Comparing Prognosis for BRCA1, BRCA2, and Non-BRCA Breast Cancer.

BACKGROUND: Germline pathogenic variants (PV) in BRCA1 and BRCA2 genes, which account for 20% of familial breast cancer (BC) cases, are highly penetrant and are associated with Hereditary Breast/Ovarian Cancer Syndrome. Previous studies, mostly including higher numbers of BRCA1 BC patients, yielded conflicting results regarding BRCA1/2 BC outcomes. In the Portuguese population, BRCA2 BC is diagnosed more frequently than BRCA1 BC. We aimed to compare clinicopathological characteristics and prognosis between BC patients with BRCA1 and BRCA2 mutations and a control group without germline PV (BRCA-wt). Furthermore, we explored the frequency and outcomes of risk-reducing surgeries in BRCA-mutated patients. METHODS: Prospective follow-up was proposed for patients with a diagnosed BRCA1/2 PV. For this study, a matched control group (by age at diagnosis, by decade, and by stage at diagnosis) included BC patients without germline PV. We compared overall survival (OS) and invasive disease-free survival (iDFS) within the three groups, and the use of risk-reducing surgeries among the BRCA cohort. RESULTS: For a mean follow-up time of 113.0 months, BRCA-wt patients showed longer time to recurrence (p = 0.002) and longer OS (p < 0.001). Among patients with BRCA mutations, no statistical differences were found, although patients with BRCA2 BC had longer iDFS and OS. Uptake of risk-reducing surgeries (contralateral prophylactic mastectomy and salpingo-oophorectomy) were negative predictors of invasive disease and death, respectively. CONCLUSIONS: Testing positive for a BRCA PV is associated with a higher risk of relapse and death in patients with BC in the Portuguese population. Risk-reducing mastectomy and salpingo-oophorectomy were associated with lower incidence of relapse and longer median iDFS and OS, respectively.

Is There a Role for Risk-Reducing Bilateral Breast Surgery in BRCA1/2 Ovarian Cancer Survivors? An Observational Study.

BACKGROUND: Risk-reducing surgeries are an option for cancer risk management in BRCA1/2 individuals. However, while adnexectomy is commonly recommended in breast cancer (BC) survivors, risk-reducing bilateral breast surgery (RRBBS) is controversial in ovarian cancer (OC) survivors due to relapse rates and mortality. METHODS: We conducted a retrospective analysis of BRCA1/2-OC survivors, with OC as first cancer diagnosis. RESULTS: Median age at OC diagnosis for the 69 BRCA1/2-OC survivors was 54 years. Median overall survival was 8 years, being significantly higher for BRCA2 patients than for BRCA1 patients (p = 0.011). Nine patients (13.2%) developed BC at a median age of 61 years. The mean overall BC-free survival was 15.5 years (median not reached). Eight patients (11.8%) underwent bilateral mastectomy (5 simultaneous with BC treatment; 3 RRBBS) at a median age of 56.5 years. The median time from OC to bilateral mastectomy/RRBBS was 5.5 years. CONCLUSIONS: This study adds evidence regarding a lower BC risk after BRCA1/2-OC and higher survival for BRCA2-OC patients. A comprehensive analysis of the competing risks of OC mortality and recurrence against the risk of BC should be individually addressed. Surgical BC risk management may be considered for longer BRCA1/2-OC disease-free survivors. Ultimately, these decisions should always be tailored to patients' characteristics and preferences.

Hereditary breast cancer and ancestry in the Madeira archipelago: an exploratory study.

Access to genetic testing and counselling in remote areas such as the Madeira archipelago, in the Northern Atlantic Ocean, may be complex. Different counselling methods, including telegenetics, should be explored. In this study, we characterise the Hereditary Breast/Ovarian Cancer (HBOC) families with Madeira ancestry enrolled in our programme. Of a total of 3,566 index patients tested between January 2000 and June 2018, 68 had Madeira ancestry and 22 were diagnosed with a pathogenic germline variant (PV). As in the whole group, BRCA2 PV were more frequent in Madeira patients (68.4%: c.9382C>T (26.3%), c.658_659del (21%), c.156_157insAlu (10.5%), c.793+1G>A (5.3%) and c.298A>T (5.3%). However, the most frequently diagnosed PV in Madeira patients was the BRCA1 c.3331_3334del (31.6%). BRCA1/2 detection rates were 27.9% and 10.5% for Madeira and the whole group, respectively. This study is the first characterisation of HBOC patients with Madeira ancestry. A distinct pattern of BRCA1/2 variants was observed, and the geographic clustering of BRCA1 c.3331_3334del variant may support the possibility of a founder mutation previously described in Northern Portugal. The high detection rate observed reinforces the need to reduce gaps in access to genetic testing in Madeira and other remote areas. According to current guidelines, timely identification of HBOC patients can contribute to their ongoing care and treatment.

High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma.

Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. CDH23, ARHGEF40, and BRD9 were identified as the most promising susceptibility genes in hereditary melanoma. In silico analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of CDH23, ARHGEF40, and BRD9 expression in sporadic melanoma by using the TCGA dataset (n = 461). No differences were observed in BRD9 expression between melanoma and normal skin samples, nor with melanoma stage, whereas ARHGEF40 was found overexpressed, and CDH23 was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.

Men seeking counselling in a Breast Cancer Risk Evaluation Clinic.

BACKGROUND: Hereditary breast and ovary cancer syndrome affects both genders but little is known about the uptake of genetic services by men. The objective of this study is to characterise the male population counselled through a multidisciplinary breast/ovarian program. METHODS: Descriptive analysis of male patients counselled from January 2000 to December 2015. Data in this analysis include new cancer diagnoses during prospective follow up. RESULTS: From 4,320 families registered, 362 male patients were identified: 236 (65.2%) from hereditary cancer families (HCF) and 126 (34.8%) from non-HCF. In HCF, 121 patients (51.3%) were mutation carriers (MC): BRCA2 - 102 (84.3%), BRCA1 - 16 (13.2%), CHEK2 - 1 (0.8%) and TP53 - 2 (1.7%). Non-HCF included 126 patients: 85 (67.5%) belonged to families without pathogenic mutations or with variants of unknown clinical significance; 22 (17.5%) refused testing after counselling and 19 (15.0%) did not meet criteria for testing. Both HCF and non-HCF included patients with previous cancer diagnoses: HCF- Breast Cancer (BC) - 18; prostate cancer (PC) - 13; melanoma - 1; others - 7) and non-HCF (BC - 77; PC - 20; gastric cancer (GC) - 1; melanoma - 8; bladder cancer - 1; others - 22). From the 121 MC identified (including the TP53 and CHEK2 carriers), 97 patients (80.2%) adhered to prospective surveillance. With a median follow-up of 36.9 months, 17 cancers were diagnosed in 14 patients, PC being the most frequently diagnosed neoplasia (5 cases). Eleven patients (78.6%) are alive and three patients died of advanced cancer (2 with GC, 1 with disseminated adenocarcinoma). CONCLUSION: We observed a high adherence to counselling, genetic testing and active surveillance by men belonging to hereditary BC families. Male carriers of pathogenic DNA variants are at risk for several cancers and should be included in prospective follow-up studies.

Aggressive phenotype of MYH-associated polyposis with jejunal cancer and intra-abdominal desmoid tumor: report of a case.

MYH-associated polyposis is an inherited autosomal recessive disease, linked to biallelic germline MYH mutations, which predisposes to the development of multiple colorectal adenomas and cancer. The colonic and extracolonic phenotype of this syndrome is very heterogeneous. We report the case of a young male patient with an aggressive MYH-associated polyposis phenotype. He presented at aged 30 years with more than 100 colonic polyps and 4 colonic adenocarcinomas. At aged 35 years, Spigelman Stage IV duodenal adenomatosis was detected. When he was 39 years old, he developed three synchronous jejunal adenocarcinomas and a mesenteric desmoid tumor. Based on this report, we believe that screening of the entire small bowel should be recommended in MYH-associated polyposis patients, especially in those with duodenal adenomas. Similar to patients with familial adenomatous polyposis, desmoid tumors also may be part of the clinical spectrum of MYH-associated polyposis and may prove to be a significant clinical problem in patients submitted to prophylactic colectomy.

[MYH associated polyposis: severe phenotype in the homozygosity for the 1103delC mutation]. / Polipose associada ao MYH: fenótipo grave na homozigotia para a mutação 1103delC.

MYH-associated polyposis (MAP) is an autosomal recessive disease associated with multiple colonic adenomas and colorectal cancer. Y165C and G382D MYH missense mutations are involved in more than 80% of cases in Caucasians and the large series published do not include patients homozygous for other mutations. We present the report of two siblings homozygous for the nonsense frameshift mutation 1103delC. The proband aged 28 presented with four colonic adenocarcinomas and 20-30 synchronous adenomas. Her sister aged 24 had 20 colonic adenomas and a severe Spigelman's III duodenal adenomatosis. Their parents, aged 60 and 51, heterozygous for the 1103delC MYH mutation, presented 5 and 2 low risk colorectal adenomas, respectively.