Germline drivers of gynecologic carcinosarcomas.

Objectives: To describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma.

Methods: Patients with endometrial or ovarian carcinosarcomas who underwent clinical tumor-normal sequencing from 1/1/2015 to 6/1/2021 and consented to germline assessment of ≥76 cancer predisposition genes were included. In patients with gPVs, biallelic inactivation was identified through analysis of loss of heterozygosity and somatic pathogenic alterations.

Methylation Analyses Reveal Promoter Hypermethylation as a Rare Cause of "Second Hit" in Germline BRCA1-Associated Pancreatic Ductal Adenocarcinoma.

Background And Objective: Pancreatic ductal adenocarcinoma (PDAC) is characterized by the occurrence of pathogenic variants in BRCA1/2 in 5-6% of patients. Biallelic loss of BRCA1/2 enriches for response to platinum agents and poly (ADP-ribose) polymerase 1 inhibitors. There is a dearth of evidence on the mechanism of inactivation of the wild-type BRCA1 allele in PDAC tumors with a germline BRCA1 (gBRCA1) pathogenic or likely pathogenic variant (P/LPV).

Gene-based Confirmatory Germline Testing Following Tumor-only Sequencing of Prostate Cancer.

Background: Tumor-only genomic profiling is an important tool in therapeutic management of men with prostate cancer. Since clinically actionable germline variants may be reflected in tumor profiling, it is critical to identify which variants have a higher risk of being germline in origin to better counsel patients and prioritize genetic testing.

Objective: To determine when variants found on tumor-only sequencing of prostate cancers should prompt confirmatory germline testing.

Author Correction: Tumour lineage shapes BRCA-mediated phenotypes.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma.

Fumarate hydratase (FH) mutations underpin the autosomal recessive syndrome. FH deficiency and the autosomal dominant syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH c.

Tumour lineage shapes BRCA-mediated phenotypes.

Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP).

Development and Validation of a Mass Spectrometry-Based Assay for the Molecular Diagnosis of Mucin-1 Kidney Disease.

Mucin-1 kidney disease, previously described as medullary cystic kidney disease type 1 (MCKD1, OMIM 174000), is an autosomal dominant tubulointerstitial kidney disease recently shown to be caused by a single-base insertion within the variable number tandem repeat region of the MUC1 gene. Because of variable age of disease onset and often subtle signs and symptoms, clinical diagnosis of mucin-1 kidney disease and differentiation from other forms of hereditary kidney disease have been difficult. The causal insertion resides in a variable number tandem repeat region with high GC content, which has made detection by standard next-generation sequencing impossible to date.