Genetics of Colorectal Cancer (PDQ®)

Health Professional Version

PDQ Cancer Genetics Editorial Board.

Published online: June 14, 2018.

This executive summary reviews the topics covered in the PDQ summary on the genetics of colorectal cancer (CRC), with hyperlinks to detailed sections below that describe the evidence on each topic.

Inheritance and Risk
Factors suggestive of a genetic contribution to CRC include the following: (1) a strong family history of CRC and/or polyps; (2) multiple primary cancers in a patient with CRC; (3) the existence of other cancers within the kindred consistent with known syndromes causing an inherited risk of CRC, such as endometrial cancer; and (4) early age at diagnosis of CRC. Hereditary CRC is most commonly inherited in an autosomal dominant pattern, although two syndromes are inherited in an autosomal recessive pattern (MUTYH-associated polyposis and NTHL1).
At least three validated computer models are available to estimate the probability that an individual affected with cancer carries a pathogenic variant in a mismatch repair (MMR) gene associated with Lynch syndrome, the most common inherited CRC syndrome. These include the MMRpro, MMRpredict, and PREMM5 (PREdiction Model for gene Mutations) prediction models. Individuals with a quantified risk of 2.5% or greater on PREMM5 or 5% or greater on MMRpro and MMRpredict are recommended for genetic evaluation referral and testing.
Associated Genes and Syndromes
Hereditary CRC has two well-described forms: (1) polyposis (including familial adenomatous polyposis [FAP]and attenuated FAP (AFAP), which are caused by pathogenic variants in the APC gene; and MUTYH-associated polyposis, which is caused by pathogenic variants in the MUTYH gene); and (2) Lynch syndrome(often referred to as hereditary nonpolyposis colorectal cancer), which is caused by germline pathogenic variants in DNA MMR genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM. Other CRC syndromes and their associated genes include oligopolyposis (POLE, POLD1), NTHL1, juvenile polyposis syndrome (BMPR1A, SMAD4), Cowden syndrome (PTEN), and Peutz-Jeghers syndrome (STK11). Many of these syndromes are also associated with extracolonic cancers and other manifestations. Serrated polyposis syndrome, which is characterized by the appearance of hyperplastic polyps, appears to have a familial component, but the genetic basis remains unknown. The natural history of some of these syndromes is still being described. Many other families exhibit aggregation of CRC and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial CRC. In addition, most individuals with CRC diagnosed before age 50 years and without a family history of cancer do not have a pathogenic variant associated with an inherited cancer syndrome.
Genome-wide searches are showing promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including CRCs, but the clinical utility of these findings remains uncertain.
Clinical Management
It is becoming the standard of care at many centers that all individuals with newly diagnosed CRC are evaluated for Lynch syndrome through molecular diagnostic tumor testing assessing MMR deficiency. A universal screening approach to tumor testing is supported, in which all CRC cases are evaluated regardless of age at diagnosis or fulfillment of existing clinical criteria for Lynch syndrome. A more cost-effective approach has been reported whereby all patients aged 70 years or younger with CRC and older patients who meet the revised Bethesda guidelines are tested for Lynch syndrome. Tumor evaluation often begins with immunohistochemistry testing for the expression of the MMR proteins associated with Lynch syndrome or microsatellite instability (MSI) testing, BRAF testing, and MLH1 hypermethylation analyses.
Colonoscopy for CRC screening and surveillance is commonly performed in individuals with hereditary CRC syndromes and has been associated with improved survival outcomes. For example, surveillance of Lynch syndrome patients with colonoscopy every 1 to 2 years, and in one study up to 3 years, has been shown to reduce CRC incidence and mortality. Extracolonic surveillance is also a mainstay for some hereditary CRC syndromes depending on the other cancers associated with the syndrome. For example, regular endoscopic surveillance of the duodenum in FAP patients has been shown to improve survival.
Prophylactic surgery (colectomy) has also been shown to improve survival in patients with FAP. The timing and extent of risk-reducing surgery usually depends on the number of polyps, their size, histology, and symptomatology. For patients with Lynch syndrome and a diagnosis of CRC, extended resection is associated with fewer metachronous CRCs and additional surgical procedures for colorectal neoplasia than in patients who undergo segmental resection for CRC. The surgical decision must take into account the age of the patient, comorbidities, clinical stage of the tumor, sphincter function, and the patient’s wishes.
Chemopreventive agents have also been studied in the management of FAP and Lynch syndrome. In FAP patients, celecoxib and sulindac have been associated with a decrease in polyp size and number. A double-blind, randomized, controlled trial evaluating the efficacy of sulindac plus an epidermal growth factor receptor inhibitor, erlotinib, versus placebo in FAP or AFAP patients with duodenal polyps suggested that erlotinib has the potential to inhibit duodenal polyps in FAP patients. An ongoing trial will determine whether lower doses of erlotinib alone will significantly reduce duodenal polyp burden. Aspirin use (600 mg daily) was shown to have a preventive effect on cancer incidence in Lynch syndrome patients in a large randomized trial; lower doses are being examined in an ongoing study.
Novel therapies that stimulate the immune system have been evaluated in MMR-deficient tumors, including those related to Lynch syndrome. The dense immune infiltration and cytokine-rich environment in MMR-deficient tumors may improve clinical outcomes. A critical pathway responsible for mediating tumor-induced immune suppression is the programmed cell death-1 (PD-1)–mediated checkpoint pathway. Two phase 2 studies using anti–PD-1 immune checkpoint inhibitors (pembrolizumab and nivolumab) demonstrated favorable outcomes, including progression-free survival, radiographic response rates, and disease control rates in metastatic CRC with MMR deficiency and MSI that had progressed on prior cytotoxic chemotherapy. Pembrolizumab has shown similar benefit in other noncolorectal cancers with MMR deficiency and MSI, but not in tumors that are microsatellite stable.
Psychosocial and Behavioral Issues
Psychosocial factors influence decisions about genetic testing for inherited cancer risk and risk-management strategies. Uptake of genetic counseling and genetic testing for Lynch syndrome and FAP varies widely across studies. Factors that have been associated with genetic counseling and testing uptake in Lynch syndrome families include having children, the number of affected relatives, perceived risk of developing CRC, and frequency of thoughts about CRC. Psychological studies have shown low levels of distress, particularly in the long term, after genetic testing for Lynch syndrome in both carriers and noncarriers. However, other studies have demonstrated the possibility of increased distress following genetic testing for FAP. Colon and gynecologic cancer screening rates have been shown to increase or be maintained among carriers of MMR pathogenic variants within the year after disclosure of results, while screening rates decrease among noncarriers. The latter is expected as the screening recommendations for unaffected individuals are those that apply to the general population. Studies measuring quality-of-life variables in FAP patients show normal-range results; however, these studies suggest that risk-reducing surgery for FAP may have negative quality-of-life effects for at least some proportion of those affected. Patients' communication with their family members about an inherited risk of CRC is complex; gender, age, and the degree of relatedness are some elements that affect disclosure of this information. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.