Genetic Counseling in Hereditary Non-Polyposis Colorectal Cancer

Genetic counseling is a medical process aimed at providing information about disease risks for hereditary conditions. For adult-onset diseases, such as cancer, the main purpose consists in formulating probability estimates of disease appearance, along with details on preventive or follow-up measures. The process of genetic counseling has been substantially modified by the availability of molecular tests to identify mutant gene carriers. So far, 16 autosomal dominant genes associated with cancer susceptibility have been cloned. Four of these, which encode for components of the DNA mismatch repair machinery, have been implicated in hereditary non-polyposis colorectal cancer, one of the most common hereditary cancer syndromes. Genetic counseling and testing in hereditary non-polyposis colorectal cancer is associated with several problems that are common to other hereditary conditions (psychologic consequences, confidentiality, genetic “discrimination”, testing of minors, prenatal diagnosis) and peculiar to the specific condition (incomplete penetrance, genotypic and phenotypic heterogeneity, limits of currently available tests). For such reasons, genetic testing should be performed in qualified research laboratories and restricted to highly selected families. In this way, pilot studies, involving both clinicians and researchers, can be undertaken with the aim of providing comprehensive results, potentially applicable to other cancer-predisposing conditions.

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TUMOUR PATHOLOGY PREDICTS MICROSATELLITE INSTABILITY IN A POPULATION-BASED SERIES OF COLORECTAL CANCER CASES

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4807 ◽

2008 ◽

Vol 31 (4) ◽

pp. 12

Author(s):

A J Hyde ◽

D Fontaine ◽

R C Green ◽

M Simms ◽

P S Parfrey ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Population Based ◽

Pathological Features ◽

Predictive Tool ◽

Entire Cohort ◽

Dna Mismatch ◽

Bethesda Guidelines ◽

Revised Bethesda Guidelines

Background: Lynch Syndrome is an autosomal dominant trait that accounts forapproximately 3% of all cases of colorectal cancer (CRC). It is caused by mutations in DNA mismatch repair (MMR) genes, most commonly MLH1 or MSH2. These MMR defects cause high levels of microsatellite instability (MSI-H) in the tumours. MSI testing of all CRCs to identify potential Lynch Syndrome cases is not practical, so the Bethesda Guidelines, which use clinical and pathological features, were created to identify those tumours most likely to be MSI-H^1. In 2007 Jenkins et. al. created MsPath, a tool based on the pathological features described in the rarely used 3^rd Bethesda criterion, to improve prediction of MSI-H tumours among CRC cases diagnosed before age 60 years^2. Methods: We collected a population-based cohort of 716 CRC cases diagnosed before age 75 years in Newfoundland. For each of these cases we collected family history, performed MSI analysis, and scored a number of pathological features for the purpose of evaluating the accuracy of the Bethesda Criteria and MsPath at predicting MSI-H tumours. Results: Our work validates the MsPath tool in the Newfoundland population for the same age group used to create the tool. We found it identified MSI-H cases with a sensitivity of 95% and specificity of 35% in our population of CRCcases diagnosed before age 60 years (n=290). We also tested this tool on our older population of CRCcases, diagnosed at ages 60 to 74 years (n=426). We found it to be at least as predictive in this population,with a sensitivity of 95% and a specificity of 42%. We then used our entire cohort (N=716) to compare MsPath with the other Bethesda criteria.Bethesda criteria 1, 2, 4 and 5 together predicted MSI-H cases with a sensitivity of 67% and a specificity of 51%. MsPath was better at identifying these cases, with a sensitivity of 95% and a specificity of 39%. Conclusions: We conclude that MsPath can be extended to include patients diagnosed with CRC before age 75 years. As well, we have found that MsPath is a better predictive tool than the Revised Bethesda Guidelines for identifying MSI-H cases within a population-based setting of colorectal cancer. References: 1. Umar, A. et. al. J Natl Cancer Inst 2004;96:261-8 2.Jenkins, M.A. et. al. Gastroenterology 2007;133:48-56

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Genetic Counseling for Breast Cancer Susceptibility in African American Women

10.21236/ada475548 ◽

2007 ◽

Author(s):

Chanita Hughes

Keyword(s):

Breast Cancer ◽

African American ◽

Genetic Counseling ◽

African American Women ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

American Women

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Complex Interplay of CYP1A1 Genetic Polymorphism on Colorectal Cancer Susceptibility

Bulletin of Egyptian Society for Physiological Sciences ◽

10.21608/besps.2011.36145 ◽

2011 ◽

Vol 31 (2) ◽

pp. 251-261

Author(s):

Reem Jan ◽

Mariam Yacoub ◽

Mohamed Sokkar

Keyword(s):

Colorectal Cancer ◽

Genetic Polymorphism ◽

Cancer Susceptibility ◽

Complex Interplay

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Oncogenomics and CYP450 Implications in Personalized Cancer Therapy

Current Pharmacogenomics and Personalized Medicine ◽

10.2174/1875692117999200517122652 ◽

2020 ◽

Vol 17 (2) ◽

pp. 104-113

Author(s):

G.K. Udayaraja ◽

I. Arnold Emerson

Keyword(s):

Cytochrome P450 ◽

Cancer Treatment ◽

Cancer Susceptibility ◽

Mutant Gene ◽

Genome Project ◽

Interdisciplinary Field ◽

Precision Therapy ◽

Personalized Cancer Therapy ◽

Personalized Cancer ◽

Genetic Events

Background: The Human Genome Project has unleashed the power of genomics in clinical practice as a choice of individualized therapy, particularly in cancer treatment. Pharmacogenomics is an interdisciplinary field of genomics that deals with drug response, based on individual genetic makeup. Objective: The main genetic events associated with carcinogenesis activate oncogenes or inactivate tumor-suppressor genes. Therefore, drugs should be specific to inactivate or regulate these mutant genes and their protein products for effective cancer treatment. In this review, we summarize how polymedication decisions in cancer treatments based on the evaluation of cytochrome P450 (CYP450) polymorphisms are applied for pharmacogenetic assessment of anticancer therapy outcomes. Results: However, multiple genetic events linked, inactivating a single mutant gene product, may be insufficient to inhibit tumor progress. Thus, genomics and pharmacogenetics directly influence a patient’s response and aid in guiding clinicians to select the safest and most effective combination of medications for a cancer patient from the initial prescription. Conclusion: This review outlines the roles of oncogenes, the importance of cytochrome P450 (CYP450) in cancer susceptibility, and its impact on drug metabolism, proposing combined approaches to achieve precision therapy.

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Comparing models of delivery for cancer genetics services among patients receiving primary care who meet criteria for genetic evaluation in two healthcare systems: BRIDGE randomized controlled trial

BMC Health Services Research ◽

10.1186/s12913-021-06489-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Kimberly A. Kaphingst ◽

Wendy Kohlmann ◽

Rachelle Lorenz Chambers ◽

Melody S. Goodman ◽

Richard Bradshaw ◽

...

Keyword(s):

Primary Care ◽

Genetic Counseling ◽

Cancer Susceptibility ◽

Cancer Genetics ◽

Controlled Trial ◽

Standard Of Care ◽

Healthcare Systems ◽

Genetic Services ◽

Inherited Cancer ◽

Services Delivery

Abstract Background Advances in genetics and sequencing technologies are enabling the identification of more individuals with inherited cancer susceptibility who could benefit from tailored screening and prevention recommendations. While cancer family history information is used in primary care settings to identify unaffected patients who could benefit from a cancer genetics evaluation, this information is underutilized. System-level population health management strategies are needed to assist health care systems in identifying patients who may benefit from genetic services. In addition, because of the limited number of trained genetics specialists and increasing patient volume, the development of innovative and sustainable approaches to delivering cancer genetic services is essential. Methods We are conducting a randomized controlled trial, entitled Broadening the Reach, Impact, and Delivery of Genetic Services (BRIDGE), to address these needs. The trial is comparing uptake of genetic counseling, uptake of genetic testing, and patient adherence to management recommendations for automated, patient-directed versus enhanced standard of care cancer genetics services delivery models. An algorithm-based system that utilizes structured cancer family history data available in the electronic health record (EHR) is used to identify unaffected patients who receive primary care at the study sites and meet current guidelines for cancer genetic testing. We are enrolling eligible patients at two healthcare systems (University of Utah Health and New York University Langone Health) through outreach to a randomly selected sample of 2780 eligible patients in the two sites, with 1:1 randomization to the genetic services delivery arms within sites. Study outcomes are assessed through genetics clinic records, EHR, and two follow-up questionnaires at 4 weeks and 12 months after last genetic counseling contactpre-test genetic counseling. Discussion BRIDGE is being conducted in two healthcare systems with different clinical structures and patient populations. Innovative aspects of the trial include a randomized comparison of a chatbot-based genetic services delivery model to standard of care, as well as identification of at-risk individuals through a sustainable EHR-based system. The findings from the BRIDGE trial will advance the state of the science in identification of unaffected patients with inherited cancer susceptibility and delivery of genetic services to those patients. Trial registration BRIDGE is registered as NCT03985852. The trial was registered on June 6, 2019 at clinicaltrials.gov.

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