SMAD4 and breast cancer: Intratumoral heterogeneity subclonal driver mutations that govern tumor metabolism have been identified in breast cancer (TP53, SMAD4) (238), consistent with studies of subclonal diversification of primary breast cancer revealed by multi region sequencing of the coding region (238), the non-coding region (242) and evidence for further genetic evolution upon relapse (SWI-SNF and JAK2-STAT3) (243).