Mutational spectrum of breast cancer by shallow whole-genome sequencing of cfDNA and tumor gene panel analysis

Abstract

Breast cancer (BC) has various molecular subgroups with differing risks and treatments. Tumor biopsies for BC detection are invasive and may not reflect tumor heterogeneity. Liquid biopsies have become relevant because they might overcome these limitations. We evaluated the feasibility to detect somatic copy number alterations (SCNAs) in BC using shallow whole genome sequencing (sWGS) in cfDNA from archived samples from National Cancer Institute of Colombia patients. We sequenced tumor tissues from 38 BC patients with different molecular subtypes using a panel of genes, and sWGS on 20 paired cfDNA samples to detect SCNAs and compare with the tumor samples. We identified an extensive intertumoral heterogeneity between the molecular subtypes of BC, with a mean tumor load of 602 mutations in the gene panel of tumor tissues. There was a 12.3% of concordance in deletions in the cfDNA-tumor pairs encompassing seven genes: BRCA1, CDK12, NF1, MAP2K4, NCOR1, TP53, and KEAP1 in 3 patients. Amplifications were only detected in tumor tissues. This study shows the feasibility to detect SCNAs in BC using sWGS in cfDNA. This strategy may improve tumor SCNA events detection, complementing tumor tissue biopsies, and facilitating a wider identification of potential therapeutic targets.