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Clin Cancer Res. 2017 Oct 1;23(19):5936-5947. doi: 10.1158/1078-0432.CCR-17-0821. Epub 2017 Jun 23.

Mutational Heterogeneity in APC and KRAS Arises at the Crypt Level and Leads to Polyclonality in Early Colorectal Tumorigenesis.

Author information

1
Hereditary Cancer Program, Catalan Institute of Oncology (ICO - IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
2
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
5
Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO-IDIBELL) and CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain.
6
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Pathology, University Hospital Bellvitge (HUB - IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
8
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Avera Institute for Human Genetics, Sioux Falls, South Dakota.
10
Department of Clinical Sciences, Medical School, University of Barcelona, Barcelona, Spain.
11
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
12
Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.
13
Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
14
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
15
Hereditary Cancer Program, Catalan Institute of Oncology (ICO - IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. EVilar@mdanderson.org gcapella@iconcologia.net.
16
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. EVilar@mdanderson.org gcapella@iconcologia.net.
17
Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract

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

PMID:
28645942
PMCID:
PMC5626604
DOI:
10.1158/1078-0432.CCR-17-0821
[Indexed for MEDLINE]
Free PMC Article

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