Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.

Mutations in BRCA1 or BRCA2 (BRCA) is synthetic lethal with poly(ADP-ribose) polymerase inhibitors (PARPi). Lethality is thought to derive from DNA double-stranded breaks (DSBs) necessitating BRCA function in homologous recombination (HR) and/or fork protection (FP). Here, we report instead that toxicity derives from replication gaps. BRCA1- or FANCJ-deficient cells, with common repair defects but distinct PARPi responses, reveal gaps as a distinguishing factor. We further uncouple HR, FP, and fork speed from PARPi response. Instead, gaps characterize BRCA-deficient cells, are diminished upon resistance, restored upon resensitization, and, when exposed, augment PARPi toxicity. Unchallenged BRCA1-deficient cells have elevated poly(ADP-ribose) and chromatin-associated PARP1, but aberrantly low XRCC1 consistent with defects in backup Okazaki fragment processing (OFP). 53BP1 loss resuscitates OFP by restoring XRCC1-LIG3 that suppresses the sensitivity of BRCA1-deficient cells to drugs targeting OFP or generating gaps. We highlight gaps as a determinant of PARPi toxicity changing the paradigm for synthetic lethal interactions.

Targeted genotyping for recurring variants in cancer susceptibility genes in non-Ashkenazi Jewish patients with breast cancer diagnosed ≥50 years.

PURPOSE: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in the ethnically diverse Israeli population. Since 2019, testing for these recurring PVs is reimbursed unselectively for all patients with breast cancer (BC) in Israel. The aim was to evaluate the yield of genotyping for these PVs in non-Ashkenazi Jewish (AJ) patients with BC diagnosed ≥age 50 years. METHODS: Clinical and genotyping data of all patients with BC undergoing oncogenetic counseling at the Oncology Institute at Sheba Medical Center from June 2017 to December 2023 were reviewed. RESULTS: Of 2706 patients with BC (mean age at diagnosis, 54 years; range, 20-92 years) counseled, 515 patients of non-AJ (all four grandparents) descent, diagnosed ≥age 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) of non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants were found in 2.5% of genotyped TNBC and in 3.7% of patients with non-TNBC, including CHEK2 c.499G>A (n = 3), APC c.3920T > A (n = 4), and heterozygous MUTYH c.1187G>A (n = 5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n = 2, c.846+1G>C and c.592+3A>T), ATM c.103C>T (n = 2), and NBN c.966C>G (n = 1). CONCLUSIONS: The observed low rates of PV detection in non-AJ non-TNBC cases ≥age 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.

Non-BRCA1/BRCA2 high-risk familial breast cancers are not associated with a high prevalence of BRCAness.

BACKGROUND: Familial breast cancer is in most cases unexplained due to the lack of identifiable pathogenic variants in the BRCA1 and BRCA2 genes. The somatic mutational landscape and in particular the extent of BRCA-like tumour features (BRCAness) in these familial breast cancers where germline BRCA1 or BRCA2 mutations have not been identified is to a large extent unknown. METHODS: We performed whole-genome sequencing on matched tumour and normal samples from high-risk non-BRCA1/BRCA2 breast cancer families to understand the germline and somatic mutational landscape and mutational signatures. We measured BRCAness using HRDetect. As a comparator, we also analysed samples from BRCA1 and BRCA2 germline mutation carriers. RESULTS: We noted for non-BRCA1/BRCA2 tumours, only a small proportion displayed high HRDetect scores and were characterized by concomitant promoter hypermethylation or in one case a RAD51D splice variant previously reported as having unknown significance to potentially explain their BRCAness. Another small proportion showed no features of BRCAness but had mutationally active tumours. The remaining tumours lacked features of BRCAness and were mutationally quiescent. CONCLUSIONS: A limited fraction of high-risk familial non-BRCA1/BRCA2 breast cancer patients is expected to benefit from treatment strategies against homologue repair deficient cancer cells.

Pilot Trial of Streamlined Genetic Education and Traceback Genetic Testing in Prostate Cancer Survivors.

BACKGROUND: Germline genetic testing is recommended for men with metastatic or high-risk prostate cancer to inform treatment and risk management for other cancers and inform genetic testing in at-risk relatives. However, relatively few patients with prostate cancer undergo genetic testing. Given the low rate of testing and increasing demands on genetic service providers, strategies are needed that reduce barriers to testing while conserving genetic counseling resources. The primary goal of this study was to determine whether a proactive and streamlined "traceback" approach could yield increased genetic testing participation among prostate cancer survivors. METHODS: We randomized 107 survivors of metastatic and high-risk prostate cancer to streamlined testing (ST) versus enhanced usual care (EUC). ST participants were proactively provided with print genetic education materials and the option to proceed to genetic testing without pre-test genetic counseling. EUC participants were sent a letter from their physician advising them of their eligibility for genetic testing and recommending they schedule genetic counseling. The primary outcome was genetic testing participation. Secondary outcomes were distress, knowledge, decision satisfaction, and regret. RESULTS: In the ST group, 41.5% of participants completed genetic testing compared with 27.8% in the EUC group. After adjusting for education and marital status, the odds of testing were more than twice as high for the ST group as for the EUC group (odds ratio, 2.57; 95% CI, 1.05-6.29). The groups did not differ on any of the psychosocial outcomes at the 3-month follow-up. CONCLUSIONS: Proactive outreach paired with streamlined genetic testing delivery may be a safe, effective, and resource-efficient approach to facilitate traceback genetic testing in prostate cancer survivors.

Psychological distress and decision-making factors for prophylactic bilateral mastectomy in cancer-unaffected BRCA1/2 pathogenic variant carriers.

OBJECTIVE: Women carrying a BRCA1/2 pathogenic variant have an increased risk for breast cancer and may opt for risk-reducing bilateral mastectomy. In this study, we examine which demographic, psychosocial, and personality factors are associated with their decision to undergo risk-reducing bilateral mastectomy. METHODS: Cancer-unaffected women with a pathogenic variant in BRCA1 or BRCA2 were recruited before receiving their genetic test result and completed follow-up including decision to undergo mastectomy over 6-8 months after genetic test result disclosure. Anxiety, depression, breast cancer worry, personality and sociodemographic data were assessed. RESULTS: A total of 125 cancer-unaffected women were included in the analysis. Participants were found to have higher anxiety levels than the general female population regardless of mastectomy decision. Breast cancer worry was higher among women who opted for risk-reducing mastectomy and did not decrease over time. By contrast, women who did not opt for surgery experienced decreasing levels of breast cancer worry. Regression analysis found that women with a pathogenic variant in BRCA1, younger women and women with higher breast cancer worry were more likely to opt for surgery. CONCLUSIONS: Our study provides valuable insights into the factors that influence women with a BRCA1/2 pathogenic variant to undergo risk-reducing mastectomy. These findings may be helpful in understanding individual differences in decision-making concerning preventive options and show the need to address negative anticipatory feelings associated with carrying a pathogenic variant in a high breast cancer risk gene in clinical care.

Does a proactive procedure lead to a higher uptake of predictive testing in families with a pathogenic BRCA1/BRCA2 variant? A family cancer clinic evaluation.

The uptake of genetic counseling and predictive genetic testing by family members at risk for hereditary tumor syndromes is generally below 50%. To address this issue, a new guideline was introduced in the Netherlands in 2019 that aims to improve the sharing of information within families. In addition to cascade screening supported by follow-up telephone calls with the proband, municipal records were accessed to allow the geneticist to contact at-risk family members directly. We evaluated this procedure in 32 families with a (likely) pathogenic germline BRCA1/BRCA2 variant diagnosed at our hospital between May 1, 2020, and July 31, 2021, comparing current uptake with outcomes achieved for 33 families diagnosed in 2014. Fifteen months after diagnostic testing of the proband, the uptake was 43% (120/277), comparable to the 44% (87/200) registered previously. Among a subgroup of women at 50% risk aged 25-75 years, 71% (47/66) were tested, comparable to an earlier uptake of 69% (59/86). Of the 34 at-risk relatives we contacted directly, 17 (50%) underwent predictive testing. In conclusion, we found no evidence that the new procedure leads to a substantially increased uptake. Future research should be primarily aimed at understanding intrafamilial communication barriers.

Randomised trial of population-based BRCA testing in Ashkenazi Jews: long-term secondary lifestyle behavioural outcomes.

OBJECTIVE: Ashkenazi-Jewish (AJ) population-based BRCA testing is acceptable, cost-effective and amplifies primary prevention for breast & ovarian cancer. However, data describing lifestyle impact are lacking. We report long-term results of population-based BRCA testing on lifestyle behaviour and cancer risk perception. DESIGN: Two-arm randomised controlled trials (ISRCTN73338115, GCaPPS): (a) population-screening (PS); (b) family history (FH)/clinical criteria testing. SETTING: North London AJ-population. POPULATION/SAMPLE: AJ women/men >18 years. EXCLUSIONS: prior BRCA testing or first-degree relatives of BRCA-carriers. METHODS: Participants were recruited through self-referral. All participants received informed pre-test genetic counselling. The intervention included genetic testing for three AJ BRCA-mutations: 185delAG(c.68_69delAG), 5382insC(c.5266dupC) and 6174delT(c.5946delT). This was undertaken for all participants in the PS arm and participants fulfilling FH/clinical criteria in the FH arm. Patients filled out customised/validated questionnaires at baseline/1-year/2-year/3-year follow-ups. Generalised linear-mixed models adjusted for covariates and appropriate contrast tests were used for between-group/within-group analysis of lifestyle and behavioural outcomes along with evaluating factors associated with these outcomes. Outcomes are adjusted for multiple testing (Bonferroni method), with P < 0.0039 considered significant. OUTCOME MEASURES: Lifestyle/behavioural outcomes at baseline/1-year/2-year/3-year follow-ups. RESULTS: 1034 participants were randomised to PS (n = 530) or FH (n = 504) arms. No significant difference was identified between PS- and FH-based BRCA testing approaches in terms of dietary fruit/vegetable/meat consumption, vitamin intake, alcohol quantity/ frequency, smoking behaviour (frequency/cessation), physical activity/exercise or routine breast mammogram screening behaviour, with outcomes not affected by BRCA test result. Cancer risk perception decreased with time following BRCA testing, with no difference between FH/PS approaches, and the perception of risk was lowest in BRCA-negative participants. Men consumed fewer fruits/vegetables/vitamins and more meat/alcohol than women (P < 0.001). CONCLUSION: Population-based and FH-based AJ BRCA testing have similar long-term lifestyle impacts on smoking, alcohol, dietary fruit/vegetable/meat/vitamin, exercise, breast screening participation and reduced cancer risk perception.

"It was an important part of my treatment": a qualitative study of Norwegian breast Cancer patients' experiences with mainstreamed genetic testing.

BACKGROUND: In South-Eastern Norway, genetic testing for BRCA1 and BRCA2 is offered to breast cancer patients by their treating surgeon or oncologist. Genetic counselling from a geneticist or a genetic counsellor is offered only to those who test positive for a pathogenic variant or have a family history of cancer. This practice is termed "mainstreamed genetic testing". The aim of this study was to learn about patients' experience of this healthcare service. METHODS: Qualitative in-depth interviews were conducted with 22 breast cancer patients who had been diagnosed during the first half of 2016 or 2017 at one regional and one university hospital and who had been offered testing by their treating physician. A six-phase thematic approach was used to analyse the data. RESULTS: The participants had varied experiences of how and when testing was offered. Three main themes emerged from the analysis: 1. informational and communicational needs and challenges during a chaotic time, 2. the value of genetic testing and 3. the importance of standardised routines for mainstreamed genetic testing. CONCLUSIONS: Despite the shock of their diagnosis and the varying experiences they had in respect of how and when testing was offered, all of the participants emphasised that genetic testing had been an important part of their diagnosis and treatment. Our results indicate that there is a need for continuous collaboration between geneticists, surgeons, oncologists and laboratory specialists in order to establish simple and robust routines so as to ensure that all eligible breast cancer patients are offered testing at a point when the test result can have an impact on treatment.

Identification and Verification of the Ability of Cdk5 to Phosphorylate Deubiquitinating Enzyme BRCC3 In Vitro.

It is known that the expression of the deubiquitinating enzyme BRCA1-BRCA2-containing complex subunit 3 (BRCC3) and cyclin-dependent protein kinase 5 (Cdk5) is increased in Parkinson's disease (both are involved in neuroinflammatory response). However, the regulatory mechanism of Cdk5 on the post-translational modification of BRCC3 remains unclear. Here we studied whether Cdk5 phosphorylates BRCC3. Phosphorylation of BRCC3 by Cdk5 was predicted by GPS 5.0 software. His-BRCC3 plasmid was constructed by cloning the BRCC3 gene into pGEX-6P-1 vector, and then His-BRCC3 fusion protein was induced with isopropyl ß-d-1-thiogalactopyranoside and purified using His-Tag affinity chromatography purification agarose. Phosphorylation of BRCC3 fusion protein by Cdk5 in vitro was detected by mass spectrometry and Western blotting. The results showed that multiple phosphorylation sites were predicted by GPS 5.0, and the His-BRCC3 fusion protein was successfully induced and purified. In vitro kinase assay, Western blotting, and mass spectrometry showed that Cdk5 can phosphorylate BRCC3. It has been demonstrated that protein kinase Cdk5 can phosphorylate the deubiquitinating enzyme BRCC3 in vitro, which provides new data for further study on the mechanism of neurodegeneration.

Yield of targeted genotyping for the recurring pathogenic variants in cancer susceptibility genes in a healthy, multiethnic Israeli population.

BACKGROUND: Several recurring pathogenic variants in BRCA1/BRCA2 and other cancer susceptibility genes are encountered in ethnically diverse Jewish populations. The yield of genotyping for these recurring pathogenic variants in healthy Israeli individuals unselected for ethnicity, sex, or a family history of cancer has not been previously reported. METHODS: Individuals voluntarily participating in annual medical surveillance at the Institute of Medical Screening of Sheba Medical Center were offered genotyping for predominant pathogenic variants in BRCA1/BRCA2 and recurring variants in CHEK2, MUTYH, APC, and the Lynch syndrome genes via a chip-based assay at the oncogenetic service of Sheba Medical Center from May 15, 2018, to December 15, 2020. All study participants were unrelated to one another. The study was approved by the Sheba ethics committee. RESULTS: Overall, 1764 individuals, including 1008 females (57%), with a mean age of 54.2 years (range, 25-86 years) were genotyped. The yield of the testing was 4% (71 of 1764), and it was higher in Ashkenazi Jews (AJs) and mixed AJ-non-AJ participants (4.75% [58 of 1222]; 1.8% for BRCA1/BRCA2 pathogenic variants) than non-AJ patients (2.2% [9 of 401]; 1% for BRCA1 pathogenic variants). When BRCA1/BRCA2 pathogenic variants were excluded, 2.44% carried low-penetrance variants, including CHEK2 c.1283C>T (n = 3), APC c.3920T>A (n = 36), and heterozygous MUTYH c.1187G>A (n = 4). A family history of cancer was not associated with a higher yield of pathogenic variant detection. CONCLUSIONS: The observed rates of positive genotyping in a healthy, unselected, multiethnic Israeli population warrant consideration of the inclusion of targeted genotyping of selected pathogenic variants in high-penetrance and perhaps lower penetrance cancer susceptibility genes for all Jewish individuals in Israel, regardless of their ethnicity or family history of cancer.

Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial.

BACKGROUND: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). RESULTS: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. CONCLUSIONS: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.

Post-mastectomy surveillance of BRCA1/BRCA2 mutation carriers: Outcomes from a specialized clinic for high-risk breast cancer patients.

Female BRCA1/BRCA2 mutation carriers may elect bilateral risk-reducing mastectomy. There is a paucity of data on yield of imaging surveillance after risk-reducing mastectomy. This retrospective study focused on female BRCA1/BRCA2 mutation carriers who underwent bilateral mastectomy either as primary preventative, or as secondary preventative, after breast cancer diagnosis. All participants underwent breast imaging at 6- to 12-month intervals after mastectomy. Data on subsequent breast cancer diagnosis and timing were collected and compared between the groups. Overall, 184 female mutation carriers (134 BRCA1, 45 BRCA2, 5 both BRCA genes) underwent bilateral mastectomy after initial breast cancer diagnosis, between April 1, 2009 and August 31, 2018. During a mean follow-up of 6.2 ± 4.2 years, 13 (7.06%) were diagnosed with breast cancer; 12 ipsilateral (range: 0.4-28.8 years) and 1 contralateral breast cancer, 15.9 years after surgery. On the contrary, among asymptomatic BRCA1 (n = 40) and BRCA2 (n = 13) mutation carriers who underwent primary risk-reducing mastectomy (mean age at surgery 39.5 ± 8.4 years); none has developed breast cancer after a mean follow-up of 5.4 ± 3.4 years. BRCA1/BRCA2 mutation carriers with prior disease who underwent risk-reducing mastectomy after breast cancer diagnosis are still prone for developing ipsi or contralateral breast cancer, and therefore may benefit from continues clinical and imaging surveillance, unlike BRCA1/BRCA2 mutation carriers who undergo primary preventative bilateral mastectomy.

Breast Cancer Predisposition Genes and Synthetic Lethality.

BRCA1 and BRCA2 are tumor suppressor genes with pivotal roles in the development of breast and ovarian cancers. These genes are essential for DNA double-strand break repair via homologous recombination (HR), which is a virtually error-free DNA repair mechanism. Following BRCA1 or BRCA2 mutations, HR is compromised, forcing cells to adopt alternative error-prone repair pathways that often result in tumorigenesis. Synthetic lethality refers to cell death caused by simultaneous perturbations of two genes while change of any one of them alone is nonlethal. Therefore, synthetic lethality can be instrumental in identifying new therapeutic targets for BRCA1/2 mutations. PARP is an established synthetic lethal partner of the BRCA genes. Its role is imperative in the single-strand break DNA repair system. Recently, Olaparib (a PARP inhibitor) was approved for treatment of BRCA1/2 breast and ovarian cancer as the first successful synthetic lethality-based therapy, showing considerable success in the development of effective targeted cancer therapeutics. Nevertheless, the possibility of drug resistance to targeted cancer therapy based on synthetic lethality necessitates the development of additional therapeutic options. This literature review addresses cancer predisposition genes, including BRCA1, BRCA2, and PALB2, synthetic lethality in the context of DNA repair machinery, as well as available treatment options.

The Genetic Education for Men (GEM) Trial: Development of Web-Based Education for Untested Men in BRCA1/2-Positive Families.

Cascade testing for hereditary breast/ovarian cancer is an important public health priority. Increasing attention has been paid to the relevance of testing for men within BRCA1/2-positive families given that such testing may provide important information about their cancer risks, particularly for prostate cancer, and risks to their offspring. However, men are much less likely to seek genetic counseling and testing than their at-risk female relatives. To facilitate access to pre-test information and testing, we developed a web-based intervention (WI) for men that we are evaluating in a pilot randomized controlled trial (RCT). This paper describes three phases of research in the development of the WI: (1) formative (qualitative) research among men from BRCA1/2 families to assess needs and preferences for education; (2) a detailed description of the organization, format, and content of the WI; and (3) usability testing. We discuss the aims and hypotheses of the pilot RCT in which the WI is being compared with an enhanced usual care condition among at-risk men. We expect that the WI described here will foster informed decisions and lead to increased use of BRCA1/2 counseling and testing, potentially yielding improved cancer control outcomes for this understudied group, and for their at-risk relatives.

Application of Panel-Based Tests for Inherited Risk of Cancer.

Next-generation or massively parallel sequencing has transformed the landscape of genetic testing for cancer susceptibility. Panel-based genetic tests evaluate multiple genes simultaneously and rapidly. Because these tests are frequently offered in clinical settings, understanding their clinical validity and utility is critical. When evaluating the inherited risk of breast and ovarian cancers, panel-based tests provide incremental benefit compared with BRCA1/2 genetic testing. For inherited risk of other cancers, such as colon cancer and pheochromocytoma-paraganglioma, the clinical utility and yield of panel-based testing are higher; in fact, simultaneous evaluation of multiple genes has been the historical standard for these diseases. Evaluating inherited risk with panel-based testing has recently entered clinical practice for prostate and pancreatic cancers, with potential therapeutic implications. The resulting variants of uncertain significance and mutations with unclear actionability pose challenges to service providers and patients, underscoring the importance of genetic counseling and data-sharing initiatives. This review explores the evolving merits, challenges, and nuances of panel-based testing for cancer susceptibility.

The development and evaluation of a nationwide training program for oncology health professionals in the provision of genetic testing for ovarian cancer patients.

BACKGROUND: BRCA1/2 mutation status has increasing relevance for ovarian cancer treatments, making traditional coordination of genetic testing by genetic services unsustainable. Consequently alternative models of genetic testing have been developed to improve testing at the initial diagnosis for all eligible women. METHODS: A training module to enable mainstreamed genetic testing by oncology healthcare professionals was developed by genetic health professionals. Oncology healthcare professionals completed questionnaires before and 12 months post-training to assess perceived skills, competence and barriers to their coordinating genetic testing for women with high-grade non-mucinous epithelial ovarian cancer. Genetic health professionals were surveyed 12 months post-training to assess perceived barriers to implementation of mainstreaming. RESULTS: 185 oncology healthcare professionals were trained in 42 workshops at 35 Australasian hospitals. Of the 273 tests ordered by oncology healthcare professionals post-training, 241 (93.1%) met national testing guidelines. The number of tests ordered by genetic health professionals reduced significantly (z = 45.0, p = 0.008). Oncology healthcare professionals' perceived barriers to mainstreamed testing decreased from baseline to follow-up (t = 2.39, p = 0.023), particularly perceived skills, knowledge and attitudes. However, only 58% reported either 'always' or 'nearly always' having ordered BRCA testing for eligible patients at 12 months, suggesting oncology healthcare professionals' perceived barriers were not systematically addressed through training. CONCLUSIONS: Oncology healthcare professionals have demonstrated a willingness to be involved in the provision of genetic testing in a mainstreaming model. If oncology services are to hold responsibility for coordinating genetic testing, their readiness will require understanding of barriers not addressed by training alone to inform future intervention design.

An overview of cancer genetics with focus on involvement of BRCA1/2 genes in breast carcinomas.

Cancer is a kind of disease which can be explained at the molecular level as triggered by accretion of damaged deoxyribonucleic acid. There are several genes involved in cancer, mainly belonging to two classes called tumour suppressors and oncogenes. Other than the well-known breast cancer susceptibility 1/2 genes, there are several other genes involved in the development of breast and ovarian cancers. However, since the past two decades the focus of research has been on and breast cancer susceptibility 1/2 genes. The current review was planned to delve into the structure and function of breast cancer susceptibility 1/2 genes to augment research on the genetics of breast cancer. The understanding of tumour suppressor genes is also helpful in the analysis of mutational spectra and to determine the treatment strategies in clinical interventional studies.

The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries.

BRCA1 BRCA2 mutational spectrum in the Middle East, North Africa, and Southern Europe is not well characterized. The unique history and cultural practices characterizing these regions, often involving consanguinity and inbreeding, plausibly led to the accumulation of population-specific founder pathogenic sequence variants (PSVs). To determine recurring BRCA PSVs in these locales, a search in PUBMED, EMBASE, BIC, and CIMBA was carried out combined with outreach to researchers from the relevant countries for unpublished data. We identified 232 PSVs in BRCA1 and 239 in BRCA2 in 25 of 33 countries surveyed. Common PSVs that were detected in four or more countries were c.5266dup (p.Gln1756Profs), c.181T>G (p.Cys61Gly), c.68_69del (p.Glu23Valfs), c.5030_5033del (p.Thr1677Ilefs), c.4327C>T (p.Arg1443Ter), c.5251C>T (p.Arg1751Ter), c.1016dup (p.Val340Glyfs), c.3700_3704del (p.Val1234Glnfs), c.4065_4068del (p.Asn1355Lysfs), c.1504_1508del (p.Leu502Alafs), c.843_846del (p.Ser282Tyrfs), c.798_799del (p.Ser267Lysfs), and c.3607C>T (p.Arg1203Ter) in BRCA1 and c.2808_2811del (p.Ala938Profs), c.5722_5723del (p.Leu1908Argfs), c.9097dup (p.Thr3033Asnfs), c.1310_1313del (p. p.Lys437Ilefs), and c.5946del (p.Ser1982Argfs) for BRCA2. Notably, some mutations (e.g., p.Asn257Lysfs (c.771_775del)) were observed in unrelated populations. Thus, seemingly genotyping recurring BRCA PSVs in specific populations may provide first pass BRCA genotyping platform.

Genetic testing for hereditary prostate cancer: Current status and limitations.

A significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Men who have multiple single-gene polymorphisms and a family history of prostate cancer have a significantly greater risk of developing prostate cancer. Numerous single-gene alterations have been confirmed to increase the risk of prostate cancer. These include breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively), mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and ataxia telangiectasia mutated (ATM). Currently, there are no uniform guidelines on the definition of hereditary prostate cancer and genetic testing. With the advent of next-generation sequencing, which is capable of testing multiple genes simultaneously, and the approval of olaparib for BRCA1/BRCA2 or ATM-mutated, metastatic, castrate-resistant prostate cancer, it is being recognized that the results of genetic testing have an impact on therapeutic strategies. In this review, the authors examine the role of genetic counseling and testing, the challenges of insurance coverage for testing, the available germline and somatic testing panels, and the complexity of each testing method and its implications. Cancer 2018. © 2018 American Cancer Society.

The yield of full BRCA1/2 genotyping in Israeli high-risk breast/ovarian cancer patients who do not carry the predominant mutations.

PURPOSE: BRCA1 and BRCA2 genotyping results have clinical implications for cancer risk assessment and targeted therapy. Current practice in Israel is to genotype for the predominant BRCA1/2 mutations first, followed by full gene analysis in eligible mutation-negative individuals. This work assessed the rate of non-predominant mutations in BRCA1/2 in ethnically diverse high-risk cases. METHODS: Breast and/or ovarian cancer patients who tested negative for the predominant BRCA1/2 mutations were referred for comprehensive BRCA1/2 genotyping if calculated risk for carrying a BRCA mutation was ≥ 10%. RESULTS: Of 1258 eligible patients, 41 (3.3%) carried one of 38 mutations: 3% of Ashkenazi Jews and 3.4% of mixed ethnicities. Detection rate was < 5% among patients diagnosed with cancer younger than 40 or with bilateral breast cancer, and was 5.5% of ovarian cancer patients. Three of the carriers (7.3%) carried gene rearrangements. Three mutations were reported in more than one case. CONCLUSIONS: The overall yield of comprehensive BRCA1/2 testing in ethnically diverse high-risk Israeli individuals is 3.3%. This is lower than expected by probability models. A slightly higher rate of BRCA1/2 carriers was seen among ovarian cancer cases. These data should guide BRCA1/2 optimal testing strategy in Israel.