Confounding effects in "A six-gene signature predicting breast cancer lung metastasis"

Abstract

The majority of breast cancer deaths result from metastases rather than from direct effects of the primary tumor itself. Recently, Landemaine and colleagues described a six-gene signature purported to predict lung metastasis risk. They analyzed gene expression in 23 metastases from breast cancer patients (5 lung, 18 non-lung) identifying a 21-gene signature. Expression of 16 of these was analyzed in primary breast tumors from 72 patients with known outcome, and six were selected that were predictive of lung metastases: DSC2, TFCP2L1, UGT8, ITGB8, ANP32E, and FERMT1. Despite the value of such a signature, our analysis indicates that this analysis ignored potentially important confounding factors and that their signature is instead a surrogate for molecular subtype.

Figure 1

Heat maps show results of hierarchical clustering analysis of gene expression profiles of (A) 12 intrinsic molecular subtype genes (Affymetrix probe sets are given in Supplementary Table S2) and (B) the six-gene signature in the Landemaine data set (6).

Figure 2

Results of globaltest analysis, which tested the association between gene expression profiles and (A) metastasis status and (B) molecular subtype in the MSK data set (8). The bar height indicates the influence of the respective gene on the test statistic. Note that A and B are very different scales. The color shows in which of the phenotype group the gene has higher expression values. *, four probe sets that intersect with the Landemaine six probe sets.