Muy Kheng Tea

Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes

Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.

Profiling of Cross-Functional Peptidases Regulated Circulating Peptides in BRCA1 Mutant Breast Cancer

Women with inherited BRCA1 mutations are more likely to develop breast cancer (BC); however, not every carrier will progress to BC. The aim of this study was to identify and characterize circulating peptides that correlate with BC patients carrying BRCA1 mutations. Circulating peptides were enriched using our well-designed nanoporous silica thin films (NanoTraps) and profiled by mass spectrometry to identify among four clinical groups. To determine the corresponding proteolytic processes and their sites of activity, purified candidate peptidases and synthesized substrates were assayed to verify the processes predicted by the MERPOS database. Proteolytic processes were validated using patient serum samples. The peptides, KNG1K438-R457 and C 3fS1304-R1320, were identified as putative peptide candidates to differentiate BRCA1 mutant BC from sporadic BC and cancer-free BRCA1 mutant carriers. Kallikrein-2 (KLK2) is the major peptidase that cleaves KNG1K438-R457 from kininogen-1, and its expressions and activities were also found to be dependent on BRCA1 status. We further determined that KNG1K438-R457 is cleaved at its C-terminal arginine by carboxypeptidase N1 (CPN1). Increased KLK2 activity, with decreased CPN1 activity, results in the accumulation of KNG1K438-R457 in BRCA1-associated BC. Our work outlined a useful strategy for determining the peptide-petidase relationship and thus establishing a biological mechanism for changes in the peptidome in BRCA1-associated BC.