Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia

Sanjiban Chakrabarty, Vinay Koshy Varghese, Pranoy Sahu, Pradyumna Jayaram, Bhadravathi M. Shivakumar, Cannanore Ganesh Pai, Kapaettu Satyamoorthy

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background:Long-standing ulcerative colitis (UC) leading to colorectal cancer (CRC) is one of the most serious and life-threatening consequences acknowledged globally. Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma.Methods:Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma (UCHR) was performed to identify somatic driver mutations, which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia. Findings from the study are also compared with previously published genome wide and exome sequencing data in inflammatory bowel disease-associated and sporadic colorectal carcinoma.Results:Next-generation sequencing analysis identified 1107 mutations in 275 genes in UCHR subjects. In addition to TP53 (17%) and KRAS (22%) mutations, recurrent mutations in APC (33%), ACVR2A (61%), ARID1A (44%), RAF1 (39%) and MTOR (61%) were observed in UCHR subjects. In addition, APC, FGFR3, FGFR2 and PIK3CA driver mutations were identified in UCHR subjects. Recurrent mutations in ARID1A (44%), SMARCA4 (17%), MLL2 (44%), MLL3 (67%), SETD2 (17%) and TET2 (50%) genes involved in histone modification and chromatin remodelling were identified in UCHR subjects.Conclusions:Our study identifies new oncogenic driver mutations which may be involved in the transition of non-dysplastic cells to dysplastic phenotype in the subjects with long-standing UC with high risk of progression into colorectal neoplasia.

Original languageEnglish
Pages (from-to)136-143
Number of pages8
JournalBritish Journal of Cancer
Volume117
Issue number1
DOIs
Publication statusPublished - 27-06-2017

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Genetic Association Studies
Ulcerative Colitis
Mutation
Colorectal Neoplasms
Neoplasms
Histone Code
Genes
Exome
Chromatin Assembly and Disassembly
Inflammatory Bowel Diseases
Carcinogenesis
Mucous Membrane
Genome
Phenotype

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia",
abstract = "Background:Long-standing ulcerative colitis (UC) leading to colorectal cancer (CRC) is one of the most serious and life-threatening consequences acknowledged globally. Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma.Methods:Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma (UCHR) was performed to identify somatic driver mutations, which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia. Findings from the study are also compared with previously published genome wide and exome sequencing data in inflammatory bowel disease-associated and sporadic colorectal carcinoma.Results:Next-generation sequencing analysis identified 1107 mutations in 275 genes in UCHR subjects. In addition to TP53 (17{\%}) and KRAS (22{\%}) mutations, recurrent mutations in APC (33{\%}), ACVR2A (61{\%}), ARID1A (44{\%}), RAF1 (39{\%}) and MTOR (61{\%}) were observed in UCHR subjects. In addition, APC, FGFR3, FGFR2 and PIK3CA driver mutations were identified in UCHR subjects. Recurrent mutations in ARID1A (44{\%}), SMARCA4 (17{\%}), MLL2 (44{\%}), MLL3 (67{\%}), SETD2 (17{\%}) and TET2 (50{\%}) genes involved in histone modification and chromatin remodelling were identified in UCHR subjects.Conclusions:Our study identifies new oncogenic driver mutations which may be involved in the transition of non-dysplastic cells to dysplastic phenotype in the subjects with long-standing UC with high risk of progression into colorectal neoplasia.",
author = "Sanjiban Chakrabarty and Varghese, {Vinay Koshy} and Pranoy Sahu and Pradyumna Jayaram and Shivakumar, {Bhadravathi M.} and Pai, {Cannanore Ganesh} and Kapaettu Satyamoorthy",
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Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia. / Chakrabarty, Sanjiban; Varghese, Vinay Koshy; Sahu, Pranoy; Jayaram, Pradyumna; Shivakumar, Bhadravathi M.; Pai, Cannanore Ganesh; Satyamoorthy, Kapaettu.

In: British Journal of Cancer, Vol. 117, No. 1, 27.06.2017, p. 136-143.

Research output: Contribution to journalArticle

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AU - Chakrabarty, Sanjiban

AU - Varghese, Vinay Koshy

AU - Sahu, Pranoy

AU - Jayaram, Pradyumna

AU - Shivakumar, Bhadravathi M.

AU - Pai, Cannanore Ganesh

AU - Satyamoorthy, Kapaettu

PY - 2017/6/27

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N2 - Background:Long-standing ulcerative colitis (UC) leading to colorectal cancer (CRC) is one of the most serious and life-threatening consequences acknowledged globally. Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma.Methods:Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma (UCHR) was performed to identify somatic driver mutations, which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia. Findings from the study are also compared with previously published genome wide and exome sequencing data in inflammatory bowel disease-associated and sporadic colorectal carcinoma.Results:Next-generation sequencing analysis identified 1107 mutations in 275 genes in UCHR subjects. In addition to TP53 (17%) and KRAS (22%) mutations, recurrent mutations in APC (33%), ACVR2A (61%), ARID1A (44%), RAF1 (39%) and MTOR (61%) were observed in UCHR subjects. In addition, APC, FGFR3, FGFR2 and PIK3CA driver mutations were identified in UCHR subjects. Recurrent mutations in ARID1A (44%), SMARCA4 (17%), MLL2 (44%), MLL3 (67%), SETD2 (17%) and TET2 (50%) genes involved in histone modification and chromatin remodelling were identified in UCHR subjects.Conclusions:Our study identifies new oncogenic driver mutations which may be involved in the transition of non-dysplastic cells to dysplastic phenotype in the subjects with long-standing UC with high risk of progression into colorectal neoplasia.

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