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.

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.

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.

Introduction:HBOPC syndrome is mostly associated with germline pathogenic and likely pathogenic variants (PV) in BRCA1 and BRCA2 genes. Other high and moderate penetrance genes are increasingly diagnosed in these families, especially after implementation of NGS methodologies in clinical practice. In this study we analyze the global and regional mutational patterns of Portuguese HBOPC families, looking for associated phenotypes and possible clusters of specific PV. Methods:Observational study including all index patients (pts) with identified PV in genes associated with breast, ovarian and prostate cancers in our Centre, between 2000 and 2020. Geographical mapping of variants was done regarding residency and birth origin. Main cancer diagnoses of pts were also registered. Results:Between January 2000 and December 2020, 5233 index pts consented in genetic testing and 658 (12.6%) tested positive for a PV associated with HBOPC syndrome (84 were non-Portuguese residents). Regarding these 658 positive pts, 537 (81.6%) had breast (BC), 113 (17.2%) had ovarian and 9 (1.4%) had prostate cancer. BRCA2 was the most mutated gene (302 pts, 45.9%), followed by BRCA1 (179 pts, 27.2%), while PV in other genes were diagnosed in 177 (26.9%) pts (CHEK2, ATM, PALB2, RAD51C, TP53, RAD51D, MUTYH, BRIP1, RAD50, BLM and PTEN PV were identified in 54 (8.2%), 27 (4.1%), 21 (3.2%), 17 (2.6%), 16 (2.4%), 14 (2.1%), 11 (1.7%), 7 (1.1%), 4 (0.6%), 4 (0.6%) and 2 (0.3%) pts, respectively). PV in MSH2, MLH1, FAM175A and MRE11A were each described in 1 (0.15%) pt, all diagnosed with BC. Double heterozygosity was identified in 7 (1.1%) pts: BRCA1/BRCA2, BRCA1/CHEK2, BRCA2/PALB2, BRCA2/CHEK2, ATM/PALB2, ATM/RAD51C and MUTYH/MSH2. BRCA2 PV were more frequent than BRCA1 in all Portuguese regions except Algarve, where BRCA2 frequency was lower (BRCA1:BRCA2 > 1). The known BRCA2 founder c.156_157insAlu was the most recurrently diagnosed PV: 36.4% of all BRCA2 families including 8 non-Portuguese families (6 from Angola, 1 from France and 1 from Brazil). Further analysis revealed 3 possible regional clusters: 1- Duplication of exon 12 (previously described as ins6KbEx13) was the only BRCA1 identified in Algarve, with 90.9% of all families with this PV originating in this region; 2- 75% of all BRCA2 c.6405_6409del; p.(Asn2135LysfsTer3) families have origin in Alentejo, being the third most diagnosed BRCA event in the region, after c.156_157insAlu and c.5266dup; p.(Gln1756ProfsTer74); 3- c.3331_3334del; (p.Gln1111AsnfsTer5) was the only BRCA1 PV identified in Madeira (6 families). When comparing Portuguese and foreign pts, similar rates of breast, ovarian and prostate cancers were found (81.5%, 17.2% and 1.2% versus 82.1%, 16.7% and 2.4%, respectively). Most foreign residents lived in Lisboa and Vale do Tejo (82,1%) and their BRCA1:BRCA2 ratio was 0,87 (versus 0,46 in Portuguese pts), while in Algarve (13,5%) their BRCA1:BRCA2 was even higher (1.5 versus 0,69 in Portuguese pts). Discussion and conclusion:Our study confirms that BRCA2 PV are more frequent than BRCA1 PV in Portugal, with the exception of the Algarve region. Our data suggests that foreign pts accessing genetic testing in this region may have imbalanced the BRCA1:BRCA2 ratio, while for the whole population the imbalance towards BRCA2 is associated with the known founder BRCA2 c.156_157insAlu. Our data identified 2 BRCA1 (Algarve and Madeira) and 1 BRCA2 (Alentejo) geographical clusters. Citation Format: Inês Calvinho de Oliveira, Sofia Fragoso, Sidónia Santos, Teresa Duarte, Catarina Bexiga, Beatriz Mira, Isália Miguel, Ana Luís, Fátima Vaz. Geographical patterns of pathogenic genetic variants associated with hereditary breast, ovarian and prostate cancer (HBOPC) in Portugal [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-04.

Ovarian cancer (OC) is the most lethal gynecological malignancy, largely because non-specific symptoms contribute to advanced-stage diagnosis and poor prognosis, underscoring the need for improved non-invasive biomarkers. Circulating microRNAs (c-miRNAs) have emerged as promising candidates for OC detection, risk stratification, prognosis, and treatment monitoring. This systematic review, prospectively registered in PROSPERO (CRD420251230898), evaluated the diagnostic and prognostic performance of c-miRNAs and miRNA-based multivariate signatures. MEDLINE/PubMed, Scopus, and CENTRAL were searched from inception to 30 May 2026. Eligible studies assessed c-miRNAs in serum, plasma, whole blood, or extracellular vesicle fractions from women with confirmed or suspected OC including studies using prediagnostic samples from women subsequently diagnosed with OC. Records were screened, data extracted, and risk of bias evaluated according to the type of result using QUADAS-2 for diagnostic accuracy, QUIPS for prognostic-factor associations, and PROBAST for multivariable prediction models. Of 697 records identified, 91 publications met the inclusion criteria. Most studies used case–control or observational designs and analysed serum or plasma samples. Single c-miRNAs generally showed moderate diagnostic accuracy, whereas multivariate miRNA panels and multimodal models incorporating CA-125 or HE4 generally reported higher AUC values, including in some early-stage cohorts. Frequently reported candidates included members of the miR-200 family, miR-21, miR-1246, miR-125b, miR-145, miR-205, and miR-130a. Prognostic studies associated c-miRNAs with survival, recurrence, treatment response, and chemoresistance, although findings were more heterogeneous than diagnostic findings. Risk-of-bias concerns were common, particularly for patient selection in diagnostic studies, confounding in prognostic-factor analyses, and statistical analysis in prediction-model studies. Overall, c-miRNAs represent promising non-invasive biomarkers for OC, particularly when integrated into multivariate or multimodal models. However, methodological heterogeneity, small cohort sizes, limited external validation, and inconsistent reporting currently restrict clinical translation. Future studies should prioritize standardized pre-analytical and analytical workflows, adequately powered prospective cohorts, and independent multicenter validation.