Identifying Etiologically Distinct Sub-Types of Cancer: A Demonstration Project Involving Breast Cancer.

With the advent of increasingly detailed molecular portraits of tumor specimens, much attention has been directed toward identifying clinically distinct subtypes of cancer. Subtyping of tumors can also be accomplished with the goal of identifying distinct etiologies. We demonstrate the use of new methodologies to identify genes that distinguish etiologically heterogeneous subtypes of breast cancer using data from the case-control Cancer and Steroid Hormone Study. Tumor specimens were evaluated using a breast cancer expression panel of 196 genes. Using a statistical measure that distinguishes the degree of etiologic heterogeneity in tumor subtypes, each gene is ranked on the basis of its ability to distinguish etiologically distinct subtypes. This is accomplished independently using case-control comparisons and by examining the concordance odds ratios in double primaries. The estrogen receptor gene, and others in this pathway with expression levels that correlated strongly with estrogen receptor levels, demonstrate high degrees of etiologic heterogeneity in both methods. Our results are consistent with a growing literature that confirms the distinct etiologies of breast cancers classified on the basis of estrogen receptor expression levels. This proof-of-principle project demonstrates the viability of new strategies to identify genomic features that distinguish subtypes of cancer from an etiologic perspective.