A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer

Robbert D A Weren; Marjolijn J L Ligtenberg; C Marleen Kets; Richarda M de Voer; Eugène T P Verwiel; Liesbeth Spruijt; Wendy A G van Zelst-Stams; Marjolijn C Jongmans; Christian Gilissen; Jayne Y Hehir-Kwa; Alexander Hoischen; Jay Shendure; Evan A Boyle; Eveline J Kamping; Iris D Nagtegaal; Bastiaan B J Tops; Fokko M Nagengast; Ad Geurts van Kessel; J Han J M van Krieken; Roland P Kuiper; Nicoline Hoogerbrugge

doi:10.1038/ng.3287

A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer

Robbert D A Weren, Marjolijn J L Ligtenberg, C Marleen Kets, Richarda M de Voer, Eugène T P Verwiel, Liesbeth Spruijt, Wendy A G van Zelst-Stams, Marjolijn C Jongmans, Christian Gilissen, Jayne Y Hehir-Kwa, Alexander Hoischen, Jay Shendure, Evan A Boyle, Eveline J Kamping, Iris D Nagtegaal, Bastiaan B J Tops, Fokko M Nagengast, Ad Geurts van Kessel, J Han J M van Krieken, Roland P KuiperNicoline Hoogerbrugge

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284 Citations (Scopus)

Abstract

The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.

Original language	English
Pages (from-to)	668-71
Number of pages	4
Journal	Nature Genetics
Volume	47
Issue number	6
DOIs	https://doi.org/10.1038/ng.3287
Publication status	Published - Jun 2015
Externally published	Yes

Keywords

Adenomatous Polyposis Coli/genetics
Case-Control Studies
Codon, Nonsense
DNA Mutational Analysis
DNA Repair
Deoxyribonuclease (Pyrimidine Dimer)/genetics
Female
Genetic Association Studies
Genetic Predisposition to Disease
Germ-Line Mutation
Homozygote
Humans
Middle Aged
Pedigree

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10.1038/ng.3287

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Weren, R. D. A., Ligtenberg, M. J. L., Kets, C. M., de Voer, R. M., Verwiel, E. T. P., Spruijt, L., van Zelst-Stams, W. A. G., Jongmans, M. C., Gilissen, C., Hehir-Kwa, J. Y., Hoischen, A., Shendure, J., Boyle, E. A., Kamping, E. J., Nagtegaal, I. D., Tops, B. B. J., Nagengast, F. M., Geurts van Kessel, A., van Krieken, J. H. J. M., ... Hoogerbrugge, N. (2015). A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nature Genetics, 47(6), 668-71. https://doi.org/10.1038/ng.3287

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title = "A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer",

abstract = "The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC. ",

keywords = "Adenomatous Polyposis Coli/genetics, Case-Control Studies, Codon, Nonsense, DNA Mutational Analysis, DNA Repair, Deoxyribonuclease (Pyrimidine Dimer)/genetics, Female, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, Homozygote, Humans, Middle Aged, Pedigree",

author = "Weren, {Robbert D A} and Ligtenberg, {Marjolijn J L} and Kets, {C Marleen} and {de Voer}, {Richarda M} and Verwiel, {Eug{\`e}ne T P} and Liesbeth Spruijt and {van Zelst-Stams}, {Wendy A G} and Jongmans, {Marjolijn C} and Christian Gilissen and Hehir-Kwa, {Jayne Y} and Alexander Hoischen and Jay Shendure and Boyle, {Evan A} and Kamping, {Eveline J} and Nagtegaal, {Iris D} and Tops, {Bastiaan B J} and Nagengast, {Fokko M} and {Geurts van Kessel}, Ad and {van Krieken}, {J Han J M} and Kuiper, {Roland P} and Nicoline Hoogerbrugge",

year = "2015",

month = jun,

doi = "10.1038/ng.3287",

language = "English",

volume = "47",

pages = "668--71",

journal = "Nature Genetics",

issn = "1061-4036",

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Weren, RDA, Ligtenberg, MJL, Kets, CM, de Voer, RM, Verwiel, ETP, Spruijt, L, van Zelst-Stams, WAG, Jongmans, MC, Gilissen, C, Hehir-Kwa, JY, Hoischen, A, Shendure, J, Boyle, EA, Kamping, EJ, Nagtegaal, ID, Tops, BBJ, Nagengast, FM, Geurts van Kessel, A, van Krieken, JHJM, Kuiper, RP & Hoogerbrugge, N 2015, 'A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer', Nature Genetics, vol. 47, no. 6, pp. 668-71. https://doi.org/10.1038/ng.3287

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T1 - A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer

AU - Weren, Robbert D A

AU - Ligtenberg, Marjolijn J L

AU - Kets, C Marleen

AU - de Voer, Richarda M

AU - Verwiel, Eugène T P

AU - Spruijt, Liesbeth

AU - van Zelst-Stams, Wendy A G

AU - Jongmans, Marjolijn C

AU - Gilissen, Christian

AU - Hehir-Kwa, Jayne Y

AU - Hoischen, Alexander

AU - Shendure, Jay

AU - Boyle, Evan A

AU - Kamping, Eveline J

AU - Nagtegaal, Iris D

AU - Tops, Bastiaan B J

AU - Nagengast, Fokko M

AU - Geurts van Kessel, Ad

AU - van Krieken, J Han J M

AU - Kuiper, Roland P

AU - Hoogerbrugge, Nicoline

PY - 2015/6

Y1 - 2015/6

N2 - The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.

AB - The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.

KW - Adenomatous Polyposis Coli/genetics

KW - Case-Control Studies

KW - Codon, Nonsense

KW - DNA Mutational Analysis

KW - DNA Repair

KW - Deoxyribonuclease (Pyrimidine Dimer)/genetics

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Germ-Line Mutation

KW - Homozygote

KW - Humans

KW - Middle Aged

KW - Pedigree

U2 - 10.1038/ng.3287

DO - 10.1038/ng.3287

M3 - Article

C2 - 25938944

SN - 1061-4036

VL - 47

SP - 668

EP - 671

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer

Abstract

Keywords

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