Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators

Tomomitsu Tahara, Eiichiro Yamamoto, Priyanka Madireddi, Hiromu Suzuki, Reo Maruyama, Woonbok Chung, Judith Garriga, Jaroslav Jelinek, Hiro O. Yamano, Tamotsu Sugai, Yutaka Kondo, Minoru Toyota, Jean Pierre J. Issa, Marcos R.H. Estécio

Research output: Contribution to journalArticle

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Abstract

Background & Aims Subgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients' prognoses and responses to treatment, differ from those of other CRCs. We sought to identify genetic somatic alterations associated with CIMP1 CRCs. Methods We examined genomic DNA samples from 100 primary CRCs, 10 adenomas, and adjacent normal-appearing mucosae from patients undergoing surgery or colonoscopy at 3 tertiary medical centers. We performed exome sequencing of 16 colorectal tumors and their adjacent normal tissues. Extensive comparison with known somatic alterations in CRCs allowed segregation of CIMP1-exclusive alterations. The prevalence of mutations in selected genes was determined from an independent cohort. Results We found that genes that regulate chromatin were mutated in CIMP1 CRCs; the highest rates of mutation were observed in CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate-dependent chromatin remodeling family. Somatic mutations in these 2 genes were detected in 5 of 9 CIMP1 CRCs. A prevalence screen showed that nonsilencing mutations in CHD7 and CHD8 occurred significantly more frequently in CIMP1 tumors (18 of 42 [43%]) than in CIMP2 (3 of 34 [9%]; P <.01) or CIMP-negative tumors (2 of 34 [6%]; P <.001). CIMP1 markers had increased binding by CHD7, compared with all genes. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with mutations in CHD7. Conclusions Aberrations in chromatin remodeling could contribute to the development of CIMP1 CRCs. A better understanding of the biological determinants of CRCs can be achieved when these tumors are categorized according to their epigenetic status.

Original languageEnglish
JournalGastroenterology
Volume146
Issue number2
DOIs
Publication statusPublished - 01-01-2014

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CpG Islands
Chromatin
Colorectal Neoplasms
Phenotype
Mutation
Chromatin Assembly and Disassembly
Genes
CHARGE Syndrome
Exome
Neoplasms
Mutation Rate
DNA Methylation
Colonoscopy
Nose
Epigenomics
Adenoma
Ear
Mucous Membrane
Central Nervous System
Adenosine Triphosphate

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Tahara, Tomomitsu ; Yamamoto, Eiichiro ; Madireddi, Priyanka ; Suzuki, Hiromu ; Maruyama, Reo ; Chung, Woonbok ; Garriga, Judith ; Jelinek, Jaroslav ; Yamano, Hiro O. ; Sugai, Tamotsu ; Kondo, Yutaka ; Toyota, Minoru ; Issa, Jean Pierre J. ; Estécio, Marcos R.H. / Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators. In: Gastroenterology. 2014 ; Vol. 146, No. 2.
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title = "Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators",
abstract = "Background & Aims Subgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients' prognoses and responses to treatment, differ from those of other CRCs. We sought to identify genetic somatic alterations associated with CIMP1 CRCs. Methods We examined genomic DNA samples from 100 primary CRCs, 10 adenomas, and adjacent normal-appearing mucosae from patients undergoing surgery or colonoscopy at 3 tertiary medical centers. We performed exome sequencing of 16 colorectal tumors and their adjacent normal tissues. Extensive comparison with known somatic alterations in CRCs allowed segregation of CIMP1-exclusive alterations. The prevalence of mutations in selected genes was determined from an independent cohort. Results We found that genes that regulate chromatin were mutated in CIMP1 CRCs; the highest rates of mutation were observed in CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate-dependent chromatin remodeling family. Somatic mutations in these 2 genes were detected in 5 of 9 CIMP1 CRCs. A prevalence screen showed that nonsilencing mutations in CHD7 and CHD8 occurred significantly more frequently in CIMP1 tumors (18 of 42 [43{\%}]) than in CIMP2 (3 of 34 [9{\%}]; P <.01) or CIMP-negative tumors (2 of 34 [6{\%}]; P <.001). CIMP1 markers had increased binding by CHD7, compared with all genes. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with mutations in CHD7. Conclusions Aberrations in chromatin remodeling could contribute to the development of CIMP1 CRCs. A better understanding of the biological determinants of CRCs can be achieved when these tumors are categorized according to their epigenetic status.",
author = "Tomomitsu Tahara and Eiichiro Yamamoto and Priyanka Madireddi and Hiromu Suzuki and Reo Maruyama and Woonbok Chung and Judith Garriga and Jaroslav Jelinek and Yamano, {Hiro O.} and Tamotsu Sugai and Yutaka Kondo and Minoru Toyota and Issa, {Jean Pierre J.} and Est{\'e}cio, {Marcos R.H.}",
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Tahara, T, Yamamoto, E, Madireddi, P, Suzuki, H, Maruyama, R, Chung, W, Garriga, J, Jelinek, J, Yamano, HO, Sugai, T, Kondo, Y, Toyota, M, Issa, JPJ & Estécio, MRH 2014, 'Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators', Gastroenterology, vol. 146, no. 2. https://doi.org/10.1053/j.gastro.2013.10.060

Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators. / Tahara, Tomomitsu; Yamamoto, Eiichiro; Madireddi, Priyanka; Suzuki, Hiromu; Maruyama, Reo; Chung, Woonbok; Garriga, Judith; Jelinek, Jaroslav; Yamano, Hiro O.; Sugai, Tamotsu; Kondo, Yutaka; Toyota, Minoru; Issa, Jean Pierre J.; Estécio, Marcos R.H.

In: Gastroenterology, Vol. 146, No. 2, 01.01.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators

AU - Tahara, Tomomitsu

AU - Yamamoto, Eiichiro

AU - Madireddi, Priyanka

AU - Suzuki, Hiromu

AU - Maruyama, Reo

AU - Chung, Woonbok

AU - Garriga, Judith

AU - Jelinek, Jaroslav

AU - Yamano, Hiro O.

AU - Sugai, Tamotsu

AU - Kondo, Yutaka

AU - Toyota, Minoru

AU - Issa, Jean Pierre J.

AU - Estécio, Marcos R.H.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background & Aims Subgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients' prognoses and responses to treatment, differ from those of other CRCs. We sought to identify genetic somatic alterations associated with CIMP1 CRCs. Methods We examined genomic DNA samples from 100 primary CRCs, 10 adenomas, and adjacent normal-appearing mucosae from patients undergoing surgery or colonoscopy at 3 tertiary medical centers. We performed exome sequencing of 16 colorectal tumors and their adjacent normal tissues. Extensive comparison with known somatic alterations in CRCs allowed segregation of CIMP1-exclusive alterations. The prevalence of mutations in selected genes was determined from an independent cohort. Results We found that genes that regulate chromatin were mutated in CIMP1 CRCs; the highest rates of mutation were observed in CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate-dependent chromatin remodeling family. Somatic mutations in these 2 genes were detected in 5 of 9 CIMP1 CRCs. A prevalence screen showed that nonsilencing mutations in CHD7 and CHD8 occurred significantly more frequently in CIMP1 tumors (18 of 42 [43%]) than in CIMP2 (3 of 34 [9%]; P <.01) or CIMP-negative tumors (2 of 34 [6%]; P <.001). CIMP1 markers had increased binding by CHD7, compared with all genes. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with mutations in CHD7. Conclusions Aberrations in chromatin remodeling could contribute to the development of CIMP1 CRCs. A better understanding of the biological determinants of CRCs can be achieved when these tumors are categorized according to their epigenetic status.

AB - Background & Aims Subgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients' prognoses and responses to treatment, differ from those of other CRCs. We sought to identify genetic somatic alterations associated with CIMP1 CRCs. Methods We examined genomic DNA samples from 100 primary CRCs, 10 adenomas, and adjacent normal-appearing mucosae from patients undergoing surgery or colonoscopy at 3 tertiary medical centers. We performed exome sequencing of 16 colorectal tumors and their adjacent normal tissues. Extensive comparison with known somatic alterations in CRCs allowed segregation of CIMP1-exclusive alterations. The prevalence of mutations in selected genes was determined from an independent cohort. Results We found that genes that regulate chromatin were mutated in CIMP1 CRCs; the highest rates of mutation were observed in CHD7 and CHD8, which encode members of the chromodomain helicase/adenosine triphosphate-dependent chromatin remodeling family. Somatic mutations in these 2 genes were detected in 5 of 9 CIMP1 CRCs. A prevalence screen showed that nonsilencing mutations in CHD7 and CHD8 occurred significantly more frequently in CIMP1 tumors (18 of 42 [43%]) than in CIMP2 (3 of 34 [9%]; P <.01) or CIMP-negative tumors (2 of 34 [6%]; P <.001). CIMP1 markers had increased binding by CHD7, compared with all genes. Genes altered in patients with CHARGE syndrome (congenital malformations involving the central nervous system, eye, ear, nose, and mediastinal organs) who had CHD7 mutations were also altered in CRCs with mutations in CHD7. Conclusions Aberrations in chromatin remodeling could contribute to the development of CIMP1 CRCs. A better understanding of the biological determinants of CRCs can be achieved when these tumors are categorized according to their epigenetic status.

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