Subclonal diversification of primary breast cancer revealed by multiregion sequencing

By L. Yates, Moritz Gerstung, S. Knappskog, C. Desmedt, G. Gundem, P. van Loo, T. Aas, Ludmil B. Alexandrov, D. Larsimont, Helen R. Davies and 28 more. Nature Medicine, 2015

764 citations recorded by the source corpus.

The sequencing of 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 (303 samples in total). 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 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of 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.

Subfields: Cancer Research, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/141458d8a02c2244d75308b22fe48380a90c3e91

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Citations in the corpus

Genomic Evolution of Breast Cancer Metastasis and Relapse (2017, methodology): “…typically acquired additional variants not detectable in the primary lesion (Brastianos et al., 2015; De Mattos-Arruda et al., 2014; Ding et al., 2010; Hoadley et al., 2016; Juric et al., 2015; Savas et al., 2016; Shah et al., 2009; 170 Cancer Cell 32, 169–184, August 14, 2017 Yates et al., 2015).”
Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations (2018, background): “…below the detection limits of conventional NGS techniques, can both drive tumour growth 120 and be an important source of resistance to therapy and basis for relapse 5,121–123 ; in fact, a higher degree of subclonal heterogeneity portends a worse prognosis in multiple tumour types 124–126 .”
Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “Multiregional sequencing of renal carcinoma, glioblastoma and lung cancer have all showed significant divergence between distinct areas of the same tumor (Gerlinger et al., 2012; Thrane et al., 2018; Yates et al., 2015; Zhang et al., 2014).”
The PI3K pathway in human disease (2017, neutral): “Subclonal mutations in PIK3CA were re-ported in several cancer subtypes, including NSCLC, colorectal cancer, breast cancer, and others (Harbst et al., 2016; de Bruin et al., 2014; McGranahan and Swanton, 2017; Uchi et al., 2016; Yates et al., 2015).”
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational-signatures (2017, methodology): “However, distinguishing ongoing from historic mutational signatures of BRCA1 / BRCA2 deficiency is already a possibility, given the advances in exploiting the digital nature of modern sequencing technologies to construct phylogenetic trees of each person’s tumor 30,37 .”