Risk For Hereditary Colorectal Cancer Research Articles

Mexican physicians' knowledge and attitudes towards hereditary colorectal cancer risk management.

e22552 Background: Genetic cancer risk assessment (GCRA) has become an integral component of the management of patients with colorectal cancer (CRC). Understanding clinical criteria and interpreting screening tests to identify patients who should be prioritized for genetic testing is especially critical in resource-constrained settings such as Mexico, where access to genetic testing is limited. Methods: We designed a self-applicable survey consisting of 18 items, divided into three sections: 7 on knowledge, 5 on clinical approaches, and 6 on access to genetic testing. The aim was to assess the practice patterns of Mexican physicians in contact with patients at risk for hereditary CRC. Initially, the survey was piloted among oncology fellows to refine and improve its relevance and applicability. Following adjustments, it was disseminated using a QR code at the annual meeting of the Mexican Society of Oncology (SMeO) in September 2023. Descriptive statistics were performed using frequency and proportions for categorical variables and median and range for quantitative variables. Results: A total of 78 physicians completed the survey, with a median age of 37 years (range, 27-70). Among them, 47.2% were female, 82% were medical oncologists, with a median practice duration of 6 years (range, 1- 40). 52.6% practice in cancer community centers, 83.4% were employed in public primary care settings, and 60% were affiliated to academic centers. Referral criteria for GCRA was identified correctly in 66.7% who recognized age at CRC diagnosis < 50 years, 57.7% synchronous or metachronous CRC, 50% deficient mismatch repair CRC, and 37.2% PREMM5 score of ≥2.5%. Lynch syndrome, Familial Adenomatous Polyposis (FAP), and Cowden syndrome were identified as syndromes with an increased CRC risk by 76.9%, 71.8% and 56.7% of respondents, respectively. Decision-making based on likely pathogenic and pathogenic variants was indicated by 26.9% and 69.2%, while 12.8% reported making decisions based on variants of uncertain significance (VUS). Regarding clinical approach, 74.4% inquired about a family history of cancer at the initial consultation, and 66.7% referred patients for genetic counseling. The primary obstacles to accessing GCRA were the cost of genetic testing (43.6%) and the absence of medical genetics services at their centers (39.7%). Only 23% reported the availability of cascade testing within their practice. Conclusions: The identification of patients at risk of hereditary CRC was suboptimal among Mexican physicians. A high proportion of respondents were not fully qualified to interpret correctly genetic testing results. These indicate a need for awareness and educational programs to improve providers’ knowledge on predisposition cancer syndromes.

Screening and surveillance for hereditary colorectal cancer.

Hereditary colorectal cancer is a type of cancer that is caused by a genetic mutation. Individuals with a family history of colorectal cancer, or who have a known hereditary syndrome, are at an increased risk of developing the disease. Screening and surveillance are important tools for managing the risk of hereditary colorectal cancer. Screening involves a combination of tests that can detect precancerous or cancerous changes in the colon and rectum. Surveillance involves regular follow-up examinations to monitor disease progression and to identify new developments. The frequency and type of screening and surveillance tests may vary depending on an individual's risk factors, genetic profile, and medical history. However, early detection and treatment of hereditary colorectal cancer can significantly improve patient outcomes and reduce mortality rates. By implementing comprehensive screening and surveillance strategies, healthcare providers can help individuals at risk of hereditary colorectal cancer to receive timely interventions and make informed decisions about their health. Specific examples of screening and surveillance tests for hereditary colorectal cancer include colonoscopy, genetic testing, and imaging tests. In this review article, we will discuss detailed screening and surveillance of hereditary colorectal cancer.

Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer

IntroductionThe increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel.Materials and methodsPatients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR.ResultsOut of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes.ConclusionThe high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.

A152 ASSESSING THE USE OF A VALIDATED LYNCH SCREENING QUESTIONNAIRE IN THE OUTPATIENT SETTING AND SUBSEQUENT CHANGES IN PATIENT MANAGEMENT

Abstract Background Colorectal cancer (CRC) is the second most common cause of cancer related deaths in Canada. Approximately 1 in 13 males and 1 in 18 females will develop colorectal cancer in their lifetimes. As many as 10% of CRC may be associated with an inherited syndrome. Lynch Syndrome (LS) is the most common cause of inherited CRC, estimated to account for 3-4% of all CRC cases. . A study by Kastrinos et al. found that a simple, 3 item survey, identified 77% of individuals with known LS. Implementation of this questionnaire at a gastroenterology office may help identify patients at risk for LS. Purpose To assess whether implementation of a validated questionnaire to screen for LS is feasible in an outpatient gastroenterology clinic, and if these results would change patient management by gastroenterologists. Method Included in this study were all patients 18 years or older, who had been referred to one of the gastroenterologists at Pacific Gastroenterology Associates in Vancouver, British Columbia. Exclusion criteria included those patients less than 18 years of age, and patients previously seen by the HCP. Each subject was asked the following three questions: (1) Do you have a first-degree relative with CRC or LS-related cancer diagnosed before age 50? (2) Have you had CRC or polyps diagnosed before age 50? (3) Do you have ≥3 relatives with CRC?. Answering yes to any question was considered a positive screen. Gastroenterologists were initially blinded to the content of the questionnaire and results. After completion of the questionnaire and formal gastroenterology consultation, the patients who screened positive for an increased risk of LS had their results unblinded to their primary gastroenterologist. Gastroenterologists were then asked if the survey results changed their management. Result(s) A total of 655 patients were screened, with 33 (5.0%) screening positive for question 1, 71 (10.8%) screening positive for question 2, and 17 (2.6%) screening positive for question 3. In total, 106 (15.9%) of individuals surveyed screened positive indicating higher risk for hereditary colorectal cancer. Subsequent reassessment by gastroenterologists of patients screening positive with the LS questionnaire (n=51) yielded no change to 47 patients (92%), screening with colonoscopy not originally planned for 1 patient (2%), re-consultation for further risk assessment for 2 patients (4%) and 1 referral to the Hereditary Cancer Program (2%). Conclusion(s) Utilization of a simple 3-question survey as part of regular patient intake in a gastroenterology office resulted in an increased number of individuals being identified as being high risk for Lynch syndrome, with a subsequent increase in endoscopic screening not otherwise planned, further assessment for colon cancer risk, and an increased referral to the Hereditary Cancer Program. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Application of Multigene Panel Testing in Patients With High Risk for Hereditary Colorectal Cancer: A Descriptive Report Focused on Genotype-Phenotype Correlation.

The genetic test solely based on the clinical features of hereditary colorectal cancer has limitations in clinical practice. This study aimed to analyze the results of comprehensive multigene panel tests based on clinical findings. This was a cross-sectional study based on a prospectively compiled database. The study was conducted at a tertiary hospital. A total of 381 patients with high risk for hereditary colorectal cancer syndromes were enrolled between March 2014 and December 2019. The primary outcome was to describe the mutational spectrum based on genotype-phenotype concordance and discordance. Germline mutations were identified in 89 patients for polyposis hereditary colorectal cancer genes (76 in APC; 4 in PTEN; 4 in STK11; 3 in BMPR1A; 1 in POLE; 1 in POLD1), 89 patients for nonpolyposis hereditary colorectal cancer genes (41 in MLH1; 40 in MSH2; 6 in MSH6; and 2 in PMS2), and 12 patients for other cancer predisposition genes (1 in ATM; 2 in BRCA1; 1 in BRCA2; 1 in BRIP1; 1 in MLH3; 1 in NBN; 1 in PMS1; 1 in PTCH1; 1 in TP53; and 2 in monoallelic MUTYH). If we had used direct sequencing tests of 1 or 2 major genes based on phenotype, 48 (25.3%) of 190 mutations would not have been detected due to technical differences (12.1%), less frequent genotype (4.2%), unclear phenotype (3.7%), and genotype-phenotype discordance (4.7%). The genotype-phenotype discordance is probably linked to compound heterozygote, less distinctive phenotype, and insufficient information for colorectal cancer risk. This study included a small number of patients with insufficient follow-up duration. A comprehensive multigene panel is expected to identify more genetic mutations than phenotype-based direct sequencing, with special utility for unclear phenotype or genotype-phenotype discordance. See Video Abstract at http://links.lww.com/DCR/B844. ANTECEDENTES:La prueba genética basada únicamente en la característica clínica del cáncer colorrectal hereditario tiene limitaciones en la práctica clínica.OBJETIVO:Este estudio tuvo como objetivo analizar el resultado de pruebas integrales de panel multigénico basadas en hallazgos clínicos.DISEÑO:Este fue un estudio transversal basado en una base de datos recopilada prospectivamente.AJUSTE:El estudio se realizó en un hospital terciario.PACIENTES:Se inscribió un total de 381 pacientes con alto riesgo de síndromes de cáncer colorrectal hereditario entre marzo del 2014 y diciembre del 2019.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue describir el espectro mutacional basado en la concordancia y discordancia genotipo-fenotipo.RESULTADOS:Se identificaron mutaciones de la línea germinal en 89 pacientes para genes de cáncer colorrectal hereditario con poliposis (76 en APC; 4 en PTEN; 4 en STK11; 3 en BMPR1A; 1 en POLE; 1 en POLD1), 89 pacientes para genes de CCR hereditario sin poliposis (41 en MLH1; 40 en MSH2; 6 en MSH6; y 2 ​​en PMS2) y 12 pacientes por otro gen de predisposición al cáncer (1 en ATM; 2 en BRCA1; 1 en BRCA2; 1 en BRIP1; 1 en MLH3; 1 en NBN; 1 en PMS1; 1 en PTCH1; 1 en TP53; y 2 ​​en MUTYH monoalélico). Si hubiéramos utilizado pruebas de secuenciación directa de uno o dos genes principales basados ​​en el fenotipo, 48 (25,3%) de 190 mutaciones no se habrían detectado debido a diferencias técnicas (12,1%), genotipo menos frecuente (4,2%), fenotipo poco claro (3,7%) y discordancia genotipo-fenotipo (4,7%). La discordancia genotipo-fenotipo probablemente esté relacionada con el heterocigoto compuesto, el fenotipo menos distintivo y la información insuficiente para el riesgo de cáncer colorrectal.LIMITACIONES:Este estudio incluyó una pequeña cantidad de pacientes con una duración de seguimiento insuficiente.CONCLUSIONES:Se espera que un panel multigénico completo identifique más mutaciones genéticas que la secuenciación directa basada en el fenotipo, con especial utilidad para la discordancia de fenotipo o genotipo-fenotipo poco clara. Consulte Video Resumen en http://links.lww.com/DCR/B844. Traducción- Dr. Francisco M. Abarca-Rendon).

Gut Microbial Signatures in Sporadic and Hereditary Colorectal Cancer.

Colorectal cancer (CRC) is the fourth most common cause of cancer-related death and the third most common cancer in the world. Depending on the origin of the mutation, colorectal carcinomas are classified as sporadic or hereditary. Cancers derived from mutations appearing during life, affecting individual cells and their descendants, are called sporadic and account for almost 95% of the CRCs. Less than 5% of CRC cases result from constitutional mutations conferring a very high risk of developing cancer. Screening for hereditary-related cancers is offered to individuals at risk for hereditary CRC, who have either not undergone genetic evaluation or have uncertain genetic test results. In this review, we briefly summarize the main findings on the correlation between sporadic CRC and the gut microbiota, and we specifically focus on the few evidences about the role that gut microorganisms have on the development of CRC hereditary syndromes. The characterization of a gut microbiota associated with an increased risk of developing CRC could have a profound impact for prevention purposes. We also discuss the potential role of the gut microbiota as therapeutic treatment.

Genetic testing in families with hereditary colorectal cancer in British Columbia and Yukon: a retrospective cross-sectional analysis.

Genetic testing in families with hereditary cancer enables identification of people most likely to benefit from intensive screening and preventive measures; however, the uptake of testing in relatives (known as cascade carrier testing) for hereditary colorectal cancer syndromes has been shown to be low. Our objective was to report rates of familial testing for hereditary colorectal cancer syndromes in a publicly funded hereditary cancer clinic in Canada. A cross-sectional retrospective database review was used to determine testing uptake between 1997 and 2016 for families served by the provincial Hereditary Cancer Program for British Columbia and Yukon. Analyses were conducted for genes associated with syndromes with an increased risk for colorectal cancer, including Lynch syndrome (MLH1, MSH2, MSH6, PMS2 and EPCAM) and familial adenomatous polyposis (APC), and for additional moderate- to high-penetrance genes (STK11, TP53, SMAD4, MUTYH, PTEN and CHEK2). Descriptive statistics were used and all analyses were 2-tailed. The study cohort included 245 index patients, with carrier testing performed in 382 relatives. The mean age at family member testing was 41.2 years, and most (61.0%) of the family members who underwent testing were women. The median time between disclosure of index cases and their family member's results was 8.3 months. Among eligible first-degree relatives, 32.6% (268/821) underwent testing in BC. Of 67 cancer diagnoses in family members, most (62.7%) occurred before genetic testing. A substantial proportion of people at risk for hereditary colorectal cancer do not undergo genetic testing. This gap highlights the need to explore barriers to testing and to consider interventions to promote uptake; more aggressive efforts by hereditary cancer programs are needed to reach this highest risk population.

S3120 African Americans Are Less Frequently Assessed for Hereditary Colon Cancer

INTRODUCTION: Approximately 5% of colorectal cancer (CRC) results from hereditary cancer syndromes. Identification of individuals at increased risk for CRC is important to determine initiation, frequency, method of screening and referral for genetic counselling. A detailed family history is recommended as an initial component of cancer risk assessment. African-Americans (AA) are more often diagnosed with CRC, have more advanced disease and greater mortality rate. There is limited data on screening of AA for hereditary CRC. This study evaluated the rate of hereditary CRC risk assessment in AA and white patients in a university GI clinic. METHODS: A chart review of all self-described AA and white patients referred for CRC screening in a university GI clinic during a 3 month period was performed. Patient gender, age and documentation of multi-generational family medical history (3 + generations) were obtained. Amsterdam II Criteria, Bethesda Criteria and Colorectal Cancer Risk Assessment Tool were used to determine which patients had family histories that warrant genetic counseling and referrals. Statistical analysis was performed using Fisher’s Exact Test with significance set at P < 0.05. The study was IRB approved. RESULTS: 715 medical records were reviewed. There were 452 AA (276 females, 176 males; mean age 60.2) and 263 whites (123 females, 140 males; mean age 59.4). A multi-generational family history was obtained in 62 AA (13.7%; 47 females, 15 males) and 58 whites (22.1%; 37 females, 21 whites). There was a significant difference (P = 0.0050) in the rate at which a detailed family history is obtained AA and whites. There was no significant difference (P = 0.7915) in the rate at which AA (36, 58.1%; 30 females, 6 males) and whites (29, 50%; 19 females, 10 males) qualified for genetic counselling. There was no significant difference (P = 0.7586) in the referral rate of qualified AA (7, 19.4%; 6 females, 1 male) and whites (8; 27.6%; 6 females, 2 males) for genetic testing. CONCLUSION: This study revealed that CRC risk assessment with detailed family medical histories was inconsistently performed in all patients. There was a significantly lower rate of obtaining multi-generational family medical histories in AA. Additionally, there was insufficient referrals of all patients for genetic counselling and testing. It is important that there is appropriate identification of individuals at increased risk for hereditary cancer syndromes, with special attention to decreasing potential disparities in care.

Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis.

Multigene panel tests for hereditary cancer syndromes are increasingly utilized in the care of colorectal cancer (CRC) and polyposis patients. However, widespread availability of panels raises a number of questions including which patients should undergo testing, which genes should be included on panels, and the settings in which panels should be ordered and interpreted. To address this knowledge gap, key questions regarding the major issues encountered in clinical evaluation of hereditary CRC and polyposis were designed by the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position Statement Committee and leadership. A literature search was conducted to address these questions. Recommendations were based on the best available evidence and expert opinion. This position statement addresses which genes should be included on a multigene panel for a patient with a suspected hereditary CRC or polyposis syndrome, proposes updated genetic testing criteria, discusses testing approaches for patients with mismatch repair proficient or deficient CRC, and outlines the essential elements for ordering and disclosing multigene panel test results. We acknowledge that critical gaps in access, insurance coverage, resources, and education remain barriers to high-quality, equitable care for individuals and their families at increased risk of hereditary CRC.

A168 IS ROUTINE SCREENING FOR HEREDITARY COLORECTAL CANCER FEASIBLE IN AN OUTPATIENT GASTROENTEROLOGY PRACTICE?

Abstract Background Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC), with a reported prevalence of 2–5% of all CRC cases. A study by Kastrinos et al. found that a simple 3 item survey identified 77% of individuals at high risk for hereditary CRC. Implementation of this questionnaire at a gastroenterology office may help identify patients at risk for LS and other hereditary CRC. Aims To assess whether implementation of a validated questionnaire to screen for hereditary CRC is feasible in an outpatient gastroenterology clinic. Methods Adult gastroenterology outpatients who consented to participate in the study completed the screening questionnaire. Those who had previously been assessed by the Hereditary Cancer Program were excluded. Each subject was asked the following three questions: (1) Do you have a first-degree relative with CRC or LS-related cancer diagnosed before age 50? (2) Have you had CRC or polyps diagnosed before age 50? (3) Do you have ≥3 relatives with CRC?. Answering yes to any question was considered a positive screen. Results A total of 288 patients were screened, with 12 (4.2%) screening positive for question 1, 28 (9.7%) screening positive for question 2, and 8 (2.8%) screening positive for question 3. In total, 14.2% of individuals surveyed screened positive. Conclusions Utilization of a simple 3-question survey as part of regular patient intake in a gastroenterology office resulted in 14.2% of individuals screening high-risk for hereditary CRC. This is similar to the 15% screen positive rate in the original study of individuals with CRC. Further research is needed to determine whether a physician’s knowledge of the questionnaire results will change management and whether a positive screen leads to a confirmed diagnosis of LS and other hereditary colorectal cancers. Funding Agencies None

Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an...

Parelsnoer Institute Biobank Hereditary Colorectal Cancer: A Joint Infrastructure for Patient Data and Biomaterial on Hereditary Colorectal Cancer in the Netherlands

Each year approximately 15,000 patients are diagnosed with colorectal cancer (CRC) in the Netherlands, of whom 5-10% are associated with a hereditary syndrome. To enable future research into hereditary CRC, we established a collaborative biobank for hereditary CRC in all eight University Medical Centers (UMCs) in the Netherlands in 2009. This Biobank Hereditary CRC is part of the Parelsnoer Institute (PSI), which is funded by the Dutch Federation of UMCs and the Dutch Government. Besides the multicenter collaboration, the multidisciplinary nature of this biobank - involving Gastroenterology, Genetics and Surgery - is essential for its functionality and value.Patients at increased risk of hereditary CRC and/or Polyposis, or with a proven germline mutation causing CRC and/or Polyposis are included. Both clinical data (demographic data, details on medical and family history, information on surveillance, endoscopy and surgery, results of microsatellite instability and molecular genetic tests) and biomaterial (DNA, plasma, serum and tissue) are collected in a standardized manner.

Genetic counseling, genetic testing, and risk perceptions for breast and colorectal cancer: Results from the 2015 National Health Interview Survey

We examined what proportion of the U.S. population with no personal cancer history reported receiving either genetic counseling or genetic testing for cancer risk, and also the association of these behaviors with cancer risk perceptions.We used data from the 2015 National Health Interview Survey. Objective relative risk scores for breast (women) and colorectal (men and women) cancer risk were generated for individuals without a personal history of cancer. Participants' risk perceptions were compared with their objective relative risk.Of 12,631 women, 1.2% reported receiving genetic counseling and 0.8% genetic testing for hereditary breast cancer risk. Of 15,085 men and women, 0.8% reported receiving genetic counseling and 0.3% genetic testing for hereditary colorectal cancer risk. Higher breast cancer risk perception was associated with genetic counseling (OR: 4.31, 95%CI: 2.56, 7.26) and testing (OR: 3.56, 95%CI: 1.80, 7.03). Similarly, higher perception of colorectal cancer risk was associated with genetic counseling (OR: 5.04, 95%CI: 2.57, 9.89) and testing (OR: 5.92, 95%CI: 2.40, 14.63). A higher proportion of individuals with colorectal cancer risk perceptions concordant with their objective risk (vs. discordant) had undergone genetic counseling or testing for colorectal cancer risk. Concordant risk perceptions for breast cancer were not associated with breast cancer genetic counseling or testing.Given frequent dialogue about implementing population level programs involving genetic services for cancer risk, policy makers and investigators should consider the role of risk perceptions in the effectiveness and design of such programs and potential strategies for addressing inaccuracies in risk perceptions.

Complexities of genetic screening and testing in hereditary colorectal cancer

It is becoming increasingly important to identify patients at risk for hereditary colorectal cancer (CRC) given the opportunity to impact medical management and reduce morbidity and mortality among patients and their family members once inherited CRC predisposition is confirmed. Methods by which patients are identified are evolving as genetic testing costs have plummeted, resulting in many more genetic screening and testing options. Opportunities and challenges with newer approaches to genetic testing and screening for hereditary CRC are reviewed along with benefits and limitations of each approach. Regardless of how methods evolve for identifying patients with hereditary cancer risk, the need for patient education, family history taking, appropriate risk counseling, and enhancing sharing across family members will remain critical for optimal patient care.

Universal screening for Lynch syndrome among patients with colorectal cancer: patient perspectives on screening and sharing results with at-risk relatives.

Universal screening for Lynch syndrome (LS) among all cases of colorectal cancer (CRC) could increase the diagnosis of LS and reduce morbidity and mortality of LS-associated cancers. Given universal screening includes all patients, irrespective of high risk factors such early age at onset or family history of CRC, it is important to understand perspectives of all patients and not just those at high risk. As part of a study to assess the feasibility and implementation of universal screening, 189 patients newly diagnosed with CRC were surveyed about their interest in screening for LS and communication of results with at-risk family members. Overall, participants responded positively regarding screening for LS, with most wanting to know their genetic risks in general (86%) and risk of hereditary CRC (93%). Prior to receiving screening results, most participants stated they intended to share their screening results with parents (89%), siblings (96%), and children (96%). Of the 28 participants who received a positive LS screening result, 26 (93%) reported sharing their result with at least one first-degree family member. Interest in screening for LS and communication of screening results with family members was not associated with high risk factors. This study indicates that patients are interested in being screened for LS and that sharing information on the risk of LS with at-risk family members is not a significant barrier. These findings provide novel insight into patient perspectives about screening for LS and can guide successful implementation of universal screening programs.

Abstract IA07: Germline next-generation sequencing panels for detection of inherited colorectal cancer syndromes

Abstract Background: Germline genetic testing for hereditary cancer predisposition syndromes can prevent cancer and save lives by identifying individuals who will benefit from enhanced surveillance, prophylactic surgery, and other risk-reduction strategies. Classically, hereditary cancer risk assessment has involved identification of individuals with clinical histories that fulfill specific criteria for a given syndrome followed by germline testing for mutations in the associated gene(s). Recent advances in next-generation sequencing technologies now allow individuals to undergo germline evaluation of numerous genes in parallel and a growing array of multigene panels are clinically available for such diagnostic testing. Methods: This presentation will discuss updates in clinical genetic testing, specifically the growing availability of next-generation sequencing multigene panel testing for hereditary cancer risk assessment. Findings: Data regarding next-generation sequencing multigene panel testing will be presented and will be contrasted with traditional, syndrome-specific hereditary colorectal cancer risk assessment strategies. Particular areas of focus in this talk will include: the detection of unexpected/off-target germline mutations by multigene panels (e.g. BRCA1/2 mutations in patients with colorectal cancer); cost-effectiveness considerations; the significance of moderate-penetrance cancer susceptibility gene mutations; germline variants of uncertain significance; and ways in which multigene panel testing results are expanding knowledge (and uncertainty) about both well- and poorly-defined colorectal cancer predisposition syndromes. Conclusions: Next-generation sequencing multigene panels are rapidly growing in popularity and availability for assessing hereditary cancer risk, including the identification of germline mutations linked to inherited colorectal cancer risk. In order for patients considering such testing to receive optimal care, it is essential that both they and their providers have a clear understanding of the benefits and potential limitations of multigene panels, including the possibility of identifying unexpected and/or indeterminate germline results. Citation Format: Matthew B. Yurgelun. Germline next-generation sequencing panels for detection of inherited colorectal cancer syndromes. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA07.

Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability.

Loss of function of mismatch repair (MMR) genes, mainly MLH1 and MSH2, manifests as high levels of microsatellite instability (MSI) that occurs in >90% of carcinomas in patients with Lynch syndrome (LS). The MSI-high status has also been described in sporadic colorectal cancer (CRC) associated with BRAF gene mutation (V600E); this mutation was not present in LS-associated cancers. The present study performed MSI analysis on 39 CRC patients selected according to Bethesda guidelines, and BRAF V600E genotyping was performed in 26 cases classified as MSI-high or MSI-low (15 MSI-H and 11 MSI-L). These 26 patients were then screened for MLH1 and MSH2 germ-line mutations. Germ-line mutations in these genes were detected in 11/15 patients with MSI-H tumors (73%) and in 1/11 patients with MSI-L tumors (9%). Overall, 11 germ-line mutations in 12/26 analyzed patients (46%) in these genes were identified. Two of these mutations are novel genetic MLH1 variants not previously described in the literature, c.438A>G and c.1844T>C. A combination of computational approaches, co-segregation analysis and RNA assay suggested that these novel mutations, silent and missense, respectively, were probably pathogenic. The findings of the present study further emphasized the requirement for genetic testing in patients with a risk for hereditary CRC and has broadened the spectrum of known mutations of the MLH1 gene.

Validation of an online questionnaire for identifying people at risk of familial and hereditary colorectal cancer.

We developed and validated an online questionnaire to document familial cancer history, in order to facilitate the detection of persons with a familial or hereditary colorectal cancer (CRC) risk. The development of the self-administered online questionnaire for the assessment of familial and hereditary CRC risk was based on nationwide criteria for referral to genetic specialists due to a Lynch syndrome suspicion, as well as existing criteria for surveillance colonoscopies because of an increased risk of familial CRC. The questionnaire was validated at a private colonoscopy center. Patients scheduled for colonoscopy were enrolled (n = 150). Performance of the questionnaire was assessed by comparing referrals based on questionnaire data against referral decisions based on full pedigree data. In a second validation phase, referrals based on questionnaire data were compared with referrals based on data collected in a telephone interview. We also calculated inter-observer agreement in referral decisions. In the first validation phase, the questionnaire had a sensitivity of 90 % (95 % CI 55–98 %) at a specificity of 98 % (95 % CI 87–100 %) in identifying persons qualifying for referral. In the second validation phase, sensitivity was 100 % (95 % CI 63–100) at a specificity of 97 % (95 % CI 91–99 %). In both validation phases an inter-observer agreement of 100 % in referral decisions was achieved. The online questionnaire has a high sensitivity and specificity in identifying persons qualifying for referral because of suspected Lynch syndrome or familial CRC. Implementation of this tool in colonoscopy clinics can facilitate the detection of patients with hereditary or familial CRC.

Qualitative Comparative Analysis: A Hybrid Method for Identifying Factors Associated with Program Effectiveness.

Qualitative comparative analysis (QCA) was developed over 25 years ago to bridge the qualitative and quantitative research gap. Upon searching PubMed and the Journal of Mixed Methods Research, this review identified 30 original research studies that utilized QCA. Perceptions that QCA is complex and provides few relative advantages over other methods may be limiting QCA adoption. Thus, to overcome these perceptions, this article demonstrates how to perform QCA using data from fifteen institutions that implemented universal tumor screening (UTS) programs to identify patients at high risk for hereditary colorectal cancer. In this example, QCA revealed a combination of conditions unique to effective UTS programs. Results informed additional research and provided a model for improving patient follow-through after a positive screen.

Value of Genetic Testing for Hereditary Colorectal Cancer in a Probability-Based US Online Sample.

. While choices about genetic testing are increasingly common for patients and families, and public opinion surveys suggest public interest in genomics, it is not known how adults from the general population value genetic testing for heritable conditions. We sought to understand in a US sample the relative value of the characteristics of genetic tests to identify risk of hereditary colorectal cancer, among the first genomic applications with evidence to support its translation to clinical settings. . A Web-enabled choice-format conjoint survey was conducted with adults age 50 years and older from a probability-based US panel. Participants were asked to make a series of choices between 2 hypothetical blood tests that differed in risk of false-negative test, privacy, and cost. Random parameters logit models were used to estimate preferences, the dollar value of genetic information, and intent to have genetic testing. . A total of 355 individuals completed choice-format questions. Cost and privacy were more highly valued than reducing the chance of a false-negative result. Most (97% [95% confidence interval (CI)], 95%-99%) would have genetic testing to reduce the risk of dying of colorectal cancer in the best scenario (no false negatives, results disclosed to primary care physician). Only 41% (95% CI, 25%-57%) would have genetic testing in the worst case (20% false negatives, results disclosed to insurance company). . Given the characteristics and levels included in the choice, if false-negative test results are unlikely and results are shared with a primary care physician, the majority would have genetic testing. As genomic services become widely available, primary care professionals will need to be increasingly knowledgeable about genetic testing decisions.