Impact of aging on genomic abnormalities in breast cancer

Abstract

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We have previously shown that in addition to increasing breast cancer incidence, aging can significantly alter breast cancer biology as defined by validated prognostic and predictive biomarkers. In particular, biomarkers thought to reflect breast cancer genomic instability (e.g. high nuclear grade, aneuploidy, p53 immunoreactivity) show strong inverse correlations with patient age-at-diagnosis. To more directly assess the relationship between aging and breast cancer gene copy number abnormalities, comparative genomic hybridization array (aCGH, a 1MB resolution) analyses were performed on tumor DNA samples from two age-based cohorts of breast cancer cases collected from a single geographic region (Bari) and characterized by stage and hormone receptor status (ER, PR). Using the following age-at-diagnosis cohort definitions: younger (Y) ≤ 45 and older (O) ≥ 70 years, 125 (Y = 56; O = 64) cases have been analyzed to date. Consistent with previous reports, these two age cohorts contain significantly different proportions of ER/PR breast cancer phenotypes (p = 0.003): ER+/PR+ = 56% (O) vs. 43% (Y); ER+/PR- = 30% (O) vs. 16% (Y); and ER-/PR- = 14% (O) vs. 41% (Y). Using the aCGH ERBB2 17q locus to define gene amplification and ErbB2+ status, the overall study set shows 13% ErbB2+ cases, with a significant difference between the two cohorts (p = 0.03): 6% (O) vs. 21% (Y). While PR status showed no significant relationship to ErbB2 status; the overall study set shows a significant inverse relationship between ER+ and ErbB2+ status (p = 0.001). However, this inverse relationship is only significant within the younger age cohort, where 9% of ER+ Y cases are ErbB2+ in contrast to 39% of ER- Y cases that are ErbB2+ (p = 0.02). These DNA samples are also currently being analyzed for p53 (exon 5-8) mutations. At present, the findings from this breast cancer cohort study of genomic abnormalities confirm that oncogenic mechanisms differ between younger and older aged breast cancer patients even when hormone receptor status is taken into account. In particular, ERBB2 amplification is an uncommon genomic mechanism contributing to breast tumorigenesis in older patients even within the subset of ER- tumors, yet it accounts for nearly 40% of ER- breast cancers arising in younger patients.