Multiregion Sequencing Defines Subclonal Structure in Breast Cancer

Past sequencing efforts highlighting subclonal evolution and intratumor heterogeneity in breast cancer emphasize the challenge of using single tumor region analysis to direct therapeutic strategies. To address whether breast cancer follows a temporal order of somatic mutation accumulation and geographic stratification of clonal structure, Yates and colleagues performed whole-genome and targeted sequencing of multiple tumor regions from 50 invasive breast cancers, including treatment-naïve and paired pretreatment and post-chemotherapy samples, for a total of 303 samples. Sequencing of spatially distinct regions within 12 tumors revealed mutational or copy-number heterogeneity in 10 tumors; the majority of tumors were characterized by restricted localization of subclones, whereas some tumors exhibited broad subclonal mixing. Sequencing of multifocal cancers suggested several patterns of growth, including foci-specific alterations in driver genes, related subclonal populations present in geographically distinct foci, and subclonal dissemination. Both targeted capture and whole-genome sequencing methods highlighted variable levels of genetic heterogeneity among tumors. Sequencing of pre- and post-chemotherapy biopsies revealed that resistance mechanisms were likely acquired in pretreatment subclones at very low frequency. Similarly, sequencing showed that metastatic lesions were often seeded by primary tumor subclones, suggesting that targeting subclonal mutations in the primary tumor may help to prevent disease progression. Alterations in common driver genes were observed both early and late in tumor evolution, and a subset of cancers displayed parallel evolution of subclonal driver mutations, which often cooperated with trunk mutations to disrupt tumor suppressor gene function. In addition, structural variants, including tandem duplications and complex chromosomal rearrangements, were shown to drive late-stage subclonal evolution in some cases. Together, these data emphasize the intratumor complexities of breast cancer subclonal diversification and reinforce the necessity of multiregion sequencing analysis to direct future clinical trials.

Yates LR, Gerstung M, Knappskog S, Desmedt C, Gundem G, Van Loo P, et al. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat Med 2015;21:751–9.

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