American Association for Cancer Research
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crc-23-0277-s13.xlsx (387.57 kB)

Supplementary Table S6 from Natural History of Germline BRCA1 Mutated and BRCA Wild-type Triple-negative Breast Cancer

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posted on 2024-02-14, 14:20 authored by Nilesh Gardi, Rohan Chaubal, Pallavi Parab, Sunil Pachakar, Suyash Kulkarni, Tanuja Shet, Shalaka Joshi, Yogesh Kembhavi, Pratik Chandrani, Jelmar Quist, Pradnya Kowtal, Anita Grigoriadis, Rajiv Sarin, Raman Govindarajan, Sudeep Gupta

This table shows the annotation information from Annovar for clonal architecture of Patient P4

Funding

DST | Science and Engineering Research Board (SERB)

Department of Biotechnology, Ministry of Science and Technology, India (DBT)

History

ARTICLE ABSTRACT

We report a deep next-generation sequencing analysis of 13 sequentially obtained tumor samples, eight sequentially obtained circulating tumor DNA (ctDNA) samples and three germline DNA samples over the life history of 3 patients with triple-negative breast cancer (TNBC), 2 of whom had germline pathogenic BRCA1 mutation, to unravel tumor evolution. Tumor tissue from all timepoints and germline DNA was subjected to whole-exome sequencing (WES), custom amplicon deep sequencing (30,000X) of a WES-derived somatic mutation panel, and SNP arrays for copy-number variation (CNV), while whole transcriptome sequencing (RNA-seq) was performed only on somatic tumor.There was enrichment of homologous recombination deficiency signature in all tumors and widespread CNV, which remained largely stable over time. Somatic tumor mutation numbers varied between patients and within each patient (range: 70–216, one outlier). There was minimal mutational overlap between patients with TP53 being the sole commonly mutated gene, but there was substantial overlap in sequential samples in each patient. Each patient's tumor contained a founding (“stem”) clone at diagnosis, which persisted over time, from which all other clones (“subclone”) were derived (“branching evolution”), which contained mutations in well-characterized cancer-related genes like PDGFRB, ARID2, TP53 (Patient_02), TP53, BRAF, BRIP1, CSF3R (Patient_04), and TP53, APC, EZH2 (Patient_07). Including stem and subclones, tumors from all patients were polyclonal at diagnosis and during disease progression. ctDNA recapitulated most tissue-derived stem clonal and subclonal mutations while detecting some additional subclonal mutations. RNA-seq revealed a stable basal-like pattern, with most highly expressed variants belonging to stem clone. In germline BRCA1 mutated and BRCA wild-type patients, TNBC shows a branching evolutionary pattern of mutations with a single founding clone, are polyclonal throughout their disease course, and have widespread copy-number aberrations. This evolutionary pattern may be associated with treatment resistance or sensitivity and could be therapeutically exploited.