Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers

Abstract

Women harboring heterozygous germline mutations of BRCA2 have a 50 to 80% risk of developing breast cancer, yet the pathogenesis of these cancers is poorly understood. To reveal early steps in BRCA2-associated carcinogenesis, we analyzed sorted cell populations from freshly-isolated, non-cancerous breast tissues of BRCA2 mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that >25% of BRCA2 carrier (BRCA2mut/+) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations, which are rarely observed in non-carriers. Correspondingly, primary BRCA2mut/+ breast epithelia exhibit DNA damage together with attenuated replication checkpoint and apoptotic responses, and an age-associated expansion of the LP compartment. We provide evidence that these phenotypes do not require loss of the wild-type BRCA2 allele. Collectively, our findings suggest that BRCA2 haploinsufficiency and associated DNA damage precede histologic abnormalities in vivo. Using these hallmarks of cancer predisposition will yield unanticipated opportunities for improved risk assessment and prevention strategies in high-risk patients.

Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis

“…Such tumors may lose ER and progesterone receptor (PR) expression during transformation from hormone-sensing cells. Contrary to BRCA1 , research on the effects of BRCA2 mutations are currently limited 53 , 54 . Future studies should aim at possible dysregulation of hormone-sensing lineage cells in BRCA2 mutation carriers as suggested in this study.…”

DDX17 is required for efficient DSB repair at DNA:RNA hybrid deficient loci

“…DDX17 depleted cells treated with 2 Gy IR and allowed to recover for 2 days (Supplementary Figure S2C) displayed substantial loss of chromosomes (Fig. 2F-G), consistent with sustained, unresolved DNA damage(53, 54). Combined with the comet assay results, this provides evidence for the direct involvement of DDX17 in DSB repair and the maintenance of genome stability.…”

Targeting BRCA and DNA Damage Repair Genes in GI Cancers: Pathophysiology and Clinical Perspectives

“…In BRCA1 -deficient cells, chromosomal aberrations, such as triradial or quadriradial chromosomes, or rearrangements, like translocations, have frequently been observed ( 33 ). In BRCA2 -deficient cells, aneuploidy has been observed due to deregulation of centrosomes and the mitotic spindles ( 34 ). An important step in carcinogenesis of BRCA- mutated cells seems to be the loss of heterozygosity (LOH), as this can be observed in most gBRCA-mut cancers ( 35 ).…”