DNA copy number changes define spatial patterns of heterogeneity in colorectal cancer

Abstract

Genetic heterogeneity between and within tumours is a major factor determining cancer progression and therapy response. Here we examined DNA sequence and DNA copy-number heterogeneity in colorectal cancer (CRC) by targeted high-depth sequencing of 100 most frequently altered genes. In 97 samples, with primary tumours and matched metastases from 27 patients, we observe inter-tumour concordance for coding mutations; in contrast, gene copy numbers are highly discordant between primary tumours and metastases as validated by fluorescent in situ hybridization. To further investigate intra-tumour heterogeneity, we dissected a single tumour into 68 spatially defined samples and sequenced them separately. We identify evenly distributed coding mutations in APC and TP53 in all tumour areas, yet highly variable gene copy numbers in numerous genes. 3D morpho-molecular reconstruction reveals two clusters with divergent copy number aberrations along the proximal–distal axis indicating that DNA copy number variations are a major source of tumour heterogeneity in CRC.

Rapid response of stage IV colorectal cancer with APC/TP53/KRAS mutations to FOLFIRI and Bevacizumab combination chemotherapy: a case report of use of liquid biopsy

“…1) suggests that the eradicated liver metastases may have harboured predominantly cells from the triple-mutation tumour clone. The spatial heterogeneity of CNVs and homogeneity of point mutations that we detected in our patient ties in with previous reports of colonic cancer [8].…”

Plasma HER2 (ERBB2) Copy Number Predicts Response to HER2-targeted Therapy in Metastatic Colorectal Cancer

“…The HERACLES A study further highlights the benefits of cfDNA copy number analysis and underscores the ability of cfDNA to capture tumor heterogeneity in patients with mCRC. This latter capability may be similarly important in mCRC as, despite high concordance for somatic mutations between primary tumors and metastases, there is significant discordance (6%-15%) for tissue-assessed ERBB2 copy number amplifications (25,26).…”

“…Colon cancer is the third most common cancer worldwide, and approximately 20% of patients present with metastatic disease (metastatic colorectal cancer; mCRC), which is associated with a poor prognosis and median overall survival (OS) of [24][25][26][27][28][29][30] months (1). Use of the anti-EGFR mAbs cetuximab and panitumumab has improved progression-free survival (PFS) and OS in patients who are negative for KRAS, NRAS, and BRAF mutations; however, these therapies are inevitably followed by disease progression (2).…”

ClonArch: Visualizing the Spatial Clonal Architecture of Tumors

“…Cancer genomics datasets with many spatial/regional sequencing biopsies from the same tumor are becoming increasingly available (Alves et al, 2019;Ding et al, 2019;Mamlouk et al, 2017;Ling et al, 2015;Gerlinger et al, 2012Gerlinger et al, , 2014. Using multi-sample cancer phylogeny inference methods (El-Kebir et al, 2015;Malikic et al, 2015;Deshwar et al, 2015;Popic et al, 2015), such datasets enable researchers to infer detailed information on the spatial clonal architecture of individual tumors.…”