Genetics

Hereditary non-polyposis colorectal cancer (HNPCC) and its genetic basis

Hereditary non-polyposis colorectal cancer (HNPCC) and itsgenetic basis

Group plus “mini” individual pre-test genetic counselling sessions for hereditary cancer shorten provider time and improve patient satisfaction

Background Genetic counselling (GC) is an integral component in the care of individuals at risk for hereditary cancer predisposition syndromes (CPS). In many jurisdictions, access to timely counselling and testing is limited by financial constraints, by the shortage of genetics professionals and by...
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Background Genetic counselling (GC) is an integral component in the care of individuals at risk for hereditary cancer predisposition syndromes (CPS). In many jurisdictions, access to timely counselling and testing is limited by financial constraints, by the shortage of genetics professionals and by labor-intensive traditional models of individual pre and post-test counselling. There is a need for further research regarding alternate methods of GC service delivery and implementation. This quality improvement project was initiated to determine if pretest group GC followed immediately by a ‘mini’ individual session, would be acceptable to patients at risk for hereditary breast and colon cancer. Methods Patients on waitlists for GC at the Provincial Medical Genetics Program in St. John’s, NL, Canada (<jats:italic>n</jats:italic> = 112), were contacted by telephone and offered the option of a group counselling session (GGC), followed by a “mini” individual session, versus (TGC) traditional private appointments. GGC sessions consisted of a cancer genetics information session given to groups of 6–20 followed by brief 20 min “mini” individual sessions with the patient and genetic specialist. TGC individual appointments provided the same cancer genetics information and counselling to one patient at a time in the classic model. All but 2 participants selected group+mini session. A de-identified confidential 12-item, Likert scale survey was distributed at the conclusion of mini-sessions to measure perceptions of GGC and satisfaction with this counselling model. Results Sixty participants completed questionnaires. The majority of participants strongly agreed that they were comfortable with the group session (58/60); the explanation of cancer genetics was clear (54/59); they understood their cancer risks (50/60); and they would recommend such a session to others (56/59). 38/53 respondents disagreed or strongly disagreed that they would prefer to wait for a traditional private appointment. All 5 participating genetic counselors reported a preference for this model. At the end of the pilot project, the waitlist for counselling/testing was reduced by 12 months. Conclusions Group pre-test genetic counselling combined with immediate “mini” individual session is strongly supported by patients and reduces wait times. Additional formal investigation of this approach in larger numbers of patients is warranted.
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Meeting abstracts from the Annual Conference “Clinical Genetics of Cancer 2022”

Psychological and health behaviour outcomes following multi-gene panel testing for hereditary breast and ovarian cancer risk: a mini-review of the literature

Introduction Knowledge of the genetic mechanisms driving hereditary breast and ovarian cancer (HBOC) has recently expanded due to advances in gene sequencing technologies. Genetic testing for HBOC risk now involves multi-gene panel testing, which includes well characterized high-pen...
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Introduction Knowledge of the genetic mechanisms driving hereditary breast and ovarian cancer (HBOC) has recently expanded due to advances in gene sequencing technologies. Genetic testing for HBOC risk now involves multi-gene panel testing, which includes well characterized high-penetrance genes (e.g. BRCA1 and BRCA2, as well as moderate- and low-penetrance genes. Certain moderate and low penetrance genes are associated with limited data to inform cancer risk estimates and clinical management recommendations, which create new sources of genetic and clinical uncertainty for patients. Purpose The aim of this review is to evaluate the psychological and health behaviour outcomes associated with multi-gene panel testing for HBOC risk. The search was developed in collaboration with an Information Specialist (Princess Margaret Cancer Centre) and conducted in the following databases: MEDLINE, EMBASE, EMCare, PsycINFO, Epub Ahead of Publication. Results Similar to the BRCA1/2 literature, individuals with a pathogenic variant (PV) reported higher levels of testing-related concerns and cancer-specific distress, as well as higher uptake of prophylactic surgery in both affected and unaffected individuals compared to those with variant of uncertain significance (VUS) or negative result. A single study demonstrated that individuals with a PV in a moderate penetrance gene reported higher rates of cancer worry, genetic testing concerns and cancer-related distress when compared to women with high penetrance PV. Analysis of cancer screening and prevention outcomes based upon gene penetrance were limited to two studies, with conflicting findings. Conclusion The findings in this review emphasize the need for studies examining psychological and health behavior outcomes associated with panel testing to include between group differences based upon both variant pathogenicity and gene penetrance. Future studies evaluating the impact of gene penetrance on patient-reported and clinical outcomes will require large samples to be powered for these analyses given that a limited number of tested individuals are found to have a PV.
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Next-generation universal hereditary cancer screening: implementation of an automated hereditary cancer screening program for patients with advanced cancer undergoing tumor sequencing in a large HMO

Variants in hereditary cancer risk genes are frequently identified following tumor-based DNA sequencing and represent an opportunity to diagnose hereditary cancer. We implemented an automated hereditary cancer screening program in a large HMO for all patients who underwent tumor-based DNA sequencing...
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Variants in hereditary cancer risk genes are frequently identified following tumor-based DNA sequencing and represent an opportunity to diagnose hereditary cancer. We implemented an automated hereditary cancer screening program in a large HMO for all patients who underwent tumor-based DNA sequencing to identify patients with hereditary cancer and determine if this approach augmented existing genetic counseling approaches driven by personal/family history criteria. Regular automated searches of a centralized tumor DNA variant database were performed for ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6, PALB2, and/or PMS2 variants, and germline hereditary cancer gene panel testing was offered to patients with tumor variants who had never undergone germline testing. Patients completing germline testing due to their tumor DNA test results were considered part of the tumor DNA safety net. Patients previously completing germline testing via traditional genetic counseling and tumor DNA safety net were compared for demographics, tumor type, presence of germline pathogenic/likely pathogenic (P/LP) variant, and whether NCCN criteria were met for hereditary cancer genetic testing. Germline P/LP variants were common in both groups. Patients who received germline testing through traditional genetic counseling were more likely to have cardinal hereditary tumors than the tumor DNA safety net group. Patients identified with hereditary cancer through traditional genetic counseling were more likely to meet NCCN personal/family history criteria for germline testing than the tumor DNA safety net group (99% versus 34%). A universal tumor DNA safety net screen is an important diagnostic strategy which augments traditional genetic counseling approaches based on personal/family history.
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Risk reduction strategies for BRCA1/2 hereditary ovarian cancer syndromes: a clinical practice guideline

Objective The purpose of this guideline is to make recommendations regarding the care of women who harbour a pathogenic or likely pathogenic variant in BRCA1 and BRCA2 Methods Draft recommendations were formulated based on evidence obtained ...
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Objective The purpose of this guideline is to make recommendations regarding the care of women who harbour a pathogenic or likely pathogenic variant in BRCA1 and BRCA2 Methods Draft recommendations were formulated based on evidence obtained through a systematic review of RCTs, comparative retrospective studies and guideline endorsement. The draft recommendations underwent an internal review by clinical and methodology experts, and an external review by clinical practitioners. Results The literature search yielded 1 guideline, 5 systematic reviews, and 15 studies that met the eligibility criteria. Conclusions In women who harbour a pathogenic or likely pathogenic variant in BRCA1 and BRCA2 screening for ovarian cancer is not recommended. Risk-reducing surgery is recommended to reduce the risk of ovarian cancer. In the absence of contraindications, premenopausal women undergoing RRSO should be offered hormone therapy until menopause. Systemic hormone replacement therapy, is not recommended for women who have had a personal history of breast cancer. RRSO should be considered for breast cancer risk reduction in women younger than 50 years. After a breast cancer diagnosis, RRSO for breast cancer mortality reduction can be considered within two years to women who harbour a pathogenic or likely pathogenic variant in BRCA1 if younger than the recommended age range for ovarian cancer risk reduction. RRSO before the age of 40 and specifically for breast cancer treatment in BRCA2 should be considered only if recommended by their breast cancer oncologist. Following RRSO, it is not recommended to do surveillance for peritoneal cancer.
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Could fumarate hydratase germline mutation in cutaneous leiomyomas predict Hereditary Leiomyoma and Renal Cell Cancer (HLRCC)?

Genetic testing for hereditary breast cancer in Poland: 1998–2022

BRCA1 and BRCA2 mutations contribute to both breast cancer and ovarian cancer worldwide. In Poland approximately 4% of patients with breast cancers and 10% of patients with ovarian cancer carry a mutation in BRCA1. The majority of mutations consist of three founder mutations. A rapid inexpensive tes...
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BRCA1 and BRCA2 mutations contribute to both breast cancer and ovarian cancer worldwide. In Poland approximately 4% of patients with breast cancers and 10% of patients with ovarian cancer carry a mutation in BRCA1. The majority of mutations consist of three founder mutations. A rapid inexpensive test for these three mutations can be used to screen all Polish adults at a reasonable cost. In the region of Pomerania of North-western Poland nearly half a million tests have been performed, in large part through engaging family doctors and providing ready access to testing through the Pomeranian Medical University. The following commentary provides a history of genetic testing for cancer in Pomerania and the current approach to facilitating access to genetic testing at the Cancer Family Clinic for all adults living in the region.
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Beyond the pill: contraception and the prevention of hereditary ovarian cancer

BRCA1 and BRCA2 mutation carriers face an elevated lifetime risk of developing ovarian cancer. Oral contraceptives have been shown to significantly decrease the risk of ovarian cancer by approximately 50% in this high-risk population. Changes in contraceptive formulations and patterns of use over ti...
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BRCA1 and BRCA2 mutation carriers face an elevated lifetime risk of developing ovarian cancer. Oral contraceptives have been shown to significantly decrease the risk of ovarian cancer by approximately 50% in this high-risk population. Changes in contraceptive formulations and patterns of use over time have introduced lower hormonal dosages, different steroid types and non-oral routes of administration. Specifically, there has been a considerable shift in patterns of contraceptive use and the increase in the uptake of non-oral, long-acting, reversible contraception (e.g., intrauterine devices, implants, injections) has corresponded to a decline in oral contraceptive pill use. Whether or not these other methods confer a protective effect against ovarian cancer in the general population is not clear. To our knowledge, there have been no such studies conducted among BRCA mutation carriers. Furthermore, the impact of these changes on the risk of developing ovarian cancer is not known. In this article, we will review the existing epidemiologic evidence regarding the role of contraceptives and the risk of ovarian cancer with a focus on women with a BRCA1 or BRCA2 mutation. We will discuss recent findings and gaps in the knowledge while extrapolating from studies conducted among women from the noncarrier population.
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Genetic susceptibility to hereditary non-medullary thyroid cancer

Non-medullary thyroid cancer (NMTC) is the most common type of thyroid cancer. With the increasing incidence of NMTC in recent years, the familial form of the disease has also become more common than previously reported, accounting for 5–15% of NMTC cases. Familial NMTC is further classified as no...
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Non-medullary thyroid cancer (NMTC) is the most common type of thyroid cancer. With the increasing incidence of NMTC in recent years, the familial form of the disease has also become more common than previously reported, accounting for 5–15% of NMTC cases. Familial NMTC is further classified as non-syndromic and the less common syndromic FNMTC. Although syndromic NMTC has well-known genetic risk factors, the gene(s) responsible for the vast majority of non-syndromic FNMTC cases are yet to be identified. To date, several candidate genes have been identified as susceptibility genes in hereditary NMTC. This review summarizes genetic predisposition to non-medullary thyroid cancer and expands on the role of genetic variants in thyroid cancer tumorigenesis and the level of penetrance of NMTC-susceptibility genes.
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