Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 andBRCA2 mutation carriers: A population-based study

Breast cancers arising in women with and without a germline mutation in the BRCA1 or BRCA2 gene display different histological features, which suggest s unique mechanisms of molecular pathogenesis: We used a molecular patholog ical analysis to define the genetic abnormalities relevant to these specifi c pathogeneses, Tumor material was studied from 40 women with breast cancer diagnosed before 40 years of age, sampled from a population-based study an d stratified by BRCA1 and BRCA2 germline mutation status. Cases were not se lected for family history or ethnic origin, and none were known to be genet ically related. Thus, germline mutation itself is likely to impact on the m olecular pathogenesis of these tumors, with no substantial influence due to modifying genetic or environmental factors. Breast cancers occurring in BR CA1 mutation carriers had significantly higher levels of p53 expression, in cluding the preinvasive (carcinoma in situ) stage of disease, compared with cancers occurring in BRCA2 mutation carriers or women with no detectable g ermline mutation. These cancers also had a higher proliferation rate as mea sured by Ki-67 antibody. Expression of the prognostic factors c-erbB-2, cyc lin D1, and estrogen receptor was significantly less common in BRCA1 mutati on carriers. Lower levels of cyclin D1 were also found in cancers from BRCA 1 mutation carriers compared with non-mutation carriers. Direct p53 mutatio n analysis revealed mutations in 18% of all of the early-onset breast cance rs within the study and included rare insertion and deletional mutations in cancers from BRCA1 mutation carriers. Our data indicate that a BRCA1 breas t cancer phenotype may be recognized by an exceptionally high proliferation rate and early and frequent p53 overexpression but infrequent selection fo r overexpression of several other prognostic factor proteins known to be in volved in breast oncogenesis, In contrast, breast cancers arising in BRCA2 mutation carriers have a more heterogeneous phenotypic profile.