Ewa Kaznowska | Search PubMed

PubMed2026

Germline ATRIP variants and the risk of ovarian cancer.

PURPOSE: We have previously reported that inherited variants in ATRIP confer a 3-fold risk of developing breast cancer. Here, we investigated potential association between this novel breast cancer susceptibility gene and the risk of ovarian cancer. METHODS: We genotyped the ATRIP c.1152_1155del p.(Gly385Ter) Polish founder variant on germline DNA from 3404 Polish women with ovarian cancer and 9285 healthy controls. Additionally, we sequenced all coding exons of ATRIP among 1322 unselected ovarian cancer patients and 930 cancer-free women from Ontario, Canada. RESULTS: The heterozygous ATRIP c.1152_1155del p.(Gly385Ter) variant was identified in 8 of 3404 ovarian cancer cases and 11 of 9285 controls in the Polish population (OR = 1.98, 95% CI = 0.79-4.94, P = .19). In the Ontario cohort, 4 ovarian cancer cases harbored ATRIP loss-of-function (LoF) variants, versus none observed among controls (OR = 5.6, P = .14). In a combined analysis of both cohorts, adjusted for age, self-reported ethnicity, and study, ATRIP LoF variants were significantly associated with ovarian cancer risk (OR = 2.51, 95% CI = 1.108-5.699, P = .037). CONCLUSION: ATRIP plays a critical role in DNA damage response and genomic stability. Our findings support its candidacy as a novel ovarian cancer susceptibility gene.

Humans↗

PubMed2025

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Journal Article↗