yet manifest polyps, because adenomas occasionally are not manifest until the fourth and fifth decades of life. (Refer to the Attenuated Familial Adenomatous Polyposis [AFAP] section of this summary for more information.) (Refer to the PDQ summary on Colorectal Cancer Screening for more information on these methods.)
In some circumstances, full colonoscopy may be preferred over the more limited sigmoidoscopy. Among pediatric gastroenterologists, tolerability of endoscopic procedures in general has been regarded as improved with the use of deeper intravenous sedation.
Table 7 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance of FAP.
FAP patients and their doctors should have an individualized discussion to decide when surgery will be performed. It is useful to incorporate into the discussion the risk of developing desmoid tumors after surgery. Timing of risk-reducing surgery usually depends on the number of polyps, their size, histology, and symptomatology.[153] Once numerous polyps have developed, surveillance colonoscopy is no longer useful in timing the colectomy because polyps are so numerous that it is not possible to biopsy or remove all of them. At this time, it is appropriate for patients to consult with a surgeon who is experienced with available options, including total colectomy and postcolectomy reconstruction techniques.[154] Rectum-sparing surgery, with sigmoidoscopic surveillance of the remaining rectum, is a reasonable alternative to total colectomy in those compliant individuals who understand the consequences and make an informed decision to accept the residual risk of rectal cancer occurring despite periodic surveillance.[155]
Surgical options include restorative proctocolectomy with IPAA, subtotal colectomy with ileorectal anastomosis (IRA), or total proctocolectomy with ileostomy (TPC). TPC is reserved for patients with low rectal cancer in which the sphincter cannot be spared or for patients on whom an IPAA cannot be performed because of technical problems. There is no risk of developing rectal cancer after TPC because the whole mucosa at risk is removed. Whether a colectomy and an IRA or a restorative proctocolectomy is performed, most experts suggest that periodic and lifelong surveillance of the rectum or the ileal pouch be performed to remove or ablate any polyps. This is necessitated by case series of rectal cancers arising in the rectum of FAP patients who had subtotal colectomies with an IRA in which there was an approximately 25% cumulative risk of rectal adenocarcinoma 20 years after IRA and by case reports of adenocarcinoma in the ileoanal pouch and anal canal after restorative proctocolectomy.[156-159] The cumulative risk of rectal cancer after IRA may be lower than that reported in the literature, in part because of better selection of patients for this procedure, such as those with minimal polyp burden in the rectum.[154] Other factors that have been reported to increase the rectal cancer risk after IRA include the presence of colon cancer at the time of IRA, the length of the rectal stump, and the duration of follow-up after IRA.[160-166] An abdominal colectomy with IRA as the primary surgery for FAP does not preclude later conversion to an IPAA for uncontrolled rectal polyps and/or rectal cancer. In the Danish Polyposis Registry, the morbidity and functional results of a secondary IPAA (after a previous IRA) in 24 patients were reported to be similar to those of 59 patients who underwent primary IPAA.[167]
In most cases, the clinical polyp burden in the rectum at the time of surgery dictates the type of surgical intervention, namely restorative proctocolectomy with IPAA versus IRA. Patients with a mild phenotype (<1,000 colonic adenomas) and fewer than 20 rectal polyps may be candidates for IRA at the time of prophylactic surgery.[168] In some cases, however, the polyp burden is equivocal, and in such cases, investigators have considered the role of genotype in predicting subsequent outcomes with respect to the rectum.[169] Pathogenic variants reported to increase the rectal cancer risk and eventual completion proctectomy after IRA include variants in exon 15 codon 1250, exon 15 codons 1309 and 1328, and exon 15 variants between codons 1250 and 1464.[165,156,166,170] In patients who have undergone IPAA, it is important to continue annual surveillance of the ileal pouch because the cumulative risk of developing adenomas in the pouch has been reported to be up to 75% at 15 years.[171,172] Although they are rare, carcinomas have been reported in the ileal pouch and anal transition zone after restorative proctocolectomy in FAP patients.[173] A meta-analysis of quality of life after restorative proctocolectomy and IPAA has suggested that FAP patients do marginally better than inflammatory bowel disease patients in terms of fistula formation, pouchitis, stool frequency, and seepage.[174]
Celecoxib, a specific cyclooxygenase II (COX-2) inhibitor, and nonspecific COX-2 inhibitors, such as sulindac, have been associated with a decrease in polyp size and number in FAP patients, suggesting a role for chemopreventive agents in the treatment of this disorder.[175,176] Although celecoxib had been approved by the U.S. Food and Drug Administration (FDA), its license was voluntarily withdrawn by the manufacturer. Currently, there are no FDA-approved drugs for chemoprevention in FAP. Nevertheless, agents such as celecoxib and sulindac are in sufficiently widespread use that chemopreventive clinical trials typically utilize one of these agents as the control arm. A randomized trial showed possible marginal improvement in polyp burden with the combination of celecoxib and difluoromethylornithine, compared with celecoxib alone.[177]
A small, randomized, placebo-controlled, dose-escalation trial of celecoxib in a pediatric population (aged 10–14 y) demonstrated the safety of celecoxib at all dosing levels when administered over a 3-month period.[178] This study found a dose-dependent reduction in adenomatous polyp burden. At a dose of 16 mg/kg/day, which approximates the approved dose of 400 mg twice daily in adults, the reduction in polyp burden paralleled that demonstrated with celecoxib in adults.
Omega-3-polyunsaturated fatty acid eicosapentaenoic acid in the free fatty acid form has been shown to reduce rectal polyp number and size in a small study of patients with FAP post subtotal colectomy.[179] Although not directly compared in a randomized trial, the effect appeared to be similar in magnitude to that previously observed with celecoxib.
It is unclear at present how to incorporate COX-2 inhibitors into the management of FAP patients who have not yet undergone risk-reducing surgery. A double-blind, placebo-controlled trial in 41 child and young adult carriers of APC pathogenic variants who had not yet manifested polyposis demonstrated that sulindac may not be effective as a primary treatment in FAP. There were no statistically significant differences between the sulindac and placebo groups over 4 years of treatment in incidence, number, or size of polyps.[176]
Consistent with the effects of COX-2 inhibitors on colonic polyps, in a randomized, prospective, double-blind, placebo-controlled trial, celecoxib (400 mg, administered orally twice daily) reduced, but did not eliminate, the number of duodenal polyps in 32 patients with FAP after a 6-month course of treatment. Of importance, a statistically significant effect was seen only in individuals who had more than 5% of the duodenum involved with polyps at baseline and with an oral dose of 400 mg, given twice daily.[180] A previous randomized study of 24 FAP patients treated with sulindac for 6 months showed a nonsignificant trend in the reduction of duodenal polyps.[181] The same issues surrounding the use of COX-2 inhibitors for the treatment of colonic polyps apply to their use for the treatment of duodenal polyps (e.g., only partial elimination of the polyps, complications secondary to the COX-2 inhibitors, and loss of effect after the medication is discontinued).[180]
Because of the common clustering of adenomatous polyps around the duodenal papilla (where bile enters the intestine) and preclinical data suggesting that ursodeoxycholate inhibits intestinal adenomas in mice that harbor an Apc germline variant,[182] two trials that employ ursodeoxycholate have been performed.[183,184] In both studies, ursodeoxycholate did not have a significant chemopreventive effect on duodenal polyps; paradoxically, in one study, ursodeoxycholate in combination with celecoxib appeared to promote polyp density in patients with FAP.
Because of reports demonstrating an increase in cardiac-related events in patients taking rofecoxib and celecoxib,[185-187] it is unclear whether this class of agents will be safe for long-term use for patients with FAP and in the general population. Also, because of the short-term (6 months) nature of these trials, there is currently no clinical information about cardiac events in FAP patients taking COX-2 inhibitors on a long-term basis.
One cohort study has demonstrated regression of colonic and rectal adenomas with sulindac (an NSAID) treatment in FAP. The reported outcome of this trial was the number and size of polyps, a surrogate for the clinical outcome of main interest, CRC incidence.[188]
Preclinical studies of a small-molecule epidermal growth factor receptor (EGFR) inhibitor and low-dose sulindac in the Apcmin/+ mouse diminished intestinal adenoma development by 87% [189] suggesting that EGFR inhibitors had the potential to inhibit duodenal polyps in FAP patients. A 6-month double-blind, randomized, placebo-controlled trial tested the efficacy of sulindac, 150 mg twice daily, and erlotinib, 75 mg daily, versus placebo in FAP or AFAP patients with duodenal polyps.[190] Ninety-two patients with FAP or AFAP were randomly assigned to receive study drugs or placebo and underwent pretreatment and posttreatment upper endoscopies to determine the changes in the sum diameter of the polyps and number of polyps in a 10 cm segment of proximal duodenum. The trial was terminated prematurely because the primary endpoint was met. The intent-to-treat analysis demonstrated a median decrease in duodenal polyp burden (sum of diameters) of 8.5 mm in the sulindac/erlotinib arm while there was an 8 mm increase in the placebo arm (P < .001). Significantly higher rates of grade 1 and grade 2 adverse events occurred in the treatment arm than in the placebo arm: in the treatment arm, 60.9% developed an acneiform rash and 32.6% developed oral mucositis; in the placebo arm, 19.6% developed an acneiform rash and 10.9% developed oral mucositis. Based on the previously modest effects of sulindac and celecoxib on duodenal polyps in FAP patients [176,188] and the dramatic effect of genetic EGFR inhibition on intestinal adenoma development in the Apcmin/+ mouse,[191] it is likely that erlotinib was responsible for the success of this trial. An ongoing clinical trial is determining whether lower doses of erlotinib alone are sufficient for significantly reducing duodenal polyp burden in FAP and AFAP patients.
Patients who carry APC germline pathogenic variants are at increased risk of other types of malignancies, including thyroid cancer, small bowel cancer, hepatoblastoma, and brain tumors. The risk of these tumors, however, is much lower than that for colon cancer, and the only surveillance recommendation by experts in the field is upper endoscopy of the gastric and duodenal mucosa.[12,25] The severity of duodenal polyposis detected appears to correlate with risk of duodenal adenocarcinoma.[82] (Refer to the Duodenum/small bowel tumors section and the Other tumors section in the Major Genetic Syndromessection of this summary for more information about screening for extracolonic malignancies in patients with FAP.)
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