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As the treatment of epithelial ovarian cancer (OC) moves further into personalised medicine, the importance of determining the presence or absence of inherited mutations in cancer susceptibility genes has grown. It is now becoming routine to test for germline mutations in the BRCA1 and BRCA2 genes, which are responsible for a significant proportion of hereditary epithelial OC and are established predictive biomarkers of potential benefit from poly ADP ribose polymerase (PARP) inhibitors. The identification of patients with hereditary OC allows the patient to benefit from personalised treatment, while allowing family members to undergo cascade testing, where identification of unaffected carriers can allow early detection, risk-reduction or prevention for both breast and OC, and ultimately improve long-term outcomes. Other susceptibility genes, include the Lynch Syndrome (mismatch repair) genes and several other genes involved in the homologous recombination pathway (HRD genes), are implicated in OC genesis, and are also becoming of increasing interest as therapeutic options grow for these patients. This review will highlight the importance of the early detection of a germline gene pathogenic variant, which informs on the clinical course of disease in a particular patient, and therefore, guides therapeutic management including risk reducing and personalised treatment., Competing Interests: Declaration of Competing Interest AG has received honoraria from Astra Zeneca, Tesaro and Roche. NA and NC have no conflicts of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Our current understanding of the genetic mechanisms that underly cancer pathogenesis is rapidly expanding. Hereditary cancer predisposition syndromes are important to recognize for diagnostic and treatment decision-making but also for family members so they will benefit from surveillance and treatment options. This brief review gives primary care and oncology caregivers a summary of the evolution of hereditary cancer predisposition syndromes, indications for consideration of testing and therapy of patients and families.

Background: Germline genetic testing increasingly identifies advanced prostate cancer (PCa) patients who are candidates for precision therapies. The Prostate Cancer Clinical Trials Consortium (PCCTC) established the Germline Genetics Working Group to provide guidance and resources to expand effective use of germline genetic testing., Materials and Methods: A 14-item questionnaire was e-mailed to academic oncologists at 43 PCCTC sites to collect information on germline genetic testing patterns, including patients considered, choice of assays, barriers slowing adoption, and actions to overcome barriers., Results: Twenty-six genitourinary oncologists from 19 institutions responded. Less than 40% (10 of 26) reported referring patients to a genetics department, whereas the remainder take personal responsibility for genetic testing and counseling; 16 (62%) consider testing all metastatic PCa patients, whereas 3 (12%) consider testing all patients with high-risk local disease; and 7 (27%) use multigene comprehensive pan-cancer panels, and 14 (54%) use smaller or targeted cancer gene panels. Barriers to widespread use are: (1) delayed or limited access to genetic counseling; (2) no insurance coverage; (3) lack of effective workflows; (4) insufficient educational materials; and (5) time and space constraints in busy clinics. The primary limitation was the <50% (19 of 43) response from PCCTC sites and no coverage of nonacademic cancer treatment facilities., Conclusion: Joint efforts by urologists, oncologists, genetics counselors, insurers, and cancer centers can accelerate implementation of integrated germline genetic services for personalized treatment and clinical trial eligibility for PCa patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Colorectal Cancer (CRC) is the third most prevalent cancer in men and women. Up to 15% of CRCs display microsatellite instability (MSI). MSI is reflective of a deficient mismatch repair (MMR) system and is most commonly caused by hypermethylation of the MLH1 promoter. However, it may also be due to autosomal dominant constitutional mutations in DNA MMR, termed Lynch Syndrome. MSI may be diagnosed via polymerase chain reaction (PCR) or alternatively, immunohistochemistry (IHC) can identify MMR deficiency (dMMR). Many institutions now advocate universal tumor screening of CRC via either PCR for MSI or IHC for dMMR to guide Lynch Syndrome testing. The association of sporadic MSI with methylation of the MLH1 promoter and an activating BRAF mutation may offer further exclusion criteria for genetic testing. Aside from screening for Lynch syndrome, MMR testing is important because of its prognostic and therapeutic implications. Several studies have shown MSI CRCs exhibit different clinicopathological features and prognosis compared to microsatellite-stable (MSS) CRCs. For example, response to conventional chemotherapy has been reported to be less in MSI tumours. More recently, MSI tumours have been shown to be responsive to immune-checkpoint inhibition providing a novel therapeutic strategy. This provides a rationale for routine testing for MSI or dMMR in CRC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Simple Summary: This study examined the efficacy and diagnostic yield of founder variant testing as an initial screening method for individuals with a personal or family history of cancer. The results indicate that this approach is ineffective and has a limited ability to detect significant germline variants. Given these findings, we raise doubts about the benefits of employing such testing and suggest a transition from a two-step approach to expansive genetic testing. Founder pathogenic variants (PVs) are prevalent in Israel. This study investigated the current practice of offering cancer patients two-step genetic testing, starting with targeted testing for recurring founder PVs, followed, if negative, by next-generation sequencing. A total of 2128 subjects with cancer or a positive family history underwent oncogenetic testing with a panel of 51 recurring PVs at a tertiary medical center in March 2020–January 2023. Those with a known familial PV (n = 370) were excluded from the analysis. Among the remainder, 128/1758 (7%) were heterozygous for at least one variant, and 44 (34%) carried a PV of medium-high penetrance (MHPV). Cancer was diagnosed in 1519/1758 patients (86%). The diagnostic yield of founder MHPV testing was 2% in cancer patients and 4% in healthy individuals with a positive family history. It was higher in Ashkenazi Jews than non-Ashkenazi Jews and Arabs, but not over 10% for any type of cancer, and it was significantly higher in younger (<40 years) than older (>50 years) individuals (7% vs. 1%). Eighty-four of the heterozygotes (66%), mostly Ashkenazi Jews, harbored a low-penetrance variant (LPV) not associated with the diagnosed cancer, usually APC c.3902T>A. These findings question the advantage of two-step testing. LPVs should not be included in targeted testing because this can lead to an overestimation of the yield, and their detection does not preclude further comprehensive testing. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is a condition which predisposes individuals primarily to early-onset colorectal and endometrial cancer. LS is characterized by a germline pathogenic variant in one of the MMR (MisMatch Repair) gene, inducing a phenotype of microsatellite instability in the tumor, which may be associated with a loss of expression of MMR proteins detected by standard immunohistochemistry on tumor tissue. Most of the time, LS is inherited from a parent in whom the condition may not be known due to incomplete penetrance, but de novo pathogenic variant is a rare occurrence. Here, we describe the case of a 52-year-old woman with no family history of LS, referred to the genetics department for colorectal cancer at the age of 50. Genetic analysis revealed a de novo germline pathogenic variant in the MSH6 gene. To date, this case is only the second report of a de novo pathogenic variant in the MSH6 gene in Lynch syndrome. De novo mutations have been extensively studied over the past years, but little is known about their origin and mechanism of occurrence in MMR genes. However, knowledge of mutation status allows better cancer risk management for the patient and an appropriate genetic testing and counseling for her family. [ABSTRACT FROM AUTHOR]

The clinical value of population-based genetic screening projects depends on the actions taken on the findings. The Healthy Nevada Project (HNP) is an all-comer genetic screening and research project based in northern Nevada. HNP participants with CDC Tier 1 findings of hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), or familial hypercholesterolemia (FH) are notified and provided with genetic counseling. However, the HNP subsequently takes a "hands-off" approach: it is the responsibility of notified participants to share their findings with their healthcare providers, and providers are expected to implement the recommended action plans. Thus, the HNP presents an opportunity to evaluate the efficiency of participant and provider responses to notification of important genetic findings, using electronic health records (EHRs) at Renown Health (a large regional hospital in northern Nevada). Out of 520 HNP participants with findings, we identified 250 participants who were notified of their findings and who had an EHR. 107 of these participants responded to a survey, with 76 (71%) indicating that they had shared their findings with their healthcare providers. However, a sufficiently specific genetic diagnosis appeared in the EHRs and problem lists of only 22 and 10%, respectively, of participants without prior knowledge. Furthermore, review of participant EHRs provided evidence of possible relevant changes in clinical care for only a handful of participants. Up to 19% of participants would have benefited from earlier screening due to prior presentation of their condition. These results suggest that continuous support for both participants and their providers is necessary to maximize the benefit of population-based genetic screening. We recommend that genetic screening projects require participants' consent to directly document their genetic findings in their EHRs. Additionally, we recommend that they provide healthcare providers with ongoing training regarding documentation of findings and with clinical decision support regarding subsequent care. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the fourth most common cancer among men and women. Between 3 and 6 % of all CRCs are attributed to well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis and several hamartomatous conditions. Up to 30 % of CRC cases exhibit common familial risk, likely related to a combination of inherited factors and environment. Identification of these patients through family history and appropriate genetic testing can provide estimates of cancer risk that inform appropriate cancer screening, surveillance and/or preventative interventions. This article examines the colon cancer syndromes, their genetic basis, clinical management and evidence supporting colorectal screening. It also deals with the category of common (non-syndromic) familial risk including risk determination and screening guidelines. [ABSTRACT FROM AUTHOR]

Hereditary gynecological cancers are caused by several inherited genes. Tumors that arise in the female reproductive system, such as ovaries and the uterus, overlap with hereditary cancers. Several hereditary cancer-related genes are important because they might lead to therapeutic targets. Treatment of hereditary cancers should be updated in line with the advent of various new methods of evaluation. Next-generation sequencing has led to rapid, economical genetic analyses that have prompted a concomitant and significant paradigm shift with respect to hereditary cancers. Molecular tumor profiling is an epochal method for determining therapeutic targets. Clinical treatment strategies are now being designed based on biomarkers based on tumor profiling. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines significantly changed the genetic testing process in 2020 to initially consider multi-gene panel (MGP) evaluation. Here, we reviewed the molecular features and clinical management of hereditary gynecological malignancies, such as hereditary breast and ovarian cancer (HBOC), and Lynch, Li–Fraumeni, Cowden, and Peutz–Jeghers syndromes. We also reviewed cancer-susceptible genes revealed by MGP tests. [ABSTRACT FROM AUTHOR]