Identification of Novel Breast Tumor Expression Dimensions within the PAM50 and Discovery of a Breast Cancer Susceptibility Locus at 12q15

High-risk breast cancer pedigrees contain inherited risk variants, but underlying genetic complexities impair gene-finding. Focusing on particular tumor characteristics clustering in pedigrees may simplify these complexities. PAM50 gene expression in 1149 sporadic and familial breast tumors did not indicate intrinsic subtypes were enriched in non-BRCA1/2 pedigrees. However, a principal component approach revealed five common expression dimensions: three capturing key features of intrinsic subtypes; two novel and significantly enriched in pedigrees. Proof-of-concept gene-mapping using the novel dimensions identified a 0.5 Mb genomewide significant region at 12q15 (p=2.6x10-8) segregating to 8 breast cancer cases through 32 meioses. The region contains CNOT2, a gene controlling cell viability via the CCR4-NOT transcriptional regulatory deadenylase complex. These findings support the hypothesis that germline susceptibilities influence tumor characteristics and that expression dimensions partition genetic heterogeneity providing new avenues for germline genetic studies. More broadly, this approach may clarify heterogeneities impeding other domains exploring molecular characteristics.