BUB1B monoallelic germline variants contribute to prostate cancer predisposition by triggering chromosomal instability.

BACKGROUND: Prostate cancer (PrCa) is the most frequently diagnosed cancer in men. Variants in known moderate- to high-penetrance genes explain less than 5% of the cases arising at early-onset (< 56 years) and/or with familial aggregation of the disease. Considering that BubR1 is an essential component of the mitotic spindle assembly checkpoint, we hypothesized that monoallelic BUB1B variants could be sufficient to fuel chromosomal instability (CIN), potentially triggering (prostate) carcinogenesis. METHODS: To unveil BUB1B as a new PrCa predisposing gene, we performed targeted next-generation sequencing in germline DNA from 462 early-onset/familial PrCa patients and 1,416 cancer patients fulfilling criteria for genetic testing for other hereditary cancer syndromes. To explore the pan-cancer role of BUB1B, we used in silico BubR1 molecular modeling, in vitro gene-editing, and ex vivo patients' tumors and peripheral blood lymphocytes. RESULTS: Rare BUB1B variants were found in ~ 1.9% of the early-onset/familial PrCa cases and in ~ 0.6% of other cancer patients fulfilling criteria for hereditary disease. We further show that BUB1B variants lead to decreased BubR1 expression and/or stability, which promotes increased premature chromatid separation and, consequently, triggers CIN, driving resistance to Taxol-based therapies. CONCLUSIONS: Our study shows that different BUB1B variants may uncover a trigger for CIN-driven carcinogenesis, supporting the role of BUB1B as a (pan)-cancer predisposing gene with potential impact on genetic counseling and treatment decision-making.

The Initial Journey of Patients with Metastatic Pancreatic Cancer (PaCTO Project): A Nationwide Survey among Portuguese Specialist Physicians.

Introduction: We aimed to characterize the initial healthcare journey of metastatic pancreatic ductal adenocarcinoma (mPDAC) patients in Portugal, including healthcare provision and factors affecting therapeutic decisions, namely BRCA mutations testing. Methods: This is a descriptive cross-sectional, web-based survey using a convenience sampling approach. Portuguese oncologists and pathologists that routinely work with mPDAC patients from the different geographical regions and settings were invited to participate in the study via email (December 2020). Descriptive statistical analyses were performed, with categorical variables reported as absolute and relative frequencies, and continuous variables with non-normal distribution as median and interquartile range (IQR) (Stata v.15.0). Results: Seventy physicians participated in the study (43 oncologists, 27 pathologists). According to the responses, a median of 28 patients per center (IQR 12-70) was diagnosed with PDAC in the previous year; 22 of them referring (IQR 8-70) to mPDAC. The pointed median time from patients' first hospital admission until disease diagnosis/staging is between 2 and 4 weeks. Endoscopic ultrasound with fine-needle biopsy is available in most hospitals (86%). Around 50% of physicians request BRCA testing; the assessment of additional biomarkers besides BRCA is requested by 40% of professionals. Half of them stated that BRCA testing should be requested earlier-upon histological diagnosis, especially because the median time for results is of 4.0 weeks (IQR 4-8). PARP inhibitors such as olaparib, when available, would be the therapy of choice for most oncologists (71%) if no disease' progression occurs after 4 months. Treatments' selection is usually grounded on clinical criteria (e.g., performance status, liver function). Around 45% of patients use FOLFIRINOX/mFOLFIRINOX as the first-line therapy. Gemcitabine + nab-paclitaxel is used by 35% of patients as the second-line therapy. Conclusions: Physicians in Portugal support the increasing role of patient-tailored treatments in mPDAC, whose selection should be grounded on tumoral subtyping and molecular profiling. Further efforts to develop multidisciplinary teams, standardized clinical practice, and optimize the implementation of new target therapies are needed.

Introdução: Este estudo teve como objetivo caracterizar o percurso inicial dos doentes com adenocarcinoma ductal pancreático metastático (ACDPm) em Portugal, incluindo a prestação de cuidados de saúde e determinação de fatores que afetam as decisões terapêuticas, nomeadamente o teste de mutações BRCA. Métodos: Trata-se de um estudo descritivo transversal (web-based) usando uma abordagem de amostragem por conveniência. Médicos oncologistas e anatomopatologistas portugueses dedicados ao ACDPm e de diferentes regiões geográficas e instituições foram convidados a participar do estudo por email (Dez-2020). Foram realizadas análises estatísticas descritivas, com variáveis categóricas relatadas como frequências absolutas e relativas, e variáveis contínuas com distribuição não-normal como mediana e intervalo interquartil (IIQ) (Stata v.15.0). Resultados: Setenta médicos participaram do estudo (43 oncologistas, 27 patologistas). De acordo com as respostas, uma mediana de 28 doentes por centro (IIQ 12­70) foi diagnosticada com ACDP no ano anterior; 22 deles (IIQ 8­70) referentes a ACDPm. O tempo médio desde a primeira admissão hospitalar dos doentes até o diagnóstico/estadiamento da doença foi entre 2­4 semanas. A ultrassonografia endoscópica com biópsia por agulha fina é realizada pela maioria dos hospitais (86%). Aproximadamente 50% dos médicos referem solicitar o teste BRCA; a avaliação de biomarcadores adicionais além do BRCA é solicitada por 40% dos profissionais. Metade dos médicos assume que o teste BRCA deveria ser solicitado mais precocemente ­ durante o diagnóstico histológico, principalmente porque o tempo médio para obtenção do resultado é de 4,0 semanas (IIQ 4­8). Os inibidores PARP, como o olaparibe, quando disponíveis, seriam a terapia de escolha para a maioria dos oncologistas (71%) caso não haja progressão da doença após quatro meses. A seleção dos tratamentos é usualmente baseada em critérios clínicos (por exemplo, performance status, função hepática). Em cerca de 45% dos doentes é utilizado FOLFIRINOX/mFOLFIRINOX como terapia de primeira linha. Um esquema com Gemcitabina + nab-paclitaxel é usado em 35% dos doentes como terapia de segunda linha. Conclusões: Os médicos em Portugal apoiam o papel crescente do tratamento individualizado no ACDPm, cuja seleção deve ser baseada na subtipagem tumoral e no perfil molecular. São necessários mais esforços para capacitar as equipas multidisciplinares, desenvolver práticas clínicas padronizadas e otimizar a implementação de novas terapias-alvo.

Corrigendum: Evaluation of PIK3CA mutations in advanced ER+/HER2-breast cancer in Portugal - U-PIK Project.

[This corrects the article DOI: 10.3389/fmolb.2023.1082915.].

Cluster effect for SNP-SNP interaction pairs for predicting complex traits.

Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP-SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP-SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP-SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a hub SNP with a significant main effect and a large minor allele frequency (MAF) tended to have a higher false-positive rate. In addition, peripheral null SNPs in a cluster with a small MAF tended to enhance false positivity. We also demonstrated that using the modified significance criterion based on the 3 p-value rules and the bootstrap approach (3pRule + bootstrap) can reduce false positivity and maintain high true positivity. In addition, our results also showed that a pair without a significant main effect tends to have weak or no interaction. This study identified the cluster effect and suggested using the 3pRule + bootstrap approach to enhance SNP-SNP interaction detection accuracy.