Malignant transformation and genetic alterations are uncoupled in early colorectal cancer progression

Soulafa Mamlouk,Andrea Menne,Laura Tomás,Alexander Arnold,David C Wedge,David Horst,Christine Sers,Tincy Simon,Markus Morkel,David Posada,David Capper,Hendrik Bläker

doi:10.1186/s12915-020-00844-x

Abstract

BackgroundColorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression.ResultsHere, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas.ConclusionGenetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression.

Highlights

Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression
To compare early carcinomas with their adenomatous precursors, we isolated matched adenomatous and Driver mutations can be shared by adenoma-carcinoma pairs To identify driver mutations responsible for CRC progression, we performed high-depth sequencing using a CRC-specific panel [7] on 31 microsatellite stable (MSS) and 3 microsatellite stable (MSS) or unstable (MSI), and whole-exome sequencing (WES) on 4 MSS samples
Adenomas can switch into early-stage carcinomas without additional driver mutations While the transition from adenoma to carcinoma has been proposed to be accompanied by the acquisition of new CRC driver mutations [15], we found this to be true in only 52% of our matched samples, while 48% of the samples showed no additional driver mutations private to the carcinoma

Summary

Introduction

Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. Mamlouk et al BMC Biology (2020) 18:116 latter are considered unable to metastasize, as indicated by their categorization as high-grade intraepithelial neoplasia by the WHO and as carcinoma in situ (pTis) by the UICC. Both pT1 and pTis carcinomas are occasionally found in endoscopically resected polyps together with remnants of their surrounding benign precursors. Based on genome integrity and mutation load, CRC tumors can be classified as either microsatellite stable (MSS) or unstable (MSI). Typical mutations include BRAF, an alternative initiating mutation in the MSI progression route involving serrated adenoma, and TGFBR2 [8, 9]

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Conclusion