Somatic targeted mutation profiling of colorectal cancer precursor lesions

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Abstract

Background

Most colorectal cancers (CRC) arise from precursor lesions. This study aimed to characterize the mutation profile of colorectal cancer precursor lesions in a Brazilian population.

Methods

In total, 90 formalin-fixed paraffin-embedded colorectal precursor lesions, including 67 adenomas, 7 sessile serrated lesions, and 16 hyperplastic polyps, were analyzed by next-generation sequencing using a panel of 50 oncogenes and tumor suppressor genes. The genetic ancestry of the patients was estimated.

Results

Somatic driver mutations were identified in 66.7% of cases, including alterations in APC (32.2%), TP53 (20.0%), KRAS (18.9%), BRAF (13.3%) and EGFR (7.8%). Adenomas displayed a higher number of mutations, mainly in APC, compared to serrated polyps (73.1% vs. 47.8%, p = 0.026). Advanced adenomas had a significantly higher frequency of mutation in KRAS and a high overall mutation rate than early adenomas (92.9% vs. 59%, p = 0.006). A high degree of ancestry admixture was observed in the population studied, with a predominance of European components (mean of 73%) followed by African (mean of 11.3%). No association between genetic ancestry and type of lesions was found. The mutation profile of Brazilian colorectal precursor lesions exhibits alteration in APC, KRAS, TP53, and BRAF at different frequencies according to lesion type.

Conclusions

These results bestow the knowledge of CRC's biologic history and support the potential of these biomarkers for precursor lesions detection in CRC screening of the Brazilian population.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12920-022-01294-w.

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Most cited references 68

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Inference of Population Structure Using Multilocus Genotype Data

Jonathan Pritchard, Matthew Stephens, Peter Donnelly … (2001)

We describe a model-based clustering method for using multilocus genotype data to infer population structure and assign individuals to populations. We assume a model in which there are K populations (where K may be unknown), each of which is characterized by a set of allele frequencies at each locus. Individuals in the sample are assigned (probabilistically) to populations, or jointly to two or more populations if their genotypes indicate that they are admixed. Our model does not assume a particular mutation process, and it can be applied to most of the commonly used genetic markers, provided that they are not closely linked. Applications of our method include demonstrating the presence of population structure, assigning individuals to populations, studying hybrid zones, and identifying migrants and admixed individuals. We show that the method can produce highly accurate assignments using modest numbers of loci—e.g., seven microsatellite loci in an example using genotype data from an endangered bird species. The software used for this article is available from http://www.stats.ox.ac.uk/~pritch/home.html.

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Comprehensive Molecular Characterization of Human Colon and Rectal Cancer

Nikolaus Schultz (2014)

Summary To characterize somatic alterations in colorectal carcinoma (CRC), we conducted genome-scale analysis of 276 samples, analyzing exome sequence, DNA copy number, promoter methylation, mRNA and microRNA expression. A subset (97) underwent low-depth-of-coverage whole-genome sequencing. 16% of CRC have hypermutation, three quarters of which have the expected high microsatellite instability (MSI), usually with hypermethylation and MLH1 silencing, but one quarter has somatic mismatch repair gene mutations. Excluding hypermutated cancers, colon and rectum cancers have remarkably similar patterns of genomic alteration. Twenty-four genes are significantly mutated. In addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9, and FAM123B/WTX. Recurrent copy number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive CRC and important role for MYC-directed transcriptional activation and repression.

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Author and article information

Contributors

Denise Peixoto Guimarães: guimaraes.dp@gmail.com

Journal

Journal ID (nlm-ta): BMC Med Genomics

Journal ID (iso-abbrev): BMC Med Genomics

Title: BMC Medical Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1755-8794

Publication date (Electronic): 28 June 2022

Publication date PMC-release: 28 June 2022

Publication date Collection: 2022

Volume: 15

Electronic Location Identifier: 143

Affiliations

[1 ]GRID grid.427783.d, ISNI 0000 0004 0615 7498, Molecular Oncology Research Center, , Barretos Cancer Hospital, ; Rua Antenor Duarte Vilela, 1331, Barretos, SP 14784-400 Brazil

[2 ]GRID grid.427783.d, ISNI 0000 0004 0615 7498, Department of Pathology, , Barretos Cancer Hospital, ; Barretos, Brazil

[3 ]GRID grid.427783.d, ISNI 0000 0004 0615 7498, Research and Education Institute, , Barretos Cancer Hospital, ; Barretos, Brazil

[4 ]SMW Consultants Ltd, Kaarina, Finland

[5 ]Department of Clinical Research, Biohit Oyj, Helsinki, Finland

[6 ]GRID grid.10328.38, ISNI 0000 0001 2159 175X, Life and Health Sciences Research Institute (ICVS), Medical School, , University of Minho, ; 4710-057 Braga, Portugal

[7 ]GRID grid.10328.38, ISNI 0000 0001 2159 175X, ICVS/3B’s-PT Government Associate Laboratory, ; 4710-057 Braga, Portugal

[8 ]GRID grid.427783.d, ISNI 0000 0004 0615 7498, Department of Endoscopy, , Barretos Cancer Hospital, ; Barretos, Brazil

Article

Publisher ID: 1294

DOI: 10.1186/s12920-022-01294-w

PMC ID: 9238170

PubMed ID: 35761395

SO-VID: cbca6973-334f-4ac6-a948-0697829f28a7

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 2 November 2021

Date accepted : 16 June 2022

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ScienceOpen disciplines: Genetics

Keywords: screening,adenoma,serrated polyps,mutation,molecular profiling,brazil

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ScienceOpen disciplines: Genetics

Keywords: screening, adenoma, serrated polyps, mutation, molecular profiling, brazil

Somatic targeted mutation profiling of colorectal cancer precursor lesions

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Genome Integrity

Most cited references 68

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Inference of Population Structure Using Multilocus Genotype Data

Comprehensive Molecular Characterization of Human Colon and Rectal Cancer

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