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Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9–12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9–12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT–qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9–12 alleles using nanopore long-sequencing. Using the Kruskal–Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9–12 and identifying which of them has developed cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Aim: Certain germline pathogenic variants (PVs), known as founder mutations, have been frequently observed in specific regions and ethnic groups. In Japan, several pathogenic variants of BRCA1/2 have been identified as founder mutations, with their distribution varying across different regions. This retrospective study aimed to further investigate the detailed distribution and correlation between genotype and clinical features among breast cancer patients. Patients and Methods: This study was conducted at Kobe University Hospital and three collaborating institutions. It included breast cancer patients who underwent BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021, and were found to have germline PVs. Clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those with other PVs. Additionally, the detection rate of BRCA2 c.5576_5579del was compared with that observed in a previous report. Results: A total of 38 breast cancer patients were included; PVs in BRCA1 and BRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2 c.5576_5579del carriers. BRCA2 c.5576_5579del carriers were more likely to develop triple negative breast cancers among all BRCA2 PV carriers. BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. Conclusion: BRCA2 c.5576_5579del was detected with a particularly high frequency in Hyogo Prefecture, especially in Kakogawa city. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization. [ABSTRACT FROM AUTHOR]

Abstract Background A detailed understanding of the genetic basis of cancer is of great interest to public health monitoring programs. Although many studies have been conducted in Brazil, a global view on the molecular profile related to hereditary breast and ovarian cancer (HBOC) in this large and heterogeneous population is lacking. Methods A systematic review following the PRISMA guidelines was conducted in three electronic databases (PubMed, BIREME and SciELO). Brazilian studies covering molecular analysis of genes related to HBOC, published until December 2023, were considered. Results We identified 35 original studies that met all the inclusion criteria. A total of 137 distinct mutations were found in the BRCA1 gene, but four of them corresponded to 44.5% of all mutations found in this gene. The c.5266dupC BRCA1 mutation was responsible for 26.8% of all pathogenic mutations found in the BRCA1 gene in patients with clinical criteria for HBOC from the Brazilian population. Considering all studies that track this mutation in the BRCA1 gene, we found a frequency of 2% (120/6008) for this mutation in Brazilian patients. In the BRCA2 gene, the four most frequent mutations corresponded to 29.2% of pathogenic mutations. Even though it was tracked by few studies, the c.156_157insAlu mutation was responsible for 9.6% of all pathogenic mutations reported in the BRCA2 gene. Seventeen studies found pathogenic mutations in other non-BRCA genes, the c.1010G > A mutation in the TP53 gene being the most frequent one. Considering all studies that screened for this specific mutation in patients with the clinical criteria for HBOC, the frequency of c.1010G > A was estimated at 1.83% (61/3336). Conclusions Despite significant molecular heterogeneity among mutations in HBOC patients from Brazil, three mutations deserve to be highlighted, c.5266dupC, c.156_157insAlu and c.1010G > A in the BRCA1, BRCA2 and TP53 genes, respectively. With more than 200 records, these three mutations play a vital role in the pathology of breast and ovarian cancer in Brazil. The data collected shed light on the subject, but there is still not enough data from certain subpopulations.

Background: A detailed understanding of the genetic basis of cancer is of great interest to public health monitoring programs. Although many studies have been conducted in Brazil, a global view on the molecular profile related to hereditary breast and ovarian cancer (HBOC) in this large and heterogeneous population is lacking. Methods: A systematic review following the PRISMA guidelines was conducted in three electronic databases (PubMed, BIREME and SciELO). Brazilian studies covering molecular analysis of genes related to HBOC, published until December 2023, were considered. Results: We identified 35 original studies that met all the inclusion criteria. A total of 137 distinct mutations were found in the BRCA1 gene, but four of them corresponded to 44.5% of all mutations found in this gene. The c.5266dupC BRCA1 mutation was responsible for 26.8% of all pathogenic mutations found in the BRCA1 gene in patients with clinical criteria for HBOC from the Brazilian population. Considering all studies that track this mutation in the BRCA1 gene, we found a frequency of 2% (120/6008) for this mutation in Brazilian patients. In the BRCA2 gene, the four most frequent mutations corresponded to 29.2% of pathogenic mutations. Even though it was tracked by few studies, the c.156_157insAlu mutation was responsible for 9.6% of all pathogenic mutations reported in the BRCA2 gene. Seventeen studies found pathogenic mutations in other non-BRCA genes, the c.1010G > A mutation in the TP53 gene being the most frequent one. Considering all studies that screened for this specific mutation in patients with the clinical criteria for HBOC, the frequency of c.1010G > A was estimated at 1.83% (61/3336). Conclusions: Despite significant molecular heterogeneity among mutations in HBOC patients from Brazil, three mutations deserve to be highlighted, c.5266dupC, c.156_157insAlu and c.1010G > A in the BRCA1, BRCA2 and TP53 genes, respectively. With more than 200 records, these three mutations play a vital role in the pathology of breast and ovarian cancer in Brazil. The data collected shed light on the subject, but there is still not enough data from certain subpopulations. [ABSTRACT FROM AUTHOR]

Introduction Hereditary breast and ovarian cancer (HBOC) syndrome affects a significant proportion of our breast and ovarian cancer patients. Mutations in genes, for example, BRCA1 and 2, confer a high risk of acquiring certain malignancies, including breast cancer in both men and women, and ovarian cancer in women. Mutation carriers provide a unique opportunity for healthcare professionals to intensively screen and detect malignancy at an early and curable stage. But, patient awareness and acceptance are the keys to the success of these strategies. Objective There is a need to assess the awareness of the patients in this field as the patients come from varied backgrounds, and differ in their socioeconomic profiles, educational backdrop, and cultures. In this study, done prior to establishing our cancer genetics clinic, we evaluated the knowledge and attitude toward HBOC in patients with breast cancer and ovarian cancer. Materials and Methods This cross-sectional observational study was conducted on patients registered in IRCH-AIIMS, who has a diagnosis of breast cancer or ovarian cancer using a self-administered questionnaire based on knowledge and attitude. The sample population included 84 women aged between 25 and 80 years. A binary response was given to knowledge questions, whereas a categorical response was given to attitude questions. The overall data was computed using STATA v13 software. Results According to the findings of the study, 39.3% (5.11/13) of the patients were aware of hereditary cancer. Knowledge among the targeted population was poor, but 72.1% (37.5/52) of the population had a neutral attitude toward learning more about hereditary cancer tests. Only 23/84 (27%) people had heard of genetic counseling. Seventy of eighty-four (83%) patients agreed that they would opt for a genetic test if indicated. While 60/84 (72%) of the population wanted to interact with a counselor over a telephonic call, only 41/84 (49%) wanted to interact in person. Conclusion We concluded from the study that breast and ovarian cancer patients in our clinic have little understanding of HBOC syndrome but have a neutral attitude toward learning more about it. [ABSTRACT FROM AUTHOR]

Abstract Background The results of germline genetic testing for hereditary cancer are of importance not only to the patients under investigation but also to their genetic at-risk relatives. Standard care is to encourage the proband (first family member under investigation) to pass on this risk information to the relatives. Previous research suggests that with family-mediated disclosure, only about a third of at-risk relatives contact health care to receive genetic counselling. In some studies, complementing family-mediated risk disclosure with healthcare-assisted risk disclosure almost doubles the uptake of genetic counselling in at-risk relatives. In this study, we evaluate healthcare-assisted direct letters to relatives at risk of hereditary cancer syndromes in a randomized controlled trial. Methods Probands are recruited from Swedish outpatient cancer genetics clinics to this two-arm randomized controlled trial. The study recruits probands with either a pathogenic variant in a cancer susceptibility gene (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2) or probands with familial breast and colorectal cancer based on clinical and pedigree criteria. In both arms, probands receive standard care, i.e., are encouraged and supported to pass on information to relatives. In the intervention arm, the proband is also offered to have direct letters sent to the at-risk relatives. The primary outcome measure is the proportion of at-risk relatives contacting a Swedish cancer genetics clinic within 12 months of the proband receiving the test results. Discussion This paper describes the protocol of a randomized controlled clinical trial evaluating a healthcare-assisted approach to risk disclosure by offering the probands to send direct letters to their at-risk relatives. The results of this study should be informative in the future development of risk disclosure practices in cancer genetics clinics. Trial registration ClinicalTrials.gov. Identifier NCT04197856 (pre-trial registration on December 13, 2019). Also registered at the website “RCC Cancerstudier i Sverige” as study #86719.

Abstract Background In Japan, genetic testing, surveillance, and risk-reducing surgery for hereditary breast and ovarian cancer (HBOC) syndrome have been covered by the Japanese national insurance system since April 2020. On the other hand, the current situation is that medical care, including surveillance of undiagnosed (cancer-free) patients, is self-funded even for individuals with HBOC. We report a case in which breast cancer was diagnosed at an early stage during surveillance for cancer-free HBOC at the patient’s own expense, and risk-reducing surgery was performed at the same time as treatment for breast cancer. Case presentation The patient was a 63-year-old woman. Her sister had a history of breast cancer in her 30s and was found to be a BRCA2 pathogenic variant carrier by genetic testing. The patient therefore presented to the genetic department of our hospital and underwent genetic testing (out-of-pocket). A pathogenic variant was found at the same site. During annual breast and ovarian surveillance at the patient’s own expense, a physician with sufficient expertise in contrast-enhanced breast magnetic resonance imaging (MRI) noticed a change in the contrast enhancement pattern on breast MRI and performed needle biopsy, revealing ductal carcinoma in situ. At the request of the patient, she underwent concurrent contralateral risk-reducing mastectomy and risk-reducing salpingo-oophorectomy in addition to breast cancer treatment. Conclusions We encountered a case in which cancer treatment and risk-reducing surgery were performed at the same time for a pathogenic variant carrier who was very anxious about developing cancer. Surveillance of cancer-free BRCA1/2 mutation carriers and expansion of insurance coverage for surgery are important future issues.

Simple Summary: Prophylactic interventions are critical for BRCA1/2 mutation carriers to reduce the risks of hereditary breast and ovarian cancer (HBOC). This systematic review and meta-analysis synthesizes data on the efficacy of various preventative strategies. The analysis incorporated 21 studies involving risk-reducing surgeries (RRS), chemoprevention, and screening. Findings indicate a substantial reduction in breast and ovarian cancer incidence and mortality among BRCA1/2 carriers following RRS, particularly mastectomy and oophorectomy, compared to chemoprevention. This study underscores the necessity of tailored interventions, especially considering the varied protective effects between BRCA1 and BRCA2 mutation carriers. This review aids in informing clinical decisions and underscores the importance of context-specific uptake rates in cost-effective evaluations. Background: Hereditary breast and ovarian cancers (HBOCs) pose significant health risks worldwide and are mitigated by prophylactic interventions. However, a meta-analysis of their efficacy and the impact of different genetic variants on their effectiveness is lacking. Methods: A systematic review and meta-analysis were conducted, adhering to Cochrane guidelines. The review encompassed studies that involved prophylactic interventions for healthy women with BRCA variants, focusing on cancer incidence and mortality outcomes. The Newcastle–Ottawa Scale was used for risk of bias assessment. We pooled the extracted outcomes using random effects models and conducted subgroup analyses stratified by intervention, variant, and cancer types. Results: A total of 21 studies met the inclusion criteria. The meta-analysis revealed that prophylactic interventions significantly reduced cancer risk and mortality. The subgroup analysis showed a greater protective effect for BRCA2 than BRCA1 variant carriers. Risk-reducing surgeries (RRS) were more effective than chemoprevention, with RRS notably reducing cancer risk by 56% compared to 39% for chemoprevention. Prophylactic oophorectomy significantly reduced HBOC risks, while the effect of prophylactic mastectomy and chemoprevention on mortality was less conclusive. Conclusions: Prophylactic interventions significantly reduce the risk of HBOC and associated mortality. This comprehensive analysis provides insights for future economic evaluations and clinical decision-making in HBOC interventions. [ABSTRACT FROM AUTHOR]

Background: The results of germline genetic testing for hereditary cancer are of importance not only to the patients under investigation but also to their genetic at-risk relatives. Standard care is to encourage the proband (first family member under investigation) to pass on this risk information to the relatives. Previous research suggests that with family-mediated disclosure, only about a third of at-risk relatives contact health care to receive genetic counselling. In some studies, complementing family-mediated risk disclosure with healthcare-assisted risk disclosure almost doubles the uptake of genetic counselling in at-risk relatives. In this study, we evaluate healthcare-assisted direct letters to relatives at risk of hereditary cancer syndromes in a randomized controlled trial. Methods: Probands are recruited from Swedish outpatient cancer genetics clinics to this two-arm randomized controlled trial. The study recruits probands with either a pathogenic variant in a cancer susceptibility gene (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2) or probands with familial breast and colorectal cancer based on clinical and pedigree criteria. In both arms, probands receive standard care, i.e., are encouraged and supported to pass on information to relatives. In the intervention arm, the proband is also offered to have direct letters sent to the at-risk relatives. The primary outcome measure is the proportion of at-risk relatives contacting a Swedish cancer genetics clinic within 12 months of the proband receiving the test results. Discussion: This paper describes the protocol of a randomized controlled clinical trial evaluating a healthcare-assisted approach to risk disclosure by offering the probands to send direct letters to their at-risk relatives. The results of this study should be informative in the future development of risk disclosure practices in cancer genetics clinics. Trial registration: ClinicalTrials.gov. Identifier NCT04197856 (pre-trial registration on December 13, 2019). Also registered at the website "RCC Cancerstudier i Sverige" as study #86719. [ABSTRACT FROM AUTHOR]

Low‐grade appendiceal mucinous neoplasm (LAMN) is a rare epithelial malignancy of the appendix. If it perforates the abdominal cavity, it can cause a serious clinical syndrome called pseudomyxoma peritonei. In the present case, we laparoscopically removed a LAMN encountered during risk‐reducing salpingo‐oophorectomy (RRSO). The patient was a 53‐year‐old woman who was diagnosed with hereditary breast and ovarian cancer syndrome. RRSO was planned, and magnetic resonance imaging revealed a large cystic tumor in the right lower abdomen. We expected an ovarian cyst; however, it was a primary tumor of the appendix. Partial cecal resection was performed laparoscopically by a surgical oncologist. The pathological diagnosis was LAMN. Gynecologists may encounter this disease incidentally. Mucinous appendiceal neoplasm (MAN) may be encountered during RRSO. If a right lower abdominal mass is found near a normal ovary preoperatively, gynecologists should consider MAN as well as paraovarian cyst. [ABSTRACT FROM AUTHOR]

Background: In Japan, genetic testing, surveillance, and risk-reducing surgery for hereditary breast and ovarian cancer (HBOC) syndrome have been covered by the Japanese national insurance system since April 2020. On the other hand, the current situation is that medical care, including surveillance of undiagnosed (cancer-free) patients, is self-funded even for individuals with HBOC. We report a case in which breast cancer was diagnosed at an early stage during surveillance for cancer-free HBOC at the patient's own expense, and risk-reducing surgery was performed at the same time as treatment for breast cancer. Case presentation: The patient was a 63-year-old woman. Her sister had a history of breast cancer in her 30s and was found to be a BRCA2 pathogenic variant carrier by genetic testing. The patient therefore presented to the genetic department of our hospital and underwent genetic testing (out-of-pocket). A pathogenic variant was found at the same site. During annual breast and ovarian surveillance at the patient's own expense, a physician with sufficient expertise in contrast-enhanced breast magnetic resonance imaging (MRI) noticed a change in the contrast enhancement pattern on breast MRI and performed needle biopsy, revealing ductal carcinoma in situ. At the request of the patient, she underwent concurrent contralateral risk-reducing mastectomy and risk-reducing salpingo-oophorectomy in addition to breast cancer treatment. Conclusions: We encountered a case in which cancer treatment and risk-reducing surgery were performed at the same time for a pathogenic variant carrier who was very anxious about developing cancer. Surveillance of cancer-free BRCA1/2 mutation carriers and expansion of insurance coverage for surgery are important future issues. [ABSTRACT FROM AUTHOR]

Approximately 30–50% of hereditary breast and ovarian cancer (HBOC) is due to the presence of germline pathogenic variants in the BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) onco-suppressor genes, which are involved in DNA damage response. Women who carry pathogenic BRCA1 variants are particularly likely to develop breast cancer (BC) and ovarian cancer (OC), with a 45–79 percent and 39–48 percent chance, respectively. The BRCA1 c.4096+1G>A variant has been frequently ascertained in Tuscany, Italy, and it has also been detected in other Italian regions and other countries. Its pathogenetic status has been repeatedly changed from a variant of uncertain significance, to pathogenic, to likely pathogenic. In our study, 48 subjects (38 of whom are carriers) from 27 families were genotyped with the Illumina OncoArray Infinium platform (533,531 SNPs); a 20 Mb region (24.6 cM) around BRCA1, including 4130 SNPs (21 inside BRCA1) was selected for haplotype analysis. We used a phylogenetic method to estimate the time to the most recent common ancestor (MRCA) of BRCA1 c.4096+1G>A founder pathogenic variant. This analysis suggests that the MRCA lived about 155 generations ago—around 3000 years ago. [ABSTRACT FROM AUTHOR]

Abstract Background Women with pathogenic BRCA1 or BRCA2 variants are at high risk for breast and ovarian cancer. Preventive options include risk-reducing breast and ovarian surgeries and intensified breast surveillance. However, individual decision-making is often associated with decisional conflicts. Two evidence-based decision aids have recently been developed for these women (healthy or with unilateral breast cancer) for the German context to support them in their decision-making process. This study evaluated their effectiveness. Methods In a randomized controlled study, women (aged 18–70 years) with pathogenic BRCA1 or BRCA2 variants were randomly assigned 1:1 to the intervention (IG, n = 230) or control (CG, n = 220) group. All participants received usual care. After baseline survey (t0), IG participants additionally received the DAs. Follow-up surveys were at three (t1) and six (t2) months. Primary outcome was decisional conflict at t1. Secondary analyses included decision status, decision regret, knowledge on risks and preventive options, self-reported psychological symptoms, acceptability of DAs, and preparation for decision-making. Results Of 450 women recruited, 417 completed t0, 398 completed t1 and 386 completed t2. Compared to CG, IG participants had lower decisional conflict scores at t1 (p = 0.049) and t2 (p = 0.006) and higher scores for knowledge (p = 0.004), acceptability (p = 0.000), and preparation for decision-making (p

Hereditary breast and ovarian cancer (HBOC) follows an autosomal dominant inheritance pattern of cancer susceptibility genes. The risk of developing this disease is primarily associated with germline mutations in the BRCA1 and BRCA2 genes. The advent of massive genetic sequencing technologies has expanded the mutational spectrum of this hereditary syndrome, thereby increasing the number of variants of uncertain clinical significance (VUS) detected by genetic testing.

Abstract Background Genetic testing can identify cancer risk early, enabling prevention and early detection. We describe use of risk management interventions following genetic testing in the Cancer Health Assessment Reaching Many (CHARM) study. CHARM assessed risk and provided genetic testing to low income, low literacy, and other underserved populations that historically face barriers to accessing cancer genetic services. Methods CHARM was implemented in Kaiser Permanente Northwest (KPNW) and Denver Health (DH) between 2018 and 2020. We identified post‐testing screening (mammography, breast MRI, colonoscopy) and surgical (mastectomy, oophorectomy) procedures using electronic health records. We examined utilization in participants who did and did not receive actionable risk management recommendations from study genetic counselors following national guidelines. Results CHARM participants were followed for an average of 15.4 months (range: 0.4–27.8 months) after results disclosure. Less than 2% (11/680) received actionable risk management recommendations (i.e., could be completed in the initial years following testing) based on their test result. Among those who received actionable recommendations, risk management utilization was moderate (54.5%, 6/11 completed any procedure) and varied by procedure (mammogram: 0/3; MRI: 2/4; colonoscopy: 4/5; mastectomy: 1/5; oophorectomy: 0/3). Cancer screening and surgery procedures were rare in participants without actionable recommendations. Conclusion Though the number of participants who received actionable risk management recommendations was small, our results suggest that implementing CHARM's risk assessment and testing model increased access to evidence‐based genetic services and provided opportunities for patients to engage in recommended preventive care, without encouraging risk management overuse.

Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9–12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9–12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT–qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9–12 alleles using nanopore long-sequencing. Using the Kruskal–Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9–12 and identifying which of them has developed cancer.

Purpose: To evaluate rates of familial disclosure of hereditary cancer syndrome information. Methods: A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines (PROSPERO no.: CRD42020134276). Key electronic databases were searched to identify studies evaluating hereditary cancer syndrome cascade relative disclosure. Eligible studies were subjected to meta-analysis. Results: Thirty-four studies met inclusion criteria. Among 11,711 included relatives, 70% (95% CI 60 - 78%) were informed of their risk of carrying a cancer-associated pathogenic variant; of 2,875 relatives informed of their risk who were evaluated for uptake of cascade testing, 43% (95% CI 27 - 61%) completed testing. Rates of disclosure were higher among female vs male relatives (79% [95% CI 73% - 84%] vs 67% [95% CI 57% - 75%]) and first-degree vs second-degree relatives (83% [95% CI 77% - 88%] vs 58% [95% CI 45 – 69%]). Conclusion: Nearly one-third of at-risk relatives remain uninformed of their risk of carrying a cancer-associated pathogenic variant. Even among those informed, fewer than half subsequently complete genetic testing, representing a critical missed opportunity for precision cancer prevention. Innovation: Five studies evaluating interventions to improve disclosure rates were generally ineffective. Urgent work is needed to elucidate barriers to relative disclosure by probands to develop targeted interventions that can optimize proband-mediated cascade genetic testing rates.

Background: Women with pathogenic BRCA1 or BRCA2 variants are at high risk for breast and ovarian cancer. Preventive options include risk-reducing breast and ovarian surgeries and intensified breast surveillance. However, individual decision-making is often associated with decisional conflicts. Two evidence-based decision aids have recently been developed for these women (healthy or with unilateral breast cancer) for the German context to support them in their decision-making process. This study evaluated their effectiveness. Methods: In a randomized controlled study, women (aged 18–70 years) with pathogenic BRCA1 or BRCA2 variants were randomly assigned 1:1 to the intervention (IG, n = 230) or control (CG, n = 220) group. All participants received usual care. After baseline survey (t0), IG participants additionally received the DAs. Follow-up surveys were at three (t1) and six (t2) months. Primary outcome was decisional conflict at t1. Secondary analyses included decision status, decision regret, knowledge on risks and preventive options, self-reported psychological symptoms, acceptability of DAs, and preparation for decision-making. Results: Of 450 women recruited, 417 completed t0, 398 completed t1 and 386 completed t2. Compared to CG, IG participants had lower decisional conflict scores at t1 (p = 0.049) and t2 (p = 0.006) and higher scores for knowledge (p = 0.004), acceptability (p = 0.000), and preparation for decision-making (p < 0.01). Conclusions: These DAs can help improve key parameters of decision-making in women with pathogenic BRCA1 and BRCA2 variants and, thus, provide a useful add-on to the current counseling and care concept for these women in Germany. Trial registration: German Clinical Trials Register, DRKS-ID: DRKS00015823, retrospectively registered 14/06/2019. [ABSTRACT FROM AUTHOR]

Approximately 20% of ovarian cancers are due to an underlying germline pathogenic variant. While pathogenic variants in several genes have been well-established in the development of hereditary ovarian cancer (e.g. BRCA1/2, RAD51C, RAD51D, BRIP1, mismatch repair genes), the role of partner and localizer of BRCA2 (PALB2) remains uncertain. We sought to utilize meta-analysis to evaluate the association between PALB2 germline pathogenic variants and ovarian cancer. We conducted a systematic review and meta-analysis. We searched key electronic databases to identify studies evaluating multigene panel testing in people with ovarian cancer. Eligible trials were subjected to meta-analysis. Fifty-five studies met inclusion criteria, including 48,194 people with ovarian cancer and information available on germline PALB2 pathogenic variant status. Among people with ovarian cancer and available PALB2 sequencing data, 0.4% [95% CI 0.3–0.4] harbored a germline pathogenic variant in the PALB2 gene. The pooled odds ratio (OR) for carrying a PALB2 pathogenic variant among the ovarian cancer population of 20,474 individuals who underwent germline testing was 2.48 [95% CI 1.57–3.90] relative to 123,883 controls. Our meta-analysis demonstrates that the pooled OR for harboring a PALB2 germline pathogenic variant among people with ovarian cancer compared to the general population is 2.48 [95% CI 1.57–3.90]. Prospective studies evaluating the role of germline PALB2 pathogenic variants in the development of ovarian cancer are warranted. • There is emerging evidence that germline PALB2 pathogenic variants are associated with ovarian cancer. • Meta-analysis finds 0.4% [95% CI 0.30.4] of people with ovarian cancer harbor a germline PALB2 pathogenic variant. • People with ovarian cancer are more than twice as likely to carry germline PALB2 pathogenic variants compared to controls. [ABSTRACT FROM AUTHOR]

Background: Genetic testing can identify cancer risk early, enabling prevention and early detection. We describe use of risk management interventions following genetic testing in the Cancer Health Assessment Reaching Many (CHARM) study. CHARM assessed risk and provided genetic testing to low income, low literacy, and other underserved populations that historically face barriers to accessing cancer genetic services. Methods: CHARM was implemented in Kaiser Permanente Northwest (KPNW) and Denver Health (DH) between 2018 and 2020. We identified post‐testing screening (mammography, breast MRI, colonoscopy) and surgical (mastectomy, oophorectomy) procedures using electronic health records. We examined utilization in participants who did and did not receive actionable risk management recommendations from study genetic counselors following national guidelines. Results: CHARM participants were followed for an average of 15.4 months (range: 0.4–27.8 months) after results disclosure. Less than 2% (11/680) received actionable risk management recommendations (i.e., could be completed in the initial years following testing) based on their test result. Among those who received actionable recommendations, risk management utilization was moderate (54.5%, 6/11 completed any procedure) and varied by procedure (mammogram: 0/3; MRI: 2/4; colonoscopy: 4/5; mastectomy: 1/5; oophorectomy: 0/3). Cancer screening and surgery procedures were rare in participants without actionable recommendations. Conclusion: Though the number of participants who received actionable risk management recommendations was small, our results suggest that implementing CHARM's risk assessment and testing model increased access to evidence‐based genetic services and provided opportunities for patients to engage in recommended preventive care, without encouraging risk management overuse. [ABSTRACT FROM AUTHOR]

Germline pathogenic variants of BRCA1 or BRCA2 cause hereditary breast and ovarian cancer syndromes. The present study investigated the participants' understanding and awareness of germline BRCA1/2 pathogenic variants before genetic counseling, the expectations and obstacles for genetic testing from the perspective of participants and their families, and their attitudes towards genetic testing after counseling. In this single‐country, multicenter, non‐interventional, patient‐reported outcome study, untested cancer patients and their families who visited genetic counseling clinics or who wanted to receive pre‐test genetic counseling were eligible to fill in the questionnaire after pre‐test counseling for germline BRCA1/2 testing. Demographic information, clinical characteristics, and information collected from the questionnaires, including the understanding of BRCA1/2 pathogenic variants before genetic counseling, understanding of BRCA1/2 pathogenic variants and feelings after genetic counseling, willingness to share results of genetic testing with family, and willingness to receive genetic testing, were summarized using descriptive statistics. A total of 88 participants were enrolled. The proportion of slight understanding of BRCA1/2 pathogenic variants increased from 11.4% to 67.0%, and the proportion of full understanding increased from 0% to 8.0%. After genetic counseling, most participants were willing to undergo genetic testing (87.5%) and share the results with their families (96.6%). The main factors that may affect participants' willingness to undergo BRCA1/2 testing were management (61.2%) and testing costs (25.9%). After pre‐test counseling, there was a high acceptance of BRCA1/2 testing and in‐family information sharing in Taiwanese patients with cancer and their families, which may serve as a reference for implementing genetic counseling in Taiwan. [ABSTRACT FROM AUTHOR]

Abstract Background Damaging alterations in the BRCA1 gene have been extensively described as one of the main causes of hereditary breast and ovarian cancer (HBOC). BRCA1 alterations can lead to impaired homologous recombination repair (HRR) of double-stranded DNA breaks, a process which involves the RING, BRCT and coiled-coil domains of the BRCA1 protein. In addition, the BRCA1 protein is involved in transcriptional activation (TA) of several genes through its C-terminal BRCT domain. Methods In this study, we have investigated the effect on HRR and TA of 11 rare BRCA1 missense variants classified as variants of uncertain clinical significance (VUS), located within or in close proximity to the BRCT domain, with the aim of generating additional knowledge to guide the correct classification of these variants. The variants were selected from our previous study “BRCA1 Norway”, which is a collection of all BRCA1 variants detected at the four medical genetic departments in Norway. Results All variants, except one, showed a significantly reduced HRR activity compared to the wild type (WT) protein. Two of the variants (p.Ala1708Val and p.Trp1718Ser) also exhibited low TA activity similar to the pathogenic controls. The variant p.Trp1718Ser could be reclassified to likely pathogenic. However, for ten of the variants, the total strength of pathogenic evidence was not sufficient for reclassification according to the CanVIG-UK BRCA1/BRCA2 gene-specific guidelines for variant interpretation. Conclusions When including the newly achieved functional evidence with other available information, one VUS was reclassified to likely pathogenic. Eight of the investigated variants affected only one of the assessed activities of BRCA1, highlighting the importance of comparing results obtained from several functional assays to better understand the consequences of BRCA1 variants on protein function. This is especially important for multifunctional proteins such as BRCA1.

Abstract The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair‐defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer‐initiating cells in these patients usually undergo loss of the wild‐type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients.

Abstract Background In April 2020, insurance coverage for risk-reducing salpingo-oophorectomy (RRSO) for breast cancer patients with hereditary breast and ovarian cancer (HBOC) syndrome and BRCA testing were started in Japan. We investigated the impact of insurance coverage on the number of RRSO and BRCA tests performed. Methods The subjects were 370 breast cancer patients and 23 of their relatives who received genetic counseling at our institution between April 2014 and December 2021. Finally, 349 patients and 15 relatives were analyzed. We retrospectively compared the number of BRCA tests, RRSO, insurance status, and co-payment of medical expenses before and after insurance coverage based on medical records. Results In the 6-year pre-coverage period, 226 patients (mean: 37/year) received genetic counseling and 106 (17/year) received BRCA testing. In the 21-month post-coverage period, 161 patients (92/year) received genetic counseling and 127 (72/year) received BRCA testing. The rate of testing/counseling significantly increased in the post-coverage period (46.9% vs. 78.8%; p < .001). The number of patients who were diagnosed with HBOC were 24 (4/year) and 18 (10/year) and RRSO was performed for 7 (1/year) and 11 (6/year) patients in the pre- and post-coverage periods, respectively. The rate of RRSO/HBOC was significantly increased in the post-coverage period (29.1% vs. 61.1%; p = 0.039). RRSO patients' co-payment rates decreased from 64% to 25% pre- and post-coverage. Conclusions Our findings suggest that decreased co-payments were the primary reason for these increases. Insurance coverage is an important factor when promoting preventive medical services such as RRSO.

We determined the frequency and mutational spectrum of BRCA1 and BRCA2 in a series of patients at high risk for developing breast cancer from Brazil. A total of 1267 patients were referred for BRCA genetic testing, and no obligation of fulfilling criteria of mutation probability methods for molecular screening was applied. Germline deleterious mutations in BRCA1/2 (i.e., pathogenic/likely pathogenic variants) were identified in 156 out of 1267 patients (12%). We confirm recurrent mutations in BRCA1/2, but we also report three novel mutations in BRCA2, not previously reported in any public databases or other studies. Variants of unknown significance (VUS) represent only 2% in this dataset and most of them were detected in BRCA2. The overall mutation prevalence in BRCA1/2 was higher in patients diagnosed with cancer at age > 35 years old, and with family history of cancer. The present data expand our knowledge of BRCA1/2 germline mutational spectrum, and it is a valuable clinical resource for genetic counseling and cancer management programs in the country. [ABSTRACT FROM AUTHOR]

Abstract Background and purpose Over the last decade, the implementation of multigene panels for hereditary tumor syndrome has increased at our institution (Inselspital, University Hospital Berne, Switzerland). The aim of this study was to determine the prevalence of variants of unknown significance (VUS) in patients with suspected Lynch syndrome and suspected hereditary breast and ovarian cancer syndrome, the latter in connection with the trend toward ordering larger gene panels. Results Retrospectively collected data from 1057 patients at our institution showed at least one VUS in 126 different cases (11.9%). In patients undergoing genetic testing for BRCA1/2, the prevalence of VUS was 6%. When 10 additional genes, respectively. The gene most frequently affected with a VUS was ATM. 6% of our patients who were tested for Lynch syndrome had a VUS result in either MLH1, MSH2 or MSH6. Conclusions Our data demonstrate that panel testing statistically significantly increases VUS rates due to variants in non-BRCA genes. Good genetic counseling before and after obtaining results is therefore particularly important when conducting multigene panels to minimize patient uncertainty due to VUS results.

ABSTRACTBackground: National guidelines recommend cancer genetic risk assessment (CGRA) (i.e. genetic counseling prior to genetic testing) for women at increased risk for hereditary breast and ovarian cancer (HBOC). Less than one-half of eligible women obtain CGRA, leaving thousands of women and their family members without access to potentially life-saving cancer prevention interventions.Purpose: The Genetic Risk Assessment for Cancer Education and Empowerment Project (GRACE) addressed this translational gap, testing the efficacy of a tailored counseling and navigation (TCN) intervention vs. a targeted print brochure vs. usual care on CGRA intentions. Selected behavioral variables were theorized to mediate CGRA intentions.Methods: Breast and ovarian cancer survivors meeting criteria for guideline-based CGRA were recruited from three state cancer registries (N = 654), completed a baseline survey, and were randomized. TCN and targeted print arms received the brochure; TCN also participated in a tailored, telephone-based decision coaching and navigation session grounded in the Extended Parallel Process Model and Ottawa Decision Support Framework. Participants completed a one-month assessment. Logistic regression was used to compare the rate of CGRA intentions. CGRA intentions and theorized mediator scores (continuous level variables) were calculated using mixed model analysis.Results: CGRA intentions increased for TCN (53.2%) vs. targeted print (26.7%) (OR = 3.129; 95% CI: 2.028, 4.827, p

Abstract Hereditary breast and ovarian cancer (HBOC) syndrome has increased predisposition to breast and/or ovarian cancer, and 24% of families with HBOC were associated with the germline pathogenic variants in BRCA1/2. Timely diagnosis and identification of mutation carriers is of utmost importance to improve survival benefit and quality of life. Cancers that have been included into screening of BRCA1/2 associated HBOC included prostate and pancreatic cancers etc. In this case, we reported a patient who firstly presented symptoms of CRC and was finally diagnosed as BRCA1 associated HBOC with advanced peritoneal carcinoma. With strategies of cetuximab based treatment and olaparib, and debulking surgeries, she has achieved an overall survival (OS) > 35 months. The aim was to indicate that HBOC might also first present as CRC, and comprehensive next-generation sequencing analysis might be a key complement for screening and diagnose of HBOC.

Background: Damaging alterations in the BRCA1 gene have been extensively described as one of the main causes of hereditary breast and ovarian cancer (HBOC). BRCA1 alterations can lead to impaired homologous recombination repair (HRR) of double-stranded DNA breaks, a process which involves the RING, BRCT and coiled-coil domains of the BRCA1 protein. In addition, the BRCA1 protein is involved in transcriptional activation (TA) of several genes through its C-terminal BRCT domain. Methods: In this study, we have investigated the effect on HRR and TA of 11 rare BRCA1 missense variants classified as variants of uncertain clinical significance (VUS), located within or in close proximity to the BRCT domain, with the aim of generating additional knowledge to guide the correct classification of these variants. The variants were selected from our previous study “BRCA1 Norway”, which is a collection of all BRCA1 variants detected at the four medical genetic departments in Norway. Results: All variants, except one, showed a significantly reduced HRR activity compared to the wild type (WT) protein. Two of the variants (p.Ala1708Val and p.Trp1718Ser) also exhibited low TA activity similar to the pathogenic controls. The variant p.Trp1718Ser could be reclassified to likely pathogenic. However, for ten of the variants, the total strength of pathogenic evidence was not sufficient for reclassification according to the CanVIG-UK BRCA1/BRCA2 gene-specific guidelines for variant interpretation. Conclusions: When including the newly achieved functional evidence with other available information, one VUS was reclassified to likely pathogenic. Eight of the investigated variants affected only one of the assessed activities of BRCA1, highlighting the importance of comparing results obtained from several functional assays to better understand the consequences of BRCA1 variants on protein function. This is especially important for multifunctional proteins such as BRCA1. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the knowledge and educational needs with regard to hereditary breast and ovarian cancer among nurses working in breast cancer care in the Nagasaki Prefecture. In breast cancer care, the identification of patients at risk for hereditary breast and ovarian cancer is necessary for the implementation of genetic testing and counseling. Nurses should be involved in this process, since they play a crucial role in the care of patients with breast cancer. However, the knowledge regarding hereditary breast and ovarian cancer among nurses working in oncology care in Japan has not been assessed. The design of this study is cross-sectional design. We distributed 597 surveys to nurses working in breast cancer care. The surveys assessed the nurses' demographic data, their current knowledge and practices regarding cancer genetics and hereditary breast and ovarian cancer, and their attitude and preferences regarding learning about the condition. We received 317 valid replies. Nurses had limited knowledge about hereditary breast and ovarian cancer characteristics: 41.6% reported that they do not know about the condition, whereas less than 10% knew its characteristics. However, nurses were aware of hereditary breast and ovarian cancer significance and were willing to learn about it: 91% wished to learn about the condition, and 88.6% wanted to participate in study group meetings. Further, nurses' preferences regarding educational programs were clarified. Overall, our results show that educational programs should be implemented to advance nurses' knowledge of hereditary breast and ovarian cancer characteristics. [ABSTRACT FROM AUTHOR]

In the Republic of Ireland (ROI), BRCA1/BRCA2 genetic testing has been traditionally undertaken in eligible individuals, after pre-test counselling by a Clinical Geneticist/Genetic Counsellor. Clinical Genetics services in ROI are poorly resourced, with routine waiting times for appointments at the time of this pilot often extending beyond a year. The consequent prolonged waiting times are unacceptable where therapeutic decision-making depends on the patient's BRCA status. "Mainstreaming" BRCA1/BRCA2 testing through routine oncology/surgical clinics has been implemented successfully in other centres in the UK and internationally. We aimed to pilot this pathway in three Irish tertiary centres. A service evaluation project was undertaken over a 6-month period between January and July 2017. Eligible patients, fulfilling pathology and age-based inclusion criteria defined by TGL clinical, were identified, and offered constitutional BRCA1/BRCA2 testing after pre-test counselling by treating clinicians. Tests were undertaken by TGL Clinical. Results were returned to clinicians by secure email. Onward referrals of patients with uncertain/pathogenic results, or suspicious family histories, to Clinical Genetics were made by the treating team. Surveys assessing patient and clinician satisfaction were sent to participating clinicians and a sample of participating patients. Data was collected with respect to diagnostic yield, turnaround time, onward referral rates, and patient and clinician feedback. A total of 101 patients underwent diagnostic germline BRCA1/BRCA2 tests through this pathway. Pathogenic variants were identified in 12 patients (12%). All patients in whom variants were identified were appropriately referred to Clinical Genetics. At least 12 additional patients with uninformative BRCA1/BRCA2 tests were also referred for formal assessment by Clinical Geneticist or Genetic Counsellor. Issues were noted in terms of time pressures and communication of results to patients. Results from a representative sample of participants completing the satisfaction survey indicated that the pathway was acceptable to patients and clinicians. Mainstreaming of constitutional BRCA1/BRCA2 testing guided by age- and pathology-based criteria is potentially feasible for patients with breast cancer as well as patients with ovarian cancer in Ireland. [ABSTRACT FROM AUTHOR]