Department of Biochemistry

Male breast cancer (mBC) is associated with a high prevalence of pathogenic variants (PVs) in the BRCA2 gene; however, data regarding other BC predisposition genes are limited. In this retrospective multicenter study, we investigated the prevalence of PVs in BRCA1/2 and 23 non-BRCA1/2 genes using a sample of 614 patients with mBC, recruited through the centers of the German Consortium for Hereditary Breast and Ovarian Cancer. A high proportion of patients with mBC carried PVs in BRCA2 (23.0%, 142/614) and BRCA1 (4.6%, 28/614). The prevalence of BRCA1/2 PVs was 11.0% in patients with mBC without a family history of breast and/or ovarian cancer. Patients with BRCA1/2 PVs did not show an earlier disease onset than those without. The predominant clinical presentation of tumor phenotypes was estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and HER2-negative (77.7%); further, 10.2% of the tumors were triple-positive, and 1.2% were triple-negative. No association was found between ER/PR/HER2 status and BRCA1/2 PV occurrence. Comparing the prevalence of protein-truncating variants (PTVs) between patients with mBC and control data (ExAC, n = 27,173) revealed significant associations of PTVs in both BRCA1 and BRCA2 with mBC (BRCA1: OR = 17.04, 95% CI = 10.54–26.82, p < 10−5; BRCA2: OR = 77.71, 95% CI = 58.71–102.33, p < 10−5). A case-control investigation of 23 non-BRCA1/2 genes in 340 BRCA1/2-negative patients and ExAC controls revealed significant associations of PTVs in CHEK2, PALB2, and ATM with mBC (CHEK2: OR = 3.78, 95% CI = 1.59–7.71, p = 0.002; PALB2: OR = 14.77, 95% CI = 5.02–36.02, p < 10−5; ATM: OR = 3.36, 95% CI = 0.89–8.96, p = 0.04). Overall, our findings support the benefit of multi-gene panel testing in patients with mBC irrespective of their family history, age at disease onset, and tumor phenotype.

Pancreatic cancer remains one of the most lethal malignancies and is becoming a dramatically increasing cause of cancer-related mortality worldwide. Abundant desmoplastic stroma is a histological hallmark of pancreatic ductal adenocarcinoma. Emerging evidence suggests a promising therapeutic effect of several stroma-modifying therapies that target desmoplastic stromal elements in the pancreatic cancer microenvironment. The evidence also unveils multifaceted roles of cancer-associated fibroblasts (CAFs) in manipulating pancreatic cancer progression, immunity, and chemotherapeutic response. Current state-of-the-art technologies, including single-cell transcriptomics and multiplexed tissue imaging techniques, have provided a more profound knowledge of CAF heterogeneity in real-world specimens from pancreatic cancer patients, as well as in genetically engineered mouse models. In this review, we describe recent advances in the understanding of the molecular pathology bases of pancreatic cancer desmoplastic stroma at multilayered levels of heterogeneity, namely, (1) variations in cellular and non-cellular members, including CAF subtypes and extracellular matrix (ECM) proteins; (2) geographical heterogeneity in relation to cell–cell interactions and signaling pathways at niche levels and spatial heterogeneity at locoregional levels or organ levels; and (3) intertumoral stromal heterogeneity at individual levels. This review further discusses the clinicopathological significance of desmoplastic stroma and the potential opportunities for stroma-targeted therapies against this lethal malignancy.

There is scarce evidence on the comparison between different methods for the drainage of distal malignant biliary obstruction (DMBO) after endoscopic retrograde cholangiopancreatography (ERCP) failure. Therefore, we performed a network meta-analysis to compare the outcomes of these techniques. We searched main databases through September 2021 and identified five randomized controlled trials. The primary outcome was clinical success. The secondary outcomes were technical success, overall and serious adverse event rate. Percutaneous trans-hepatic biliary drainage was found to be inferior to other interventions (PTBD: RR 1.01, 0.88–1.17 with EUS-choledochoduodenostomy (EUS-CD); RR 1.03, 0.86–1.22 with EUS-hepaticogastrostomy (EUS-HG); RR 1.42, 0.90–2.24 with surgical hepaticojejunostomy). The comparison between EUS-HG and EUS-CD was not significant (RR 1.01, 0.87–1.17). Surgery was not superior to other interventions (RR 1.40, 0.91–2.13 with EUS-CD and RR 1.38, 0.88–2.16 with EUS-HG). No difference in any of the comparisons concerning adverse event rate was detected, although PTBD showed a slightly poorer performance on ranking analysis (SUCRA score 0.13). In conclusion, all interventions seem to be effective for the drainage of DMBO, although PTBD showed a trend towards higher rates of adverse events.