Genetics of Colorectal Cancer (PDQ®)–Health Professional Version
Psychosocial Issues in Hereditary Colon Cancer Syndromes
Introduction
Psychosocial research in cancer genetic counseling and testing focuses on the interest in testing among populations at varying levels of disease risk, psychological outcomes, interpersonal and familial effects, and cultural and community reactions. This research also identifies behavioral factors that encourage or impede surveillance and other health behaviors. Data resulting from psychosocial research can guide clinician interactions with patients and may include the following:
- Decision-making about risk-reduction interventions, risk assessment, and genetic testing.
- Evaluation of psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification of genetic testing.
- Resolution of ethical concerns.
This section of the summary will focus on psychosocial aspects of genetic counseling and testing for Lynch syndrome, familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome (PJS), including issues surrounding medical screening, risk-reducing surgery, and chemoprevention for these syndromes.
Psychosocial Issues in Lynch Syndrome
Participation in genetic counseling and testing for Lynch syndrome
Early research on genetic counseling/testing uptake
Early studies that evaluated the uptake of genetic counseling and testing focused on selected, high-risk research populations, including colorectal cancer (CRC) patients and unaffected family members identified at high risk of CRC largely based on family history. The participants were recruited mainly from clinical settings and familial colon cancer registries. Most studies recruited index cancer cases, typically CRCs, specifically to offer genetic counseling and germline testing for mismatch repair (MMR) variants; these were frequently offered as free services.[1-9] Counseling and testing were similarly offered to relatives of index cases with pathogenic variants. A review that summarized these early studies reported a wide range of testing uptake rates, from 14% to 75%, and included uptake among both index cases and at-risk relatives who were offered testing.[10] The review indicated that the primary reasons for undergoing genetic testing included a desire to learn about children’s risk and to learn about early detection and screening needs, as well as a reduction in uncertainty. Reasons for declining testing included cost, insurance discrimination concerns, potential adverse emotional effects for oneself or one’s family, low anticipated benefit, and lack of time.
Uptake of genetic counseling and germline testing following universal tumor screening for microsatellite instability (MSI) and/or immunohistochemistry (IHC)
While these early studies of genetic testing uptake offered preliminary insight regarding why individuals may or may not be motivated to have testing, the process for offering genetic counseling and testing differed from what has evolved into current clinical practice. Clinical practice relies less solely on family history to identify individuals who may benefit from testing, and instead utilizes universal molecular diagnostic testing of CRC and endometrial cancer tumors in newly diagnosed patients using MSI and/or IHC as an initial screen for Lynch syndrome. (Refer to the Universal tumor testing to screen for Lynch syndrome section of this summary for more information.)
While universal MSI/IHC screening is increasingly being adopted to identify newly diagnosed patients who may have a germline variant, an important implication is that not all individuals who may be appropriate for germline testing follow through with recommended genetic counseling and testing services. Two reports from a single institution found that 20% and 13% of CRC and endometrial cancer index cases, respectively, with abnormal IHC results followed through with germline variant testing for Lynch syndrome.[11,12] These studies did not solicit reasons for follow through with genetic counseling and testing. However, it has been suggested that higher levels of patient completion of genetic testing after abnormal MSI/IHC results may be associated with having genetic counselors involved in this process to disclose screen-positive results, provide counseling after MSI/IHC testing, or facilitate referrals.[13]
In a study of 145 patients with CRC in the Kaiser Permanente Northwest health care system who were surveyed before receiving their MSI results, most patients had a positive attitude toward MSI/IHC screening.[14] The majority (84.8%) endorsed six or more benefits of MSI/IHC screening; however, 89.4% also endorsed fewer than four potential barriers, primarily the cost of additional testing and surveillance. Patients with stronger family histories of cancer were more likely to cite fewer barriers of MSI/IHC screening. Patients also experienced minimal distress associated with the screening, with 77.2% of participants having a score of zero (indicating no distress).
Education regarding family history and cancer risk and encouragement to have testing from health care providers may facilitate uptake of genetic counseling and testing. A small (n = 19) qualitative study of newly diagnosed patients with CRC who met high-risk criteria for referral to cancer genetics risk assessment and counseling identified potential reasons why patients may not seek counseling as recommended. These reasons included incomplete knowledge of family cancer history and not realizing the relevance of family history to their personal cancer diagnosis; lack of a specific, direct physician’s recommendation for counseling; and viewing counseling as a lower priority than coping with the immediate demands of a new cancer diagnosis.[15] In a follow-up survey of 91 individuals in a randomized trial to promote colonoscopy screening in those at risk for Lynch syndrome, only 24% reported ever having discussed genetic testing with their physicians, and the most common barrier to undergoing testing was lack of advice to do so by a health care provider.[16]
Uptake of cascade screening by at-risk relatives
There is increasing adoption of universal screening of newly diagnosed tumors for Lynch syndrome in clinical practice. However, the clinical benefit and cost-effectiveness of this process have been attributed to uptake of cascade screening, or predictive testing among at-risk relatives of index cancer cases who are found to have a pathogenic germline variant. A systematic review evaluated the frequency and predictors of genetic testing uptake by first-degree relatives (FDRs) of index cases with Lynch syndrome.[17] Among four studies that were included in the review and reported uptake rates among FDRs, results showed that 34% to 52% of FDRs had undergone testing. Factors associated with testing uptake in relatives included age (<50 y), female sex, parenthood, employment status, level of education, participation in medical research, psychological factors (lack of depressive symptoms), and the number of relatives affected with cancer.
A large retrospective study of genetic testing uptake across three generations of Finnish families enrolled in a Lynch syndrome registry also found an incomplete uptake of predictive testing among at-risk relatives of individuals with pathogenic variants, and a decreasing uptake rate by generation.[18] Among 1,184 probands with a Lynch syndrome variant, 67%, 43%, and 24% of at-risk adult first-, second-, and third-generation relatives, respectively, had predictive testing. Among 539 first-generation Lynch syndrome variant carriers, 62% of their at-risk adult children underwent testing. In multivariate analysis, older age, family-specific variant (MLH1 and MSH2 vs. MSH6), being an only child or having a sibling with a pathogenic variant, and having a parent who adhered to colonoscopy surveillance were associated with predictive testing uptake. This study suggested that family-level factors such as predictive testing and screening behavior may influence predictive testing among at-risk relatives of individuals with Lynch syndrome–associated variants.
Published reports of interventions to increase uptake of cascade screening in Lynch syndrome families are limited. An Australian paper compared two approaches for informing at-risk relatives about pathogenic variants for hereditary cancers, including Lynch syndrome.[19] In this study, index cases from 33 kindreds who had undergone genetic testing provided consent for their clinicians to send detailed letters to at-risk relatives advising them about the identification of an inherited cancer predisposition in the family. Letters also included a recommendation to discuss the information with a physician or genetics specialist, and provided information about what a genetics evaluation comprised. Within the first 2 years of follow-up, 40% of first- and second-degree relatives had had predictive genetic testing, were determined to be presumed noncarriers, or had undergone evaluation but declined genetic testing. The authors compared these findings with a cohort of 41 kindreds seen prior to the initiation of the clinician-generated letters, of whom variant-positive index cases had only been asked to advise relatives that genetic testing was available. In the earlier cohort, 23% of at-risk relatives had sought services to clarify their genetic risk status, which was significantly fewer compared with the group receiving clinician-generated letters (P = .001). Receipt of the letters did not generate concerns about a breach of privacy or autonomy.
Refer to the Ethical, Legal, and Social Implications section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for information about ethical concerns, including duty to warn.
Psychological impact of participating in genetic counseling and testing for Lynch syndrome
Studies have examined the psychological status of individuals before, during, and after genetic counseling and testing for Lynch syndrome. Some studies have included only persons with no personal history of any Lynch syndrome–associated cancers,[20-23] and others have included both CRC patients and cancer-unaffected persons who are at risk of having a Lynch syndrome pathogenic variant.[24-28] Cross-sectional evaluations of the psychosocial characteristics of individuals undergoing Lynch syndrome genetic counseling and testing have indicated that mean pretest scores of psychological functioning for most participants are within normal limits,[24-26] although one study comparing affected and unaffected individuals showed that affected individuals had greater distress and worry associated with Lynch syndrome.[29]
Several longitudinal studies have evaluated psychological outcomes before genetic counseling and testing for Lynch syndrome and at multiple time periods in the year after disclosure of test results. One study examined changes in anxiety based on personal cancer history, gender, and age (younger than 50 y vs. older than 50 y) before and 2 weeks after a pretest genetic-counseling session. Affected and unaffected female participants in both age groups and affected men older than 50 years showed significant decreases in anxiety over time. Unaffected men younger than 50 years maintained low levels of anxiety; however, affected men younger than 50 years showed no reductions in the anxiety levels reported at the time of pretest counseling.[30] A study that evaluated psychological distress 8 weeks postcounseling (before disclosure of test results) among both affected and unaffected individuals found a significant reduction in general anxiety, cancer worry, and distress.[29] In general, findings from studies within the time period immediately after disclosure of pathogenic variant status (e.g., 2 weeks to 1 month) suggested that carriers of mismatch repair (MMR) pathogenic variants may experience increased general distress,[22,27] cancer-specific distress,[20,21] or cancer worries [27] relative to their pretest measurements. Carriers often experienced significantly higher distress after disclosure of test results than do individuals who do not carry a pathogenic variant previously identified in the family (noncarrier).[20-22,27] However, in most cases, carriers’ distress levels subsided during the course of the year after disclosure [22,27] and did not differ from pretest distress levels at 1 year postdisclosure.[20,21] Findings from these studies also indicated that noncarriers experienced a reduction or no change in distress up to 1 year after results disclosure.[20-22,27] A study that included unaffected individuals and CRC patients found that distress levels among patients did not differ between carriers and individuals who received results that were uninformative or showed a variant of unknown significance at any point up to 1 year posttest and were similar compared with pretest distress levels.[28]
A limited number of studies have examined longer-term psychosocial outcomes after Lynch syndrome genetic counseling and testing.[20,31,32] Longitudinal studies that evaluated psychological distress before and after genetic testing found that long-term distress levels (measured at 3 or 7 years posttesting) among carriers and noncarriers of pathogenic variants were similar to distress levels at baseline.[20,32] with one exception: noncarriers’ cancer-specific distress scores in one study [20] showed a sustained decrease posttesting and were significantly lower than their baseline scores and with carriers’ scores at 1 year posttesting, with a similar trend observed at 3 years posttesting. In one study, carriers were more likely to be worried about CRC risk at 7 years posttesting; however, noncarriers who reported worry about CRC (i.e., “worried to some extent” or “very worried”) were more likely to doubt the validity of their test result than were noncarriers who reported no worry.[32] When asked about their satisfaction with the decision to have testing, the majority of carriers and noncarriers were extremely satisfied up to 7 years posttesting and indicated they would be willing to undergo testing again.[32]
Findings from some studies suggested that there may be subgroups of individuals at higher risk of psychological distress after disclosure of test results, including those who present with relatively higher scores on measures of general or cancer-specific distress before undergoing testing.[24-28,33] A study of CRC patients who had donated blood for Lynch syndrome testing found that higher levels of depressive symptoms and/or anxiety were found among women, younger persons, nonwhites, and those with less formal education and fewer and less satisfactory sources of social support.[24] A subgroup of individuals who showed higher levels of psychological distress and lower quality of life and social support were identified from the same population; in addition, this subgroup was more likely to worry about finding out that they were carriers of Lynch syndrome pathogenic variants and being able to cope with learning their test results.[25] In a follow-up report that evaluated psychological outcomes after the disclosure of test results among CRC patients and relatives at risk of having a Lynch syndrome pathogenic variant, a subgroup with the same psychosocial characteristics experienced higher levels of general distress and distress specific to the experience of having genetic testing within the year after disclosure, regardless of variant status. Nonwhites and those with lower education had higher levels of depression and anxiety scores at all times compared with whites and those with higher education, respectively.[27] Other studies have also found that a prior history of major or minor depression, higher pretest levels of cancer-specific distress, having a greater number of cancer-affected first-degree relatives, greater grief reactions, and greater emotional illness–related representations predicted higher levels of distress from 1 to 6 months after disclosure of test results.[28,33] While further research is needed in this area, case studies indicate that it is important to identify persons who may be at risk of experiencing psychiatric distress and to provide psychological support and follow-up throughout the genetic counseling and genetic testing process.[34]
Studies also have examined the effect of Lynch syndrome genetic counseling and testing on cancer risk comprehension. One study reported that nearly all carriers and noncarriers of pathogenic variants could accurately recall the test result 1 year after disclosure. More noncarriers than carriers correctly identified their risk of developing CRC at both 1 month and 1 year after result disclosure. Carriers of pathogenic variants who incorrectly identified their CRC risk were more likely to have had lower levels of pretest subjective risk perception compared with those who correctly identified their level of risk.[22] Another study reported that accuracy of estimating colorectal and endometrial cancer risk improved after disclosure of variant status in carriers and noncarriers.[23]
Psychosocial aspects of screening and risk reduction interventions for Lynch syndrome
Screening
Colorectal screening for Lynch syndrome
Benefits of genetic counseling and testing for Lynch syndrome include the opportunity for individuals to learn about options for the early detection and prevention of cancer, including screening and risk-reducing surgery. Studies suggest that many persons at risk of Lynch syndrome may have had some CRC screening before genetic counseling and testing, but most are not likely to adhere to Lynch syndrome screening recommendations. Among persons aged 18 years or older who did not have a personal history of CRC and who participated in U.S.-based research protocols offering genetic counseling and testing for Lynch syndrome, between 52% and 62% reported ever having had a colonoscopy before genetic testing.[1,3,35,36] Among cancer-unaffected persons who participated in similar research in Belgium and Australia, 51% and 68%, respectively, had ever had a colonoscopy before study entry.[23,37] Factors associated with ever having a colonoscopy before genetic testing included higher income and older age,[35] higher perceived risk of developing CRC,[37] higher education level, and being informed of increased risk of CRC.[36]
In a study of cancer-affected and cancer-unaffected persons who fulfilled clinical criteria for Lynch syndrome, 92% reported having had a colonoscopy and/or flexible sigmoidoscopy at least once before genetic testing.[38] Another study of unaffected individuals presenting for genetic risk assessment and possible consideration of Lynch syndrome, FAP, or APC I1307K genetic testing reported that 77% had undergone at least one screening exam (either colonoscopy, flexible sigmoidoscopy, or barium enema).
Three studies determined whether cancer-unaffected persons adhered to Lynch syndrome colonoscopy screening recommendations before genetic testing, and reported adherence rates of 10%,[23] 28%,[36] and 47%.[38]
Several longitudinal studies examined the use of screening colonoscopy by cancer-unaffected persons after undergoing testing for a known Lynch syndrome pathogenic variant.[23,35-37] These studies compared colonoscopy use before Lynch syndrome genetic testing with colonoscopy use within 1 year after disclosure of test results. One study reported that carriers of Lynch syndrome pathogenic variants were more likely to have a colonoscopy than were noncarriers and those who declined testing (73% vs. 16% vs. 22%) and that colonoscopy use increased among carriers (36% vs. 73%) in the year after disclosure of results.[36] Two other studies reported that carriers’ colonoscopy rates at 1 year after disclosure of results (71% and 53%) were not significantly different from rates before testing,[35,37] although noncarriers’ colonoscopy rates decreased in the same time period. Factors associated with colonoscopy use at 1 year after disclosure of results included carrying a Lynch syndrome–predisposing pathogenic variant,[35-37] older age,[35] and greater perceived control over CRC. These findings suggest that colonoscopy rates increase or are maintained among carriers of pathogenic variants within the year after disclosure of results and that rates decrease among noncarriers. Data from a longitudinal study including 134 carriers of MMR pathogenic variants with and without a prior Lynch syndrome–related cancer diagnosis found that those who did not undergo colonoscopy for surveillance within 6 months after receiving genetic test results were six times more likely to report clinically significant depressive symptoms as measured by the Center for Epidemiological Studies-Depression (CES-D) scale (odds ratio [OR], 6.06; 95% confidence interval [CI], 2.09–17.59). Higher levels of CRC worry measured before genetic testing also were associated with clinically significant depressive symptoms (OR, 1.53; 95% CI, 1.19–1.97).[39]
Two studies examined the level of adherence to published screening guidelines after Lynch syndrome genetic testing, based on variant status. One study reported a colonoscopy adherence rate of 100% among carriers of pathogenic variants.[23] Another study found that 35% of carriers and 13% of noncarriers did not adhere to published guidelines for appropriate CRC screening;[35] in both groups, about one-half screened more frequently than published guidelines recommend, and one-half screened less frequently.
The longitudinal studies described above examined colorectal screening behavior within a relatively short period of time (1 year) after receiving genetic test results, and less is known about longer-term use of screening behaviors. A longitudinal study (N = 73) that examined psychological and behavioral outcomes among cancer-unaffected persons at 3 years after disclosure of genetic test results found that all carriers (n = 19) had undergone at least one colonoscopy between 1 and 3 years postdisclosure.[20] A longitudinal study of similar outcomes up to 7 years posttesting also found that all carriers had undergone colonoscopy; most (83%) underwent the procedure every 3 years or more frequently as recommended, and 11% reported longer screening intervals.[32] In this study, those who reported longer screening intervals than recommended also were more likely to report a fear of dying soon. Also, 16% of noncarriers reported undergoing colonoscopy within the 7 years posttesting; those who indicated doubts about the validity of their test result were more likely to have had a colonoscopy.[32] Ninety-four percent of carriers in one study stated an intention to have annual or biannual colonoscopy in the future; among noncarriers, 64% did not intend to have colonoscopy in the future or were unsure, and 33% intended to have colonoscopy at 5- to 6-year intervals or less frequently.[23] A cross-sectional study conducted in the Netherlands examined the use of flexible sigmoidoscopy or colonoscopy among persons with CRC, endometrial cancer, or a clinical or genetic diagnosis of Lynch syndrome during a time that ranged from 2 years to 18 years after risk assessment and counseling.[40] Eighty-six percent of carriers of Lynch syndrome pathogenic variants, 68% of those who did not test or who had an uninformative Lynch syndrome genetic test result, and 73% of those with a clinical Lynch syndrome diagnosis were considered adherent with screening recommendations, based on data obtained from medical records. Participants also answered questions regarding screening adherence, and 16% of the overall sample reported that they had undergone screening less frequently than recommended. For the overall sample, greater perceived barriers to screening were associated with screening nonadherence as determined through medical record review, and embarrassment with screening procedures was associated with self-reported nonadherence. A second cross-sectional study, also conducted in the Netherlands, surveyed cancer-unaffected carriers of Lynch syndrome variants (n = 42) regarding their colorectal screening behaviors after learning their pathogenic variant status (range, 6 mo–8.5 y). Thirty-one percent of respondents reported that they had undergone annual colonoscopy before Lynch syndrome genetic testing, and 88% reported that they had undergone colonoscopy since their genetic diagnosis (P < .001).[31]
Less is known about Lynch syndrome screening behaviors in persons who may be at risk of having a germline pathogenic variant but who do not undergo genetic counseling and/or genetic testing to learn about their risk status. Among relatives of carriers of a Lynch syndrome germline pathogenic variant from the Australian Colorectal Cancer Family Registry, 26 who had not undergone genetic counseling and/or testing completed an interview to assess their perceived risk of developing CRC in the next 10 years and to self-report their colonoscopy status.[41] Their mean perceived risk was 30.5%, which exceeded the mean predicted risk of 4% as calculated by MMRpro software.[42] Seventy-three percent (n = 19) reported having ever undergone a colonoscopy (one for diagnostic reasons); 35% had undergone colonoscopy within the past 2 years and were considered adherent to recommendations. Perceived risk was slightly and positively correlated with years since last colonoscopy (Pearson's r, 0.49; range, 0.02–0.79) but otherwise was not associated with other screening or personal characteristics. The authors concluded that perceived risk alone may not be a sufficient predictor of colonoscopy use in relatives of carriers of Lynch syndrome pathogenic variants who have not undergone genetic counseling and/or testing.[41]
Gynecologic cancer screening in Lynch syndrome
Several small studies have examined the use of screening for endometrial and ovarian cancers associated with Lynch syndrome (refer to Table 18). There are several limitations to these studies, including small sample sizes, short follow-up, retrospective design, reliance on self-report as the data source, and some not including patients who had undergone Lynch syndrome genetic testing. Several studies have included individuals in the screening uptake analysis who do not meet the minimum age criteria for undergoing screening. Of the studies that assessed screening use after a negative test result for a known pathogenic variant in the family, only a few assessed indications for that screening, such as follow-up of a previously identified abnormality. Last, some studies have included patients in the uptake analysis who were actively undergoing treatment for another cancer, which could influence provider screening recommendations. Therefore, Table 18 is limited to studies with patients who had undergone Lynch syndrome genetic testing, larger sample sizes, longer follow-up, and analysis that included individuals of an appropriate screening age.
Overall, these studies have included relatively small numbers of women and suggest that screening rates for Lynch syndrome–associated gynecologic cancers are low before genetic counseling and testing. However, after participation in genetic education and counseling and the receipt of Lynch syndrome pathogenic variant test results, uptake of gynecologic cancer screening in carriers generally increases, while noncarriers decrease use.
Risk-reducing surgery
There is no consensus regarding the use of risk-reducing colectomy for Lynch syndrome, and little is known about decision-making and psychological sequelae surrounding risk-reducing colectomy for Lynch syndrome.
Among persons who received positive test results, a greater proportion indicated interest in having risk-reducing colectomy after disclosure of results than at baseline.[3] This study also indicated that consideration of risk-reducing surgery for Lynch syndrome may motivate participation in genetic testing. Before receiving results, 46% indicated that they were considering risk-reducing colectomy, and 69% of women were considering risk-reducing total abdominal hysterectomy (RRH) and risk reducing bilateral salpingo-oophorectomy (RRSO); however, this study did not assess whether persons actually followed through with risk-reducing surgery after they received their test results. Before undergoing Lynch syndrome genetic counseling and testing, 5% of cancer-unaffected individuals at risk of a MMR variant in a longitudinal study reported that they would consider colectomy, and 5% of women indicated that they would have an RRH and an RRSO, if they were found to be pathogenic variant–positive. At 3 years after disclosure of results, no participants had undergone risk-reducing colectomy.[20,37] Two women who had undergone an RRH before genetic testing underwent RRSO within 1 year after testing,[37] however, no other female carriers of pathogenic variants in the study reported having either procedure at 3 years after test result disclosure.[20]
In a cross-sectional quality-of-life and functional outcome survey of Lynch syndrome patients with more extensive (subtotal colectomy) or less extensive (segmental resection or hemicolectomy) resections, global quality-of-life outcomes were comparable, although patients with greater extent of resection described more frequent bowel movements and related dysfunction.[44]
Family communication
Family communication about genetic testing for hereditary CRC susceptibility, and specifically about the results of such testing, is complex. It is generally accepted that communication about genetic risk information within families is largely the responsibility of family members themselves. A few studies have examined communication patterns in families who had been offered Lynch syndrome genetic counseling and testing. Studies have focused on whether individuals disclosed information about Lynch syndrome genetic testing to their family members, to whom they disclosed this information, and family-based characteristics or issues that might facilitate or inhibit such communication. These studies examined communication and disclosure processes in families after notification by health care professionals about a Lynch syndrome predisposition and have comprised relatively small samples.
Research findings indicate that persons generally are willing to share information about the presence of a Lynch syndrome pathogenic variant within their families.[45-48] Motivations for sharing genetic risk information include a desire to increase family awareness about personal risk, health promotion options and predictive genetic testing, a desire for emotional support, and a perceived moral obligation and responsibility to help others in the family.[46-48] Findings across studies suggest that most study participants believed that Lynch syndrome genetic risk information is shared openly within families; however, such communication is more likely to occur with first-degree relatives (e.g., siblings, children) than with more distant relatives.[45-48]
One Finnish study recruited parents aged 40 years or older and known to carry an MMR pathogenic variant to complete a questionnaire that investigated how parents shared knowledge of genetic risk with their adult and minor offspring. The study also identified challenges in the communication process.[49] Of 248 parents, 87% reported that they had disclosed results to their children. Reasons for nondisclosure were consistent with previous studies (young age of offspring, socially distant relationships, or feelings of difficulty in discussing the topic).[46,47,50] Nearly all parents had informed their adult offspring about their genetic risk and the possibility of genetic testing, but nearly one-third were unsure of how their offspring had used the information. Parents identified discussing their children’s cancer risk as the most difficult aspect of the communication process. Of the 191 firstborn children informed, 69% had undergone genetic testing. One-third of the parents suggested that health professionals should be involved in disclosure of the information and that a family appointment at the genetics clinic should be made at the time of disclosure.
In regard to informing second- and third-degree relatives, individuals may favor a cascade approach; for example, it is assumed that once a relative is given information about the family’s risk of Lynch syndrome, he or she would then be responsible for informing his or her first-degree relatives.[45-47] This cascade approach to communication is distinctly preferred in regard to informing relatives’ offspring, particularly those of minor age, and the consensus suggests that it would be inappropriate to disclose such information to a second-degree or third-degree relative without first proceeding through the family relational hierarchy.[45-47,50] In one study, persons who had undergone testing and were found to carry a Lynch syndrome–predisposing pathogenic variant were more likely than persons who had received true negative or uninformative results to inform at least one second-degree or third-degree relative about their genetic test results.[48]
While communication about genetic risk is generally viewed as an open process, some communication barriers were reported across studies. Reasons for not informing a relative included lack of a close relationship and lack of contact with the individual; in fact, emotional, rather than relational, closeness seemed to be a more important determinant of the degree of risk communication. A desire to not worry relatives with information about test results and the perception that relatives would not understand the meaning of this information also have been cited as communication barriers.[48] Disclosure seemed less likely if at-risk individuals were considered too young to receive the information (i.e., children), if information about the hereditary cancer risk had previously created conflict in the family,[47] or if it was assumed that relatives would be uninterested in information about testing.[46] Prior existence of conflict seemed to inhibit discussions about hereditary cancer risk, particularly if such discussions involved disclosure of bad news.[47]
For most participants in these studies, the news that the pattern of cancers in their families was attributable to a Lynch syndrome–predisposing pathogenic variant did not come as a surprise,[45,46] as individuals had suspected a hereditary cause for the familial cancers or had prior family discussions about cancer. Identification of a Lynch syndrome–predisposing pathogenic variant in the family was considered a private matter but not necessarily a secret,[45] and many individuals had discussed the family’s pathogenic variant status with someone outside of the family. Knowledge about the detection of a Lynch syndrome–predisposing pathogenic variant in the family was not viewed as stigmatizing, though individuals expressed concern about the potential impact of this information on insurance discrimination.[45] Also, while there may be a willingness to disclose information about the presence of a pathogenic variant in the family, one study suggests a tendency to remain more private about the disclosure of individual results, distinguishing personal results from familial risk information.[50] In a few cases, individuals reported that their relatives expressed anger, shock, or other negative emotional reactions after receiving news about the family’s Lynch syndrome risk;[47] however, most indicated little to no difficulty in informing their relatives.[46] It was suggested that families who are more comfortable and open with cancer-related discussions may be more receptive and accepting of news about genetic risk.[47]
In some cases, probands reported feeling particularly obliged to inform family members about a hereditary cancer risk [47] and were often the strongest advocates for encouraging their family members to undergo genetic counseling and testing for the family pathogenic variant.[45] Some gender and family role differences also emerged in regard to the dissemination of hereditary cancer risk information. One study reported that female probands were more comfortable discussing genetic information than were male probands and that male probands showed a greater need for professional support during the family communication process.[46] Another study suggested that mothers may be particularly influential members of the family network in regard to communicating health risk information.[51] Pathogenic variant–negative individuals, persons who chose not to be tested, and spouses of at-risk persons reported not feeling as personally involved with the risk communication process compared with probands and other at-risk persons who had undergone genetic testing.[45]
Various modes of communication (e.g., in-person, telephone, or written contact) may typically be used to disclose genetic risk information within families.[45-47] In one study, communication aids such as a genetic counseling summary letter or Lynch syndrome booklet were viewed as helpful adjuncts to the communication process but were not considered central or necessary to its success.[46] Studies have suggested that recommendations by health care providers to inform relatives about hereditary cancer risk may encourage communication about Lynch syndrome [47] and that support by health care professionals may be helpful in overcoming barriers to communicating such information to family members.[50]
Much of the literature to date on family communication has focused on disclosure of test results; however, other elements of family communication are currently being explored. One study evaluated the role of older family members in providing various types of support (e.g., instrumental, emotional, crisis help, and dependability when needed) among individuals with Lynch syndrome and their family members (206 respondents from 33 families).[7,52] Respondents completed interviews about their family social network (biological and non-biological relatives and others outside the family) and patterns of communication within their family. The median age of the respondents and the members of their family social network did not differ (age 43 y). The study found that 23% of the members of the family social network encouraged CRC screening (other types of support, such as social support, were reported much more frequently). Those who encouraged screening were older, female, and significant others or biological family members, rather than nonfamily members. Given that many of the members of the family social network did not live in the same household, the study points out the importance of extended family in the context of screening encouragement and support.
Psychosocial Issues in Familial Adenomatous Polyposis (FAP)
Participation in genetic counseling and testing for FAP
The uptake for genetic testing for FAP may be higher than testing for Lynch syndrome. A study of asymptomatic individuals in the United States at risk of FAP who were enrolled in a CRC registry and were offered genetic counseling found that 82% of adults and 95% of minors underwent genetic testing.[53] Uptake rates close to 100% have been reported in the United Kingdom.[54] A possible explanation for the greater uptake of APC genetic testing is that it may be more cost-effective than annual endoscopic screening [55] and can eliminate the burden of annual screening, which must often be initiated before puberty. The opportunity to eliminate worry about potential risk-reducing surgery is another possible benefit of genetic testing for FAP. The decision to have APC genetic testing may be viewed as a medical management decision;[56] the potential psychosocial factors that may influence the testing decision are not as well studied for FAP as for other hereditary cancer syndromes. The higher penetrance of APC pathogenic variants, earlier onset of disease, and the unambiguous phenotype also may influence the decision to undergo genetic testing for this condition, possibly because of a greater awareness of the disease and more experience with multiple family members being affected.
Genetic testing for FAP is presently offered to children with affected parents, often at the age of 10 to 12 years, when endoscopic screening is recommended. Because it is optimal to diagnose FAP before age 18 years to prevent CRC and because screening and possibly surgery are warranted at the time an individual is identified as a carrier of an APC pathogenic variant, genetic testing of minors is justified in this instance. (Refer to the Testing in children section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for a more detailed discussion regarding the ethical, psychosocial, and genetic counseling issues related to genetic testing in children.)
In a survey conducted in the Netherlands of members of families with FAP, one-third (34%) believed that it was most suitable to offer APC gene testing to children before age 12 years, whereas 38% preferred to offer testing to children between the ages of 12 and 16 years, when children would be better able to understand the DNA testing process. Only 4% felt that children should not undergo DNA testing at all.[57]
Results of qualitative interview data from 28 U.S. parents diagnosed with FAP showed that 61% favored genetic testing of APC variants in their at-risk children (aged 10–17 y); 71% believed that their children should receive their test results. The primary reasons why parents chose to test their children included early detection and management, reduction in parental anxiety and uncertainty, and help with decision making regarding surveillance. Reasons provided for not testing focused on discrimination concerns and cost.[58]
Clinical observations suggest that children who have family members affected with FAP are very aware of the possibility of risk-reducing surgery, and focus on the test result as the factor that determines the need for such surgery.[53] It is important to consider the timing of disclosure of genetic test results to children in regard to their age, developmental issues, and psychological concerns about FAP. Children who carry an APC pathogenic variant have expressed concern regarding how they will be perceived by peers and might benefit from assistance in formulating an explanation for others that preserves self-esteem.[53]
Psychological impact of participating in genetic counseling and testing for FAP
Studies evaluating psychological outcomes after genetic testing for FAP suggest that some individuals, particularly carriers of pathogenic variants, may be at risk of experiencing increased distress. In a cross-sectional study of adults who had previously undergone APC genetic testing, those who were carriers of pathogenic variants exhibited higher levels of state anxiety than noncarriers and were more likely to exhibit clinically significant anxiety levels.[59] Lower optimism and lower self-esteem were associated with higher anxiety in this study,[59] and FAP-related distress, perceived seriousness of FAP, and belief in the accuracy of genetic testing were associated with more state anxiety among carriers.[60] However, in an earlier study that compared adults who had undergone genetic testing for FAP, Huntington disease, and hereditary breast/ovarian cancer syndrome, FAP-specific distress was somewhat elevated within 1 week after disclosure of either positive or negative test results and was lower overall than the other syndromes.[56]
In a cross-sectional Australian study focusing on younger adults aged 18 to 35 years diagnosed with FAP (N = 88), participants most frequently reported the following FAP-related issues for which they perceived the need for moderate-to-high levels of support or assistance: anxiety regarding their children’s risk of developing FAP, fear about developing cancer, and uncertainty about the impact of FAP.[61] Seventy-five percent indicated that they would consider prenatal testing for FAP; 61% would consider PGT, and 61% would prefer that their children undergo genetic testing at birth or before age 10 years. A small proportion of respondents (16%) reported experiencing some FAP-related discrimination, primarily indicating that attending to their medical or self-care needs (e.g., time off work for screening, need for frequent toilet breaks, and physical limitations) may engender negative attitudes in colleagues and managers.
Another large cross-sectional study of FAP families conducted in the Netherlands included persons aged 16 to 84 years who either had an FAP diagnosis, were at 50% risk of having an APC pathogenic variant, or were proven APC noncarriers.[62] Of those who had APC testing, 48% had done so at least 5 years or longer before this study. Of persons with an FAP diagnosis, 76% had undergone preventive colectomy, and 78% of those were at least 5 years postsurgery. The study evaluated the prevalence of generalized psychological distress, distress related specifically to FAP, and cancer-related worries. Mean scores on the Mental Health Index-5, a subscale of the SF-36 that assessed generalized distress, were comparable to the general Dutch population. Twenty percent of respondents were classified as having moderate to high levels of FAP-specific distress as measured by the Impact of Event scale (IES), with 23% of those with an FAP diagnosis, 11% of those at risk of FAP, and 17% of noncarriers reporting scores in this range. Five percent reported scores on the IES that indicated severe and clinically relevant distress; of those, the majority (78%) had an FAP diagnosis. Overall, mean scores on the Cancer Worry Scale were comparable to those found in another study of families with Lynch syndrome. Persons with an FAP diagnosis were more likely to report more frequent cancer worries, and the most commonly reported worries were the potential need for additional surgery (26%) and the likelihood that they (17%) or a family member (14%) will develop cancer. In multivariate analysis, factors associated with higher levels of FAP-specific distress included greater perceived risk of developing cancer, more frequent discussion about FAP with family or friends, and having no children. Factors associated with higher levels of cancer-specific worries included being female, poorer family functioning, greater actual and desired discussion about FAP with family or friends, greater perceived cancer risk, poorer general health perceptions, and having been a caregiver for a family member with cancer. The authors noted that most factors that were associated with higher levels of cancer- and FAP-specific distress or worry were psychosocial factors, rather than clinical or demographic factors.
Another cross-sectional study conducted in the Netherlands found that among FAP patients, 37% indicated that the disease had influenced their desire to have children (i.e., wanting fewer or no children). Thirty-three percent indicated that they would consider PND for FAP; 30% would consider PGT. Higher levels of guilt and more positive attitudes towards terminating pregnancy were associated with greater interest for both PND and PGT.[57] In a separate U.S. study, predictors of willingness to consider prenatal testing included having an affected child and experiencing a first-degree relative’s death secondary to FAP.[63]
The psychological vulnerability of children undergoing testing is of particular concern in genetic testing for FAP. Research findings suggest that most children do not experience clinically significant psychological distress after APC testing. As in studies involving adults, however, subgroups may be vulnerable to increased distress and would benefit from continued psychological support. A study of children who had undergone genetic testing for FAP found that their mood and behavior remained in the normal range after genetic counseling and disclosure of test results. Aspects of the family situation, including illness in the mother or a sibling were associated with subclinical increases in depressive symptoms.[64] In a long-term follow-up study of 48 children undergoing testing for FAP, most children did not suffer psychological distress; however, a small proportion of children tested demonstrated clinically significant posttest distress.[65] Another study found that although APC pathogenic variant–positive children’s perceived risk of developing the disease increased after disclosure of results, anxiety and depression levels remain unchanged in the year after disclosure.[59] Pathogenic variant–negative children in this study experienced less anxiety and improved self-esteem over this same time period.
Psychosocial aspects of screening and risk reduction interventions for FAP
Screening
Colorectal screening for FAP
Less is known about psychological aspects of screening for FAP. One study of a small number of persons (aged 17–53 y) with a family history of FAP who were offered participation in a genetic counseling and testing protocol found that among those who were asymptomatic, all reported undergoing at least one endoscopic surveillance before participation in the study.[38] Only 33% (two of six patients) reported continuing screening at the recommended interval. Of the affected persons who had undergone colectomy, 92% (11 of 12 patients) were adherent to recommended colorectal surveillance. In a cross-sectional study of 150 persons with a clinical or genetic diagnosis of classic FAP or attenuated FAP (AFAP) and at-risk relatives, 52% of those with FAP and 46% of relatives at risk of FAP, had undergone recommended endoscopic screening.[66] Among persons who had or were at risk of AFAP, 58% and 33%, respectively, had undergone screening. Compared with persons who had undergone screening within the recommended time interval, those who had not screened were less likely to recall provider recommendations for screening, more likely to lack health insurance or insurance reimbursement for screening, and more likely to believe that they are not at increased risk of CRC. Only 42% of the study population had ever undergone genetic counseling. A small percentage of participants (14%–19%) described screening as a “necessary evil,” indicating a dislike for the bowel preparation, or experienced pain and discomfort. Nineteen percent reported that these issues might pose barriers to undergoing future endoscopies. Nineteen percent reported that improved techniques and the use of anesthesia have improved tolerance for screening procedures.
Risk-reducing surgery
When persons at risk of FAP develop multiple polyps, risk-reducing surgery in the form of subtotal colectomy or proctocolectomy is the only effective way to reduce the risk of CRC. Most persons with FAP can avoid a permanent ostomy and preserve the anus and/or rectum, allowing some degree of bowel continence. (Refer to the Interventions for FAP section of this summary for more information about surgical management procedures in FAP.) Evidence on the quality-of-life outcomes from these interventions continues to accumulate and is summarized in Table 19.
Studies of risk-reducing surgery for FAP have found that general measures of quality of life have been within normal range, and the majority reported no negative impact on their body image. 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.
Chemoprevention
Chemoprevention trials are currently under way to evaluate the effectiveness of various therapies for persons at risk of Lynch syndrome and FAP.[72,73] In a sample of persons diagnosed with FAP who were invited to take part in a 5-year trial to evaluate the effects of vitamins and fiber on the development of adenomatous polyps, 55% agreed to participate.[74] Participants were more likely to be younger, to have been more recently diagnosed with FAP, and to live farther from the trial center, but did not differ from nonparticipants on any other psychosocial variables.
Reproductive Considerations in Individuals With Lynch Syndrome or FAP
Assisted reproductive technology (ART)
The possibility of transmitting a pathogenic variant to a child may pose a concern to families affected by hereditary CRC syndromes to the extent that some carriers may avoid childbearing. These concerns also may prompt individuals to consider using prenatal diagnosis (PND) methods to help reduce the risk of transmission. PND is an encompassing term used to refer to any medical procedure conducted to assess the presence of a genetic disorder in a fetus. Methods include amniocentesis and chorionic villous sampling.[75,76] Both procedures carry a small risk of miscarriage.[75,77] Moreover, discovering the fetus is a carrier of a cancer susceptibility variant may impose a difficult decision for couples regarding pregnancy continuation or termination and may require additional professional consultation and support.
An alternative to these tests is preimplantation genetic testing (PGT), a procedure used to test fertilized embryos for genetic disorders before uterine implantation.[78,79] Using the information obtained from the genetic testing, potential parents can decide whether or not to implant. PGT can be used to detect pathogenic variants in hereditary cancer predisposing genes, including APC.[57,63,80]
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Changes to This Summary (11/01/2019)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Updated National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal as reference 55.
This section was renamed from Colon Cancer Genes.
Revised text to state that tumor suppressor genes constitute the most important class of genes responsible for hereditary cancer syndromes and represent the class of genes responsible for familial adenomatous polyposis, Lynch syndrome, and juvenile polyposis syndrome (JPS), among others.
Revised Table 2. Genes Associated with a High Susceptibility of Colorectal Cancer (CRC).
Added Polygenic risk scores for colorectal cancer as a new subsection.
Updated NCCN: Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal as reference 121.
Revised Table 7. Clinical Practice Guidelines for Colon Surveillance of Attenuated Familial Adenomatous Polyposis.
Revised Table 8. Clinical Practice Guidelines for Colon Surveillance of MUTYH-Associated Polyposis.
The Oligopolyposis subsection was extensively revised.
Added text to state that clinicians are increasingly utilizing tumor sequencing to advance therapeutic decisions in a more personalized approach, particularly in patients with metastatic disease. The performance of next-generation tumor sequencing (NGS) of CRCs for the detection of Lynch syndrome was compared with existing screening protocols that include microsatellite instability (MSI) testing and immunohistochemistry (IHC) staining, in 419 CRC cases recruited in a multicenter, population-based study (cited Hampel et al. as reference 330). Twelve participants were identified as Lynch syndrome carriers by germline DNA testing and all were correctly identified by tumor sequencing while MSI plus BRAF and IHC plus BRAF missed five and six Lynch syndrome cases, respectively. This study suggested that tumor sequencing is a highly effective mode of identifying Lynch syndrome; however, the cost-effectiveness of this strategy remains to be determined.
Revised text to state that NCCN 2019 guidelines support universal screening of all CRCs with IHC and/or MSI, and/or a comprehensive tumor NGS panel or germline multigene (panel) testing.
Revised text to state that NCCN recommends tumor testing with IHC and/or MSI, a comprehensive tumor NGS panel, or germline multigene (panel) testing of all endometrial cancers.
Added MSI in all cancers as a new subsection.
Added text to state that among the key findings from a series of papers from the Prospective Lynch Syndrome Database (PLSD) was a low risk of CRC in PMS2 carriers, especially among those below age 50 years, leading the authors to conclude that surveillance in PMS2 carriers could safely be scaled back. A later initiation of colonoscopy and perhaps at longer intervals, is gradually being adopted in light of these findings. The relative risk of extracolonic cancers in PMS2 carriers was no greater or only slightly greater than population expectations, which led the authors to generally recommend against any extracolonic surveillance in PMS2 carriers. These data in aggregate support a more liberalized approach for screening PMS2 carriers, although current clinical practice guidelines do not reflect this change. The approach to screening individuals with PMS2 pathogenic variants, and to a lesser extent those with MSH6 pathogenic variants, are matters of ongoing clinical debate.
Added text to state that the PLSD includes outcome data from many European programs (cited Møller et al. as reference 390). Recognizing limitations in the larger PLSD, a subset with more detailed surveillance data has been provided (cited Engel et al. as reference 391). These prospective colonoscopy data from Germany, Holland, and Finland included 2,747 patients of whom 62 had no prior cancer at surveillance initiation. Despite differences in surveillance intervals, similar adenoma detection rates were found in those patients with a history of cancer and those without. Notably, no significant difference in CRC detection or in stage at detection was noted between screening intervals of 1, 2, or 3 years.
The Familial CRC subsection was extensively revised.
Revised text to state that the cumulative cancer risks in Peutz-Jeghers syndrome (PJS) have been estimated to be 32% to 54% for breast cancer and 21% for ovarian cancer (mainly ovarian sex-cord tumors). The risk for pancreatic cancer has been estimated to be more than 100-fold higher than that in the general population.
Added text to state that up to 30% of variants are large deletions involving one or more exons of STK11, underscoring the importance of deletion analysis in suspected cases of PJS.
Revised text to state that JPS patients with SMAD4 pathogenic variants may also have signs and symptoms of hereditary hemorrhagic telangiectasia (HHT), suggesting that the two syndromes overlap. When a patient is found clinically to have features of both JPS and HHT, the pathogenic variant will be in the SMAD4 gene. Most patients with isolated HHT will have a pathogenic variant in the ALK1 gene or in the ENG gene, but SMAD4 pathogenic variants have also been reported, although they are quite rare. One series suggested a slightly higher incidence of SMAD4 pathogenic variants in unselected patients with HHT. In this study, 3 of 30 patients with HHT without a clinical diagnosis of JPS were found to have germline variants in SMAD4.
Added text to state that patients with SMAD4 pathogenic variants are also at high risk for developing extracolonic gastrointestinal cancers such as gastric cancers, often in the context of gastric polyposis.
Added text to state that sporadic serrated polyps are the precursors to CRCs of the CpG island methylator phenotype pathway.
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of colorectal cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Genetics of Colorectal Cancer are:
- Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
- Fay Kastrinos, MD, MPH (Herbert Irving Comprehensive Cancer Center and New York-Presbyterian Hospital/Columbia University Medical Center)
- Scott Kuwada, MD, AGAF, FACP (University of Hawaii)
- Patrick M. Lynch, MD, JD (University of Texas, M.D. Anderson Cancer Center)
- Suzanne M. O'Neill, MS, PhD, CGC
- Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
- Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
- Miguel A. Rodriguez-Bigas, MD (University of Texas, M.D. Anderson Cancer Center)
- Danielle Kim Turgeon, MD (University of Michigan Comprehensive Cancer Center)
- Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
- Catharine Wang, PhD, MSc (Boston University School of Public Health)
- Matthew B. Yurgelun, MD (Dana-Farber Cancer Institute)
- Kevin Zbuk, MD, FRCPC (Margaret and Charles Juravinski Cancer Centre)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Colorectal Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/colorectal/hp/colorectal-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389505]
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