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Sapna Syngal - One of the best experts on this subject based on the ideXlab platform.
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universal tumor screening for lynch syndrome assessment of the perspectives of patients with Colorectal Cancer regarding benefits and barriers
Cancer, 2015Co-Authors: Jessica Ezzell Hunter, Sapna Syngal, Jamilyn Zepp, Mari J Gilmore, James V Davis, Elizabeth J Esterberg, Kristin R Muessig, Susan K Peterson, Louise S Acheson, Georgia L WiesnerAbstract:BACKGROUND Universal tumor screening for Lynch syndrome, the most common form of Hereditary Colorectal Cancer (CRC), has been recommended among all patients newly diagnosed with CRC. However, there is limited literature regarding patient perspectives of tumor screening for Lynch syndrome among patients with CRC who are not selected for screening based on family history criteria. METHODS A total of 145 patients aged 39 to 87 years were administered surveys assessing perceived risk, patient perspectives, and potential benefits of and barriers to tumor screening for Lynch syndrome. Associations between patient-specific and Cancer-specific factors and survey responses were analyzed. RESULTS The majority of participants perceived their risk of developing Lynch syndrome as being low, with 9 participants (6.2%) anticipating an abnormal screening result. However, most participants endorsed the potential benefits of screening for themselves and their families, with 84.8% endorsing ≥6 benefits and 50.3% endorsing all 8 benefits. Participants also endorsed few potential barriers to screening, with 89.4% endorsing ≤4 of 9 potential barriers. A common barrier was worry about the cost of additional testing and surveillance, which was endorsed by 54.5% of participants. The level of distress associated with tumor screening for Lynch syndrome, which was very low, was not associated with age or CRC stage. CONCLUSIONS The results of the current study indicate that patients with CRC overall have a positive attitude toward tumor screening for Lynch syndrome, endorse the benefits of screening, and experience low levels of distress. These findings provide insight into patient attitudes toward tumor screening for Lynch syndrome among unselected patients with CRC to inform educational approaches that assist in patient decision-making and guide the successful implementation of screening programs. Cancer 2015;121:3281–3289. © 2015 American Cancer Society.
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Attitudes toward childbearing and prenatal testing in individuals undergoing genetic testing for Lynch Syndrome
Familial Cancer, 2011Co-Authors: Akriti Dewanwala, Sapna Syngal, Anu Chittenden, Margery Rosenblatt, Rowena Mercado, Judy E. Garber, Elena M StoffelAbstract:To examine attitudes toward childbearing and prenatal genetic testing among individuals at risk for Lynch Syndrome (LS), the most common type of Hereditary Colorectal Cancer. Individuals undergoing clinical genetic testing for mismatch repair (MMR) gene mutations completed written questionnaires before and after testing. 161 of 192 (84%) eligible individuals participated in the study. Mean age was 46 years (range 20–75), 71% were female, 53% had a personal diagnosis of Cancer, and 68% had children. Eighty percent worried about their children’s risk for developing Cancer; however only 9% reported their decision to have children was affected by their family history of Cancer. When asked whether providing prenatal testing to carriers of MMR gene mutations was ethical, 66% (86/130) of respondents agreed/strongly agreed, 25% (32) were neutral and 9% (12) disagreed/strongly disagreed. Of 48 individuals planning to have children in the future, 57% (27) intended to have children regardless of their genetic test result. If found to carry a MMR gene mutation that confirmed LS, 42% (20) would consider prenatal testing for a future pregnancy and 20% (7/35) of women would consider having children earlier in order to have prophylactic surgery to reduce their risk for gynecologic Cancers. Individuals undergoing genetic testing for LS may utilize test results to make reproductive decisions. Clinicians should be prepared to discuss options of reproductive genetic technologies during counseling of LS patients of childbearing age.
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calculation of risk of Colorectal and endometrial Cancer among patients with lynch syndrome
Gastroenterology, 2009Co-Authors: Elena M Stoffel, Bhramar Mukherjee, Victoria M Raymond, Nabihah Tayob, Fay Kastrinos, Jennifer Sparr, Fei Wang, Prathap Bandipalliam, Sapna SyngalAbstract:Background & Aims Lynch syndrome is the most common Hereditary Colorectal Cancer (CRC) syndrome. Some previous estimates of lifetime risk for CRC and endometrial Cancer (EC) did not control for ascertainment and were susceptible to bias toward overestimated risk. Methods We studied 147 families with mismatch repair gene mutations (55 MLH1 , 81 MSH2 , and 11 MSH6 ) identified at 2 US Cancer genetics clinics. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general population using modified segregation analysis. The likelihood for each pedigree was conditioned on the proband and first-degree relatives affected with CRC to reduce ascertainment bias and overestimation of penetrance. Results We analyzed 628 cases of CRC, diagnosed at the median ages of 42 and 47 years for men and women, respectively. The cumulative risk of CRC was 66.08% (95% confidence interval [CI], 59.47%–76.17%) for men and 42.71% (95% CI, 36.57%–52.83%) for women, with overall HRs of 148.4 and 51.1, respectively. CRC risk was highest for males with mutations in MLH1 . There were 155 cases of EC, diagnosed at a median age of 47.5 years. The cumulative risk of EC was 39.39% (95% CI, 30.78%–46.94%) with an overall HR of 39.0 (95% CI, 30.4–50.2). For women, the cumulative risk of CRC or EC was 73.42% (95% CI, 63.76%–80.54%). Conclusions Lifetime risks of CRC and EC in mismatch repair gene mutation carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized Cancer surveillance is necessary.
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prevalence of early onset Colorectal Cancer in 397 patients with classic li fraumeni syndrome
Gastroenterology, 2006Co-Authors: Patricia Wong, Sapna Syngal, Sigitas Verselis, Judy Garber, Katherine A Schneider, Lisa Digianni, David H StockwellAbstract:Background & Aims: Hereditary Colorectal Cancer is associated most commonly with the Hereditary nonpolyposis Colorectal Cancer or familial adenomatous polyposis syndromes. We investigated the prevalence of early onset Colorectal Cancer and the frequency of p53 germline mutations in 64 families from a Li–Fraumeni syndrome (LFS) registry. Methods: Patients with documented Colorectal Cancer and a diagnosis at or before age 50 were included. P53 analyses were performed through germline mutational analyses using standard molecular techniques. Results: Among the 397 patients and 64 families in the classic LFS registry, a total of 11 patients (2.8%) from 10 different families (15.6%) met criteria for classic LFS and had documented Colorectal Cancer at less than 50 years of age. The mean age at diagnosis in this group was 33 years and of these patients 4 developed Colorectal Cancer before age 21 (ages, 9, 11, 15, and 20 y). All families that were tested for p53 mutations (8 of 10) had evidence of germline mutations by sequence analysis; therefore, 12.5% of the total number of families in the registry had Colorectal Cancer at age less than 50 years and a documented germline p53 mutation. Mutations primarily were missense or nonsense and were located between exons 4–10. Conclusions: LFS patients with germline p53 mutations may have an increased susceptibility to Colorectal Cancer and present up to several decades earlier than the general population. LFS should be considered when a young patient presents with Colorectal Cancer.
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Hereditary Colorectal Cancer syndromes
Cancer Causes & Control, 2005Co-Authors: Sapna Syngal, Lisa L StrateAbstract:The purpose of this article is to review the genetic Colorectal Cancer syndromes including Hereditary Nonpolyposis Colorectal Cancer (HNPCC), Family Polyposis (FAP) and the hamartomatous polyposis syndromes. HNPCC is the most common of the Hereditary Colorectal Cancer syndromes, and is the result of defects in the mismatch repair genes. Individuals with HNPCC have an 80 lifetime risk of Colorectal Cancer, and in females a 30–50% risk of endometrial Cancer, as well as predisposition for a number of other malignancies. Early screening and interval surveillance for Colorectal and endometrial Cancer are recommended. In FAP, mutations in the Adenomatous Polyposis Coli (APC) tumor suppressor gene give rise to hundreds to thousands of Colorectal polyps, some of which will inevitably progress to Cancer. Early diagnosis and timely prophylactic colectomy prevent this outcome. Chemoprevention with nonsteroidal anti-inflammatory drugs can reduce adenoma number and size in FAP, but the effect is incomplete. In addtion, surveillance for upper gastrointestinal tract malignancies is necessary. Attenuated forms of FAP may be the result of mutations in the APC gene, or in the recently described MYH gene. Mutations in the MYH gene should be considered in individuals with multiple adenomas whose family history does not reflect an autosomal dominant pattern of inheritance. The hamartomatous polyposis syndromes are uncommon but distinctive disorders in which multiple hamartomatous polyps develop at a young age. Our understanding of the genetic basis of these disorders is improving, and a predisposition for gastrointestinal and other malignancies has recently been recognized. This article summarizes the genetics, clinical manifestations and clinical management of each of these syndromes with an emphasis on genetic testing and prevention.
Elena M Stoffel - One of the best experts on this subject based on the ideXlab platform.
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genetics and genetic testing in Hereditary Colorectal Cancer
Gastroenterology, 2015Co-Authors: Elena M Stoffel, Richard C BolandAbstract:Colorectal Cancer (CRC) remains the third most common Cancer affecting men and women in the United States. Approximately one-third of CRCs are diagnosed in individuals who have family members also affected with the disease. Although the vast majority of Colorectal neoplasms develop as a consequence of somatic genomic alterations arising in individual cells, approximately 5% of all CRCs arise in the setting of germline mutations in genes involved in key cellular processes. To date, multiple genes have been implicated in single-gene Hereditary Cancer syndromes, many of which are associated with increased risk for CRC, as well as other tumor types. This review outlines the clinical, pathologic, and genetic features of the Hereditary Cancer syndromes known to be associated with increased risk for CRC and delineates strategies for implementing genetic risk assessments in clinical settings.
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Hereditary Colorectal Cancer syndromes american society of clinical oncology clinical practice guideline endorsement of the familial risk Colorectal Cancer european society for medical oncology clinical practice guidelines
Journal of Clinical Oncology, 2015Co-Authors: Elena M Stoffel, Pamela B Mangu, Stephen B Gruber, Stanley R Hamilton, Matthew F Kalady, Karen H Lu, Nancy Roach, Paul J LimburgAbstract:Purpose To provide recommendations on prevention, screening, genetics, treatment, and management for people at risk for Hereditary Colorectal Cancer (CRC) syndromes. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods The Familial Risk–Colorectal Cancer: European Society for Medical Oncology Clinical Practice Guideline published in 2013 on behalf of the European Society for Medical Oncology (ESMO) Guidelines Working Group in Annals of Oncology was reviewed for developmental rigor by methodologists, with content and recommendations reviewed by an ASCO endorsement panel. Results The ASCO endorsement panel determined that the recommendations of the ESMO guidelines are clear, thorough, and based on the most relevant scientific evidence. The ASCO panel endorsed the ESMO guidelines and added a few qualifying statements. Recommendations Approximately 5% to 6% of patient...
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Attitudes toward childbearing and prenatal testing in individuals undergoing genetic testing for Lynch Syndrome
Familial Cancer, 2011Co-Authors: Akriti Dewanwala, Sapna Syngal, Anu Chittenden, Margery Rosenblatt, Rowena Mercado, Judy E. Garber, Elena M StoffelAbstract:To examine attitudes toward childbearing and prenatal genetic testing among individuals at risk for Lynch Syndrome (LS), the most common type of Hereditary Colorectal Cancer. Individuals undergoing clinical genetic testing for mismatch repair (MMR) gene mutations completed written questionnaires before and after testing. 161 of 192 (84%) eligible individuals participated in the study. Mean age was 46 years (range 20–75), 71% were female, 53% had a personal diagnosis of Cancer, and 68% had children. Eighty percent worried about their children’s risk for developing Cancer; however only 9% reported their decision to have children was affected by their family history of Cancer. When asked whether providing prenatal testing to carriers of MMR gene mutations was ethical, 66% (86/130) of respondents agreed/strongly agreed, 25% (32) were neutral and 9% (12) disagreed/strongly disagreed. Of 48 individuals planning to have children in the future, 57% (27) intended to have children regardless of their genetic test result. If found to carry a MMR gene mutation that confirmed LS, 42% (20) would consider prenatal testing for a future pregnancy and 20% (7/35) of women would consider having children earlier in order to have prophylactic surgery to reduce their risk for gynecologic Cancers. Individuals undergoing genetic testing for LS may utilize test results to make reproductive decisions. Clinicians should be prepared to discuss options of reproductive genetic technologies during counseling of LS patients of childbearing age.
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calculation of risk of Colorectal and endometrial Cancer among patients with lynch syndrome
Gastroenterology, 2009Co-Authors: Elena M Stoffel, Bhramar Mukherjee, Victoria M Raymond, Nabihah Tayob, Fay Kastrinos, Jennifer Sparr, Fei Wang, Prathap Bandipalliam, Sapna SyngalAbstract:Background & Aims Lynch syndrome is the most common Hereditary Colorectal Cancer (CRC) syndrome. Some previous estimates of lifetime risk for CRC and endometrial Cancer (EC) did not control for ascertainment and were susceptible to bias toward overestimated risk. Methods We studied 147 families with mismatch repair gene mutations (55 MLH1 , 81 MSH2 , and 11 MSH6 ) identified at 2 US Cancer genetics clinics. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general population using modified segregation analysis. The likelihood for each pedigree was conditioned on the proband and first-degree relatives affected with CRC to reduce ascertainment bias and overestimation of penetrance. Results We analyzed 628 cases of CRC, diagnosed at the median ages of 42 and 47 years for men and women, respectively. The cumulative risk of CRC was 66.08% (95% confidence interval [CI], 59.47%–76.17%) for men and 42.71% (95% CI, 36.57%–52.83%) for women, with overall HRs of 148.4 and 51.1, respectively. CRC risk was highest for males with mutations in MLH1 . There were 155 cases of EC, diagnosed at a median age of 47.5 years. The cumulative risk of EC was 39.39% (95% CI, 30.78%–46.94%) with an overall HR of 39.0 (95% CI, 30.4–50.2). For women, the cumulative risk of CRC or EC was 73.42% (95% CI, 63.76%–80.54%). Conclusions Lifetime risks of CRC and EC in mismatch repair gene mutation carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized Cancer surveillance is necessary.
Paivi Peltomaki - One of the best experts on this subject based on the ideXlab platform.
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development of Colorectal tumors in colonoscopic surveillance in lynch syndrome
Gastroenterology, 2007Co-Authors: Jukkapekka Mecklin, Paivi Peltomaki, Lauri A Aaltonen, Markku Aarnio, Esa Laara, Matti V Kairaluoma, Kirsi Pylvanainen, Heikki JarvinenAbstract:Background & Aims: Mutation carriers in Lynch syndrome families have a high risk for developing Colorectal Cancer during their lifetime. This study was designed to assess the cumulative risk for the development of Colorectal adenoma or carcinoma in prospective colonoscopic surveillance. Methods: Data from the Finnish Hereditary Colorectal Cancer Registry electronic database on 420 Lynch syndrome mutation carriers without previous Colorectal tumors were reviewed. Between March 1982 and May 2005 the mutation carriers underwent a total of 1252 colonoscopies. The total follow-up time was 3150 years (mean, 6.7 y/patient). Results: The cumulative risk of adenoma by age 60 was estimated as 68% (95% confidence interval [CI], 50%–80%) in men and 48% (95% CI, 29%–62%) in women. The estimated cumulative risk up to age 60 years for the development of Cancer found as a result of surveillance at an interval of 2–3 years was 35% (95% CI, 16%–49%) in men and 22% (95% CI, 7%–34%) in women. Half of the adenomas were located proximal to the splenic flexure. Extracolonic Cancer was diagnosed in 73 patients (18%). Conclusions: Adenoma would appear to be the most important lesion preceding Cancer formation in Lynch syndrome and removal of adenomas decreases the risk for Colorectal Cancer (CRC). The Finnish surveillance protocol of colonoscopies at 2- to 3-year intervals facilitates patient adherence but includes an essential risk for CRC up to 60 years of age, but without CRC-related mortality when the surveillance instructions are followed.
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lynch syndrome Hereditary nonpolyposis Colorectal Cancer diagnostics
Journal of the National Cancer Institute, 2007Co-Authors: Kristina Lagerstedt Robinson, Mark Clendenning, Tao Liu, Jana Vandrovcova, Britta Halvarsson, Thierry Frebourg, Nickolas Papadopoulos, Kenneth W Kinzler, Bert Vogelstein, Paivi PeltomakiAbstract:Background Preventive programs for individuals who have high lifetime risks of Colorectal Cancer may reduce disease morbidity and mortality. Thus, it is important to identify the factors that are associated with Hereditary Colorectal Cancer and to monitor the effects of tailored surveillance. In particular, patients with Lynch syndrome, Hereditary nonpolyposis Colorectal Cancer (HNPCC), have an increased risk to develop Colorectal Cancer at an early age. The syndrome is explained by germline mutations in DNA mismatch repair (MMR) genes, and there is a need for diagnostic tools to preselect patients for genetic testing to diagnose those with HNPCC. Methods Patients (n = 112) from 285 families who were counseled between 1990 and 2005 at a clinic for patients at high risk for HNPCC were selected for screening to detect mutations in MMR genes MLH1, MSH2, MSH6, and PMS2 based on family history, microsatellite instability (MSI), and immunohistochemical analysis of MMR protein expression. Tumors were also screened for BRAF V600E mutations; patients with the mutation were considered as non-HNPCC. Results Among the 112 patients who were selected for screening, 69 had germline MMR mutations (58 pathogenic and 11 of unknown biologic relevance). Sixteen of the 69 mutations (23%) were missense mutations. Among patients with MSI-positive tumors, pathogenic MMR mutations were found in 38 of 43 (88%) of patients in families who met Amsterdam criteria and in 13 of 22 (59%) of patients in families who did not. Among patients with MSI-negative tumors, pathogenic MMR mutations were found in 5 of 17 (29%) of families meeting Amsterdam criteria and in 1 of 30 (3%) of non-Amsterdam families with one patient younger than age 50 years. In three patients with MSI-negative tumors who had pathogenic mutations in MLH1 or MSH6, immunohistochemistry showed loss of the mutated protein. Conclusion Our findings suggest that missense MMR gene mutations are common in HNPCC and that germline MMR mutations are also found in patients with IVISI-negative tumors. (Less)
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mutations predisposing to Hereditary nonpolyposis Colorectal Cancer
Advances in Cancer Research, 1997Co-Authors: Paivi Peltomaki, De La Chapelle AAbstract:Publisher Summary This chapter describes recent advances in the study of DNA mismatch repair (MMR) genes, with the emphasis on mutations predisposing to Hereditary nonpolyposis Colorectal Cancer (HNPCC), their phenotypic effects, and scientific and clinical implications of these findings. The main forms of Hereditary Colorectal Cancer (CRC) are familial adenomatous polyposis (FAP) and HNPCC. The diagnosis of HNPCC was mainly based on family history. HNPCC kindreds are commonly defined as those in which at least three relatives in two generations have CRC, with one of the relatives being a first-degree relative to the other two and, furthermore, one relative being diagnosed at less than 50 years of age. A definitive diagnosis of HNPCC is based on gene analyses. The normal function of the proteins encoded by these genes is to participate in DNA mismatch repair (MMR). The HNPCC syndrome is sometimes divided into Lynch syndromes I and II based on the absence or presence, respectively, of extracolonic Cancer. CRC in HNPCC develop via a preCancerous growth, adenoma. A systematic search through the entire genome using highly informative short tandem repeat (microsatellite) markers resulted in the identification of the first HNPCC susceptibility locus on chromosome 2p by linkage analysis.
Patrick M Lynch - One of the best experts on this subject based on the ideXlab platform.
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combination of sulindac and bexarotene for prevention of intestinal carcinogenesis in familial adenomatous polyposis
Cancer Prevention Research, 2021Co-Authors: Charles M Bowen, Lewins Walter, Ester Borras, Zuhal Ozcan, Kyle Chang, Prashant V Bommi, Melissa W Taggart, Selvi Thirumurthi, Patrick M Lynch, Laura ReyesuribeAbstract:Familial Adenomatous Polyposis (FAP) is a Hereditary Colorectal Cancer (CRC) syndrome that results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. Non-steroidal anti-inflammatory drugs (NSAIDs) have reduced polyp burden in FAP patients and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent CRC development. Whole transcriptomic analysis of Colorectal polyps and matched normal mucosa in a cohort of FAP patients to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored microRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 µM) and bexarotene (40 µM) was observed in FAP colonic organoid systems with primary targeting of polyp tissue compared to normal mucosa. This combination translated into a significant reduction in polyp development in ApcMin/+ and ApcLoxP/+-Cdx2 mice. Lastly, the reported data suggests microRNA-21 could serve as a predictive serum biomarker for polyposis burden in FAP patients. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for FAP patients.
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Hereditary Colorectal Cancer syndromes molecular genetics genetic counseling diagnosis and management
Familial Cancer, 2008Co-Authors: Henry T Lynch, Patrick M Lynch, Jane F Lynch, Thomas M AttardAbstract:Hereditary forms of Colorectal Cancer, as is the case with virtually all forms of Hereditary Cancer, show extensive phenotypic and genotypic heterogeneity, a phenomenon discussed throughout this special issue of Familial Cancer. Clearly, the family physician, oncology specialist, genetic counselor, and Cancer geneticist must know fully the complexity of Hereditary Cancer syndromes, their differential diagnosis, in order to establish a diagnosis, direct highly-targeted surveillance and management, and then be able to communicate effectively with the molecular geneticist so that an at-risk patient’s DNA can be tested in accord with the syndrome of concern. Thus, a family with features of the Lynch syndrome will merit microsatellite instability testing, consideration for immunohistochemistry evaluation, and mismatch repair gene testing, while, in contrast, a patient with FAP will require APC testing. However, other germline mutations, yet to be identified, may be important should testing for these mutations prove to be absent and, therein, unrewarding to the patient. Nevertheless, our position is that if the patient’s family history is consistent with one of these syndromes, but a mutation is not found in the family, we still recommend the same surveillance and management strategies for patients from families with an established Cancer-causing germline mutation. Our purpose in this paper is to provide a concise coverage of the major Hereditary Colorectal Cancer syndromes, to discuss genetic counseling, molecular genetic evaluation, highly targeted surveillance and management, so that Cancer control can be maximized for these high Hereditary Cancer risk patients.
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who should be sent for genetic testing in Hereditary Colorectal Cancer syndromes
Journal of Clinical Oncology, 2007Co-Authors: Henry T Lynch, Jane F Lynch, Richard C Boland, Miguel A Rodriguezbigas, Christopher I Amos, Patrick M LynchAbstract:Genetic testing is being adopted increasingly to identify individuals with germline mutations that predispose to Hereditary Colorectal Cancer syndromes. Deciding who to test and for which syndrome is of concern to members of the GI oncology community, molecular geneticists, and genetic counselors. The purpose of this review is to help provide guidelines for testing, given that the results influence syndrome diagnosis and clinical management. Although family history may determine whether testing is appropriate and may direct testing to the most informative family member, evolving clinicopathologic features can identify individual patients who warrant testing. Thus, although the usual absence of clinical premonitory signs in Hereditary nonpolyposis Colorectal Cancer (or Lynch syndrome) adds difficulty to its diagnosis, use of the Amsterdam Criteria and Bethesda Guidelines can prove helpful. In contrast, premonitory stigmata such as pigmentations in Peutz-Jeghers syndrome and the phenotypic features of familial adenomatous polyposis aid significantly in syndrome diagnosis. We conclude that the physician's role in advising DNA testing is no small matter, given that a Hereditary Cancer syndrome's sequelae may be far reaching. Genetic counselors may be extremely helpful to the practicing gastroenterologist, oncologist, or surgeon; when more specialized knowledge is called for, referral can be made to a medical geneticist and/or a medical genetics clinic.
Richard C Boland - One of the best experts on this subject based on the ideXlab platform.
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genetics and genetic testing in Hereditary Colorectal Cancer
Gastroenterology, 2015Co-Authors: Elena M Stoffel, Richard C BolandAbstract:Colorectal Cancer (CRC) remains the third most common Cancer affecting men and women in the United States. Approximately one-third of CRCs are diagnosed in individuals who have family members also affected with the disease. Although the vast majority of Colorectal neoplasms develop as a consequence of somatic genomic alterations arising in individual cells, approximately 5% of all CRCs arise in the setting of germline mutations in genes involved in key cellular processes. To date, multiple genes have been implicated in single-gene Hereditary Cancer syndromes, many of which are associated with increased risk for CRC, as well as other tumor types. This review outlines the clinical, pathologic, and genetic features of the Hereditary Cancer syndromes known to be associated with increased risk for CRC and delineates strategies for implementing genetic risk assessments in clinical settings.
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inversion of exons 1 7 of the msh2 gene is a frequent cause of unexplained lynch syndrome in one local population
Familial Cancer, 2014Co-Authors: Jennifer Rhees, Mildred Arnold, Richard C BolandAbstract:Germline mutations in DNA mismatch repair (MMR) genes, such as MSH2, cause Lynch syndrome, an autosomal dominant predisposition to Colorectal as well as other Cancers. Our research clinic focuses on Hereditary Colorectal Cancer, and over the past 9 years we have identified germline mutations in DNA MMR genes in 101 patients using commercial genetic reference laboratories. We also collected samples from twelve patients with absent MSH2 protein expression and microsatellite instability in tumor tissue, with a family history suggestive of Lynch syndrome, but negative germline test results. The most likely explanation for this set of results is that the germline testing did not detect true germline mutations in these patients. Two of our patients with failed commercial testing were later found to have deletions in the 3′ region of EPCAM, the gene just upstream of MSH2, but no explanation could be found for inactivation of MSH2 in the other ten patients. We used allelic dropout in long PCR to look for potential regions of rearrangement in the MSH2 gene. This method detected a potential rearrangement breakpoint in the same region of MSH2 where one breakpoint of a 10 Mb inversion was reported previously. We tested these ten patients for this inversion. Six of 10 patients had the inversion, indicating the importance of including testing for this inversion in patients suspected of having MSH2-type Lynch syndrome in our population. Additionally, this method could be further developed to look for inversions in other genes where current methods of testing fail to find a causative mutation.
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who should be sent for genetic testing in Hereditary Colorectal Cancer syndromes
Journal of Clinical Oncology, 2007Co-Authors: Henry T Lynch, Jane F Lynch, Richard C Boland, Miguel A Rodriguezbigas, Christopher I Amos, Patrick M LynchAbstract:Genetic testing is being adopted increasingly to identify individuals with germline mutations that predispose to Hereditary Colorectal Cancer syndromes. Deciding who to test and for which syndrome is of concern to members of the GI oncology community, molecular geneticists, and genetic counselors. The purpose of this review is to help provide guidelines for testing, given that the results influence syndrome diagnosis and clinical management. Although family history may determine whether testing is appropriate and may direct testing to the most informative family member, evolving clinicopathologic features can identify individual patients who warrant testing. Thus, although the usual absence of clinical premonitory signs in Hereditary nonpolyposis Colorectal Cancer (or Lynch syndrome) adds difficulty to its diagnosis, use of the Amsterdam Criteria and Bethesda Guidelines can prove helpful. In contrast, premonitory stigmata such as pigmentations in Peutz-Jeghers syndrome and the phenotypic features of familial adenomatous polyposis aid significantly in syndrome diagnosis. We conclude that the physician's role in advising DNA testing is no small matter, given that a Hereditary Cancer syndrome's sequelae may be far reaching. Genetic counselors may be extremely helpful to the practicing gastroenterologist, oncologist, or surgeon; when more specialized knowledge is called for, referral can be made to a medical geneticist and/or a medical genetics clinic.