Mutational heterogeneity in APC and KRAS arises at the crypt level and leads to polyclonality in early colorectal tumorigenesis

Purpose: The majority of genomic alterations causing intra-Results: Multiple co-occurring truncal APC and driver KRAS tumoral heterogeneity (ITH) in colorectal cancer are thought to alterations were uncovered in whole-lesion extracts from adenomas arise during early stages of carcinogenesis as a burst but only and subsequently confirmed to belong to multiple clones. Ultra-after truncal mutations in APC have expanded a single founder sensitive genotyping of bulk biopsies and crypts revealed novel clone. We have investigated if the initial source of ITH is undetected APC mutations that were prominent among carcino-consequent to multiple independent lineages derived from mas, whereas abundant wild-type APC crypts were detected in different crypts harboring distinct truncal APC and driver KRAS adenomas. KRAS mutational heterogeneity within crypts was evi-mutations, thus challenging the prevailing monoclonal mono-dent in both adenomas and carcinomas with a higher degree of cryptal model. concordance between biopsy and crypt genotyping in carcinomas. Experimental Design: High-depth next-generation sequen-Nonrandom heterogeneity among crypts was also observed. cing and SNP arrays were performed in whole-lesion extracts of Conclusions: The striking degree of nonrandom intercrypt 37 familial adenomatous polyposis colorectal adenomas. Also, heterogeneity in truncal and driver gene mutations observed in ultrasensitive genotyping of hotspot mutations of APC and adenomas and carcinomas is consistent with a polycryptal model KRAS was performed using nanofluidic PCRs in matched bulk derived from multiple independent initiation linages as the biopsies (n ¼ 59) and crypts (n ¼ 591) from 18 adenomas and source of early ITH in colorectal carcinogenesis. Clin Cancer Res; seven carcinomas and adjacent normal tissues. 23(19); 5936–47. 2017 AACR.