Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

Judith E Grolleman; Richarda M de Voer; Fadwa A Elsayed; Maartje Nielsen; Robbert D A Weren; Claire Palles; Marjolijn J L Ligtenberg; Janet R Vos; Sanne W Ten Broeke; Noel F C C de Miranda; Renske A Kuiper; Eveline J Kamping; Erik A M Jansen; M Elisa Vink-Börger; Isabell Popp; Alois Lang; Isabel Spier; Robert Hüneburg; Paul A James; Na Li; Marija Staninova; Helen Lindsay; David Cockburn; Olivera Spasic-Boskovic; Mark Clendenning; Kevin Sweet; Gabriel Capellá; Wenche Sjursen; Hildegunn Høberg-Vetti; Marjolijn C Jongmans; Kornelia Neveling; Ad Geurts van Kessel; Hans Morreau; Frederik J Hes; Rolf H Sijmons; Hans K Schackert; Clara Ruiz-Ponte; Dagmara Dymerska; Jan Lubinski; Barbara Rivera; William D Foulkes; Ian P Tomlinson; Laura Valle; Daniel D Buchanan; Sue Kenwrick; Julian Adlard; Aleksandar J Dimovski; Ian G Campbell; Stefan Aretz; Detlev Schindler; Tom van Wezel; Nicoline Hoogerbrugge; Roland Kuiper

doi:10.1016/j.ccell.2018.12.011

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

Judith E Grolleman, Richarda M de Voer, Fadwa A Elsayed, Maartje Nielsen, Robbert D A Weren, Claire Palles, Marjolijn J L Ligtenberg, Janet R Vos, Sanne W Ten Broeke, Noel F C C de Miranda, Renske A Kuiper, Eveline J Kamping, Erik A M Jansen, M Elisa Vink-Börger, Isabell Popp, Alois Lang, Isabel Spier, Robert Hüneburg, Paul A James, Na LiMarija Staninova, Helen Lindsay, David Cockburn, Olivera Spasic-Boskovic, Mark Clendenning, Kevin Sweet, Gabriel Capellá, Wenche Sjursen, Hildegunn Høberg-Vetti, Marjolijn C Jongmans, Kornelia Neveling, Ad Geurts van Kessel, Hans Morreau, Frederik J Hes, Rolf H Sijmons, Hans K Schackert, Clara Ruiz-Ponte, Dagmara Dymerska, Jan Lubinski, Barbara Rivera, William D Foulkes, Ian P Tomlinson, Laura Valle, Daniel D Buchanan, Sue Kenwrick, Julian Adlard, Aleksandar J Dimovski, Ian G Campbell, Stefan Aretz, Detlev Schindler, Tom van Wezel, Nicoline Hoogerbrugge, Roland Kuiper

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Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.

Originele taal-2	Engels
Pagina's (van-tot)	256-266.e5
Tijdschrift	Cancer cell
Volume	35
Nummer van het tijdschrift	2
DOI's	https://doi.org/10.1016/j.ccell.2018.12.011
Status	Gepubliceerd - 11 feb. 2019

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10.1016/j.ccell.2018.12.011

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Grolleman, J. E., de Voer, R. M., Elsayed, F. A., Nielsen, M., Weren, R. D. A., Palles, C., Ligtenberg, M. J. L., Vos, J. R., Ten Broeke, S. W., de Miranda, N. F. C. C., Kuiper, R. A., Kamping, E. J., Jansen, E. A. M., Vink-Börger, M. E., Popp, I., Lang, A., Spier, I., Hüneburg, R., James, P. A., ... Kuiper, R. (2019). Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype. Cancer cell, 35(2), 256-266.e5. https://doi.org/10.1016/j.ccell.2018.12.011

@article{2a98114e6b354b2092b2e46e2c0efe4e,

title = "Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype",

abstract = "Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.",

keywords = "Adult, Aged, Biomarkers, Tumor/deficiency, DNA Mutational Analysis, DNA Repair/genetics, Deoxyribonuclease (Pyrimidine Dimer)/deficiency, Europe, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Germ-Line Mutation, Heredity, Humans, Male, Middle Aged, Neoplastic Syndromes, Hereditary/enzymology, Pedigree, Phenotype, Risk Assessment, Risk Factors, Transcriptome, Young Adult",

author = "Grolleman, {Judith E} and {de Voer}, {Richarda M} and Elsayed, {Fadwa A} and Maartje Nielsen and Weren, {Robbert D A} and Claire Palles and Ligtenberg, {Marjolijn J L} and Vos, {Janet R} and {Ten Broeke}, {Sanne W} and {de Miranda}, {Noel F C C} and Kuiper, {Renske A} and Kamping, {Eveline J} and Jansen, {Erik A M} and Vink-B{\"o}rger, {M Elisa} and Isabell Popp and Alois Lang and Isabel Spier and Robert H{\"u}neburg and James, {Paul A} and Na Li and Marija Staninova and Helen Lindsay and David Cockburn and Olivera Spasic-Boskovic and Mark Clendenning and Kevin Sweet and Gabriel Capell{\'a} and Wenche Sjursen and Hildegunn H{\o}berg-Vetti and Jongmans, {Marjolijn C} and Kornelia Neveling and {Geurts van Kessel}, Ad and Hans Morreau and Hes, {Frederik J} and Sijmons, {Rolf H} and Schackert, {Hans K} and Clara Ruiz-Ponte and Dagmara Dymerska and Jan Lubinski and Barbara Rivera and Foulkes, {William D} and Tomlinson, {Ian P} and Laura Valle and Buchanan, {Daniel D} and Sue Kenwrick and Julian Adlard and Dimovski, {Aleksandar J} and Campbell, {Ian G} and Stefan Aretz and Detlev Schindler and {van Wezel}, Tom and Nicoline Hoogerbrugge and Roland Kuiper",

year = "2019",

month = feb,

day = "11",

doi = "10.1016/j.ccell.2018.12.011",

language = "English",

volume = "35",

pages = "256--266.e5",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

Grolleman, JE, de Voer, RM, Elsayed, FA, Nielsen, M, Weren, RDA, Palles, C, Ligtenberg, MJL, Vos, JR, Ten Broeke, SW, de Miranda, NFCC, Kuiper, RA, Kamping, EJ, Jansen, EAM, Vink-Börger, ME, Popp, I, Lang, A, Spier, I, Hüneburg, R, James, PA, Li, N, Staninova, M, Lindsay, H, Cockburn, D, Spasic-Boskovic, O, Clendenning, M, Sweet, K, Capellá, G, Sjursen, W, Høberg-Vetti, H, Jongmans, MC, Neveling, K, Geurts van Kessel, A, Morreau, H, Hes, FJ, Sijmons, RH, Schackert, HK, Ruiz-Ponte, C, Dymerska, D, Lubinski, J, Rivera, B, Foulkes, WD, Tomlinson, IP, Valle, L, Buchanan, DD, Kenwrick, S, Adlard, J, Dimovski, AJ, Campbell, IG, Aretz, S, Schindler, D, van Wezel, T, Hoogerbrugge, N & Kuiper, R 2019, 'Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype', Cancer cell, vol. 35, nr. 2, blz. 256-266.e5. https://doi.org/10.1016/j.ccell.2018.12.011

TY - JOUR

T1 - Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

AU - Grolleman, Judith E

AU - de Voer, Richarda M

AU - Elsayed, Fadwa A

AU - Nielsen, Maartje

AU - Weren, Robbert D A

AU - Palles, Claire

AU - Ligtenberg, Marjolijn J L

AU - Vos, Janet R

AU - Ten Broeke, Sanne W

AU - de Miranda, Noel F C C

AU - Kuiper, Renske A

AU - Kamping, Eveline J

AU - Jansen, Erik A M

AU - Vink-Börger, M Elisa

AU - Popp, Isabell

AU - Lang, Alois

AU - Spier, Isabel

AU - Hüneburg, Robert

AU - James, Paul A

AU - Li, Na

AU - Staninova, Marija

AU - Lindsay, Helen

AU - Cockburn, David

AU - Spasic-Boskovic, Olivera

AU - Clendenning, Mark

AU - Sweet, Kevin

AU - Capellá, Gabriel

AU - Sjursen, Wenche

AU - Høberg-Vetti, Hildegunn

AU - Jongmans, Marjolijn C

AU - Neveling, Kornelia

AU - Geurts van Kessel, Ad

AU - Morreau, Hans

AU - Hes, Frederik J

AU - Sijmons, Rolf H

AU - Schackert, Hans K

AU - Ruiz-Ponte, Clara

AU - Dymerska, Dagmara

AU - Lubinski, Jan

AU - Rivera, Barbara

AU - Foulkes, William D

AU - Tomlinson, Ian P

AU - Valle, Laura

AU - Buchanan, Daniel D

AU - Kenwrick, Sue

AU - Adlard, Julian

AU - Dimovski, Aleksandar J

AU - Campbell, Ian G

AU - Aretz, Stefan

AU - Schindler, Detlev

AU - van Wezel, Tom

AU - Hoogerbrugge, Nicoline

AU - Kuiper, Roland

PY - 2019/2/11

Y1 - 2019/2/11

N2 - Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.

AB - Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.

KW - Adult

KW - Aged

KW - Biomarkers, Tumor/deficiency

KW - DNA Mutational Analysis

KW - DNA Repair/genetics

KW - Deoxyribonuclease (Pyrimidine Dimer)/deficiency

KW - Europe

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Predisposition to Disease

KW - Germ-Line Mutation

KW - Heredity

KW - Humans

KW - Male

KW - Middle Aged

KW - Neoplastic Syndromes, Hereditary/enzymology

KW - Pedigree

KW - Phenotype

KW - Risk Assessment

KW - Risk Factors

KW - Transcriptome

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85060026689&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.12.011

DO - 10.1016/j.ccell.2018.12.011

M3 - Article

C2 - 30753826

SN - 1535-6108

VL - 35

SP - 256-266.e5

JO - Cancer cell

JF - Cancer cell

IS - 2

ER -

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

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