Subclonal diversification of primary breast cancer revealed by multiregion sequencing

Abstract

Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient’s tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole genome and targeted sequencing to multiple samples from each of 50 patients’ tumors (total 303). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13/50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resisting chemotherapy and acquiring invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

“…As such, our ability to distinguish truly clonal from pseudoclonal mutations thereby determine the true clonal and subclonal burder of alterations is largely dependent on the number of tumor regions sequenced (de Bruin et al, 2014;Yates et al, 2015), the depth and purity of what is sequenced, and, further, whether single-cell sequencing is also implemented (Roth et al, 2016).…”

“…Subclonal mutations in PIK3CA have been found in, among other cancer types, lung (de Bruin et al, 2014), breast (Yates et al, 2015), colorectal (Uchi et al, 2016), melanoma (Harbst et al, 2016), esophageal squamous cell carcinoma (Hao et al, 2016), ccRCC (Gerlinger et al, 2014a) and ovarian cancers (Bashashati et al, 2013). In keeping with these results, across 9 cancer types, mutations in the PI3K-AKT-mTOR pathway were found to harbor a higher proportion of subclonal mutations compared to genes associated with RAS-MAPK pathway (McGranahan et al, 2015).…”

Clock-like mutational processes in human somatic cells

“…Such factors include the number of available samples, the number of somatic mutations in a sample, the number of mutations contributed by different mutational signatures, the similarity between the patterns of the signatures of mutational processes operative in cancer samples, as well as the computational limitations of our framework. Nevertheless, in the past three years, our framework has proven robust and has described multiple similar and validated signatures across the spectrum of human cancer [3][4][5][15][16][17][18][19][20][21][22] .…”

Genomic Heterogeneity: Next-Generation Sequencing Enables Biomarker Identification for Hepatocellular Carcinoma

“…Therefore, dynamic predictive models are required in order to assess the comprehensive intrapatient variability, including intratumor heterogeneity, circulating genomic subclones and genomic alterations in relapsed (RT) or metastatic tumors (MT). Exciting breakthrough NGS applications have been developed to evaluate intratumor heterogeneity by multiregional tumor NGS analysis [22], circulating genomic subclones by noninvasive serial cell-free DNA NGS [23] and the genomic landscape of the RTs/MTs by fineneedle aspiration NGS or biopsies from the resected RTs/MTs. In summary, emerging evidence on extensive tumor heterogeneity does not only explain current negative Phase III trials on new agents for HCC but further underlies the need for the development of predictive biomarkers toward effective personalized treatment.…”