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.
Original language | English |
---|---|
Pages (from-to) | 256-266.e5 |
Journal | Cancer Cell |
Volume | 35 |
Issue number | 2 |
DOIs | |
Publication status | Published - 11 Feb 2019 |
Keywords
- adenomatous polyposis
- base excision repair
- breast cancer
- colorectal cancer
- DNA repair defect
- genetic predisposition
- multiple malignancies
- mutational signature
- NTHL1
- somatic mutation spectrum
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In: Cancer Cell, Vol. 35, No. 2, 11.02.2019, p. 256-266.e5.
Research output: Contribution to journal › Article › Academic › peer-review
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
N1 - Funding Information: We thank the patients for their cooperation, Drs. Wendy van Zelst-Stams and Marleen Kets for providing and updating clinical information on the Dutch families, Dr. Alexander Hoischen for assisting in the MIP design, the Genome Technology Platform for MIP sequencing support and Dr. Christian Gilissen for the use of the variant calling and annotation pipeline in the Radboudumc, Nijmegen. We acknowledge the networking support of the COST Actions BM1206 and CA17118. This work was supported by grants from the Dutch Cancer Society (KUN2015-7740), and the Sacha Swarttouw-Hijmans Foundation. R.M.d.V. holds a Fellowship from the Dutch Cancer Society (KWF; KUN2014-6666). A.D. and M.S. hold a grant from the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy, on molecular aspects of inherited colorectal carcinoma in Macedonia. C.R.P. holds a grant from Fondo de Investigacion Sanitaria/Plan Estatal de I + D + I 2013–2016/FEDER (PI14/00230). D.D.B. holds a Senior Research Fellowship from the University of Melbourne Research at Melbourne Accelerator Program (R@MAP) and a Fellowship from NHMRC R.D. Wright Career Development. I.P. and D.S. are supported by the Schroeder-Kurth Fund. I.G.C. and P.A.J. are supported by grants from the National Breast Cancer Foundation of Australia and Cancer Australia. L.V. and G.C. hold grants from the Spanish Ministry of Economy and Competitiveness, co-funded by FEDER funds – a way to build Europe (SAF2016-80888-R and SAF2015-68016-R). H.K.S. is supported by the Deutsche Krebshilfe. Funding Information: We thank the patients for their cooperation, Drs. Wendy van Zelst-Stams and Marleen Kets for providing and updating clinical information on the Dutch families, Dr. Alexander Hoischen for assisting in the MIP design, the Genome Technology Platform for MIP sequencing support and Dr. Christian Gilissen for the use of the variant calling and annotation pipeline in the Radboudumc, Nijmegen. We acknowledge the networking support of the COST Actions BM1206 and CA17118. This work was supported by grants from the Dutch Cancer Society (KUN2015-7740), and the Sacha Swarttouw-Hijmans Foundation. R.M.d.V. holds a Fellowship from the Dutch Cancer Society (KWF; KUN2014-6666). A.D. and M.S. hold a grant from the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy, on molecular aspects of inherited colorectal carcinoma in Macedonia. C.R.P. holds a grant from Fondo de Investigacion Sanitaria/Plan Estatal de I + D + I 2013?2016/FEDER (PI14/00230). D.D.B. holds a Senior Research Fellowship from the University of Melbourne Research at Melbourne Accelerator Program (R@MAP) and a Fellowship from NHMRC R.D. Wright Career Development. I.P. and D.S. are supported by the Schroeder-Kurth Fund. I.G.C. and P.A.J. are supported by grants from the National Breast Cancer Foundation of Australia and Cancer Australia. L.V. and G.C. hold grants from the Spanish Ministry of Economy and Competitiveness, co-funded by FEDER funds ? a way to build Europe (SAF2016-80888-R and SAF2015-68016-R). H.K.S. is supported by the Deutsche Krebshilfe. Funding Information: We thank the patients for their cooperation, Drs. Wendy van Zelst-Stams and Marleen Kets for providing and updating clinical information on the Dutch families, Dr. Alexander Hoischen for assisting in the MIP design, the Genome Technology Platform for MIP sequencing support and Dr. Christian Gilissen for the use of the variant calling and annotation pipeline in the Radboudumc, Nijmegen. We acknowledge the networking support of the COST Actions BM1206 and CA17118 . This work was supported by grants from the Dutch Cancer Society ( KUN2015-7740 ), and the Sacha Swarttouw-Hijmans Foundation . R.M.d.V. holds a Fellowship from the Dutch Cancer Society (KWF; KUN2014-6666 ). A.D. and M.S. hold a grant from the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy, on molecular aspects of inherited colorectal carcinoma in Macedonia. C.R.P. holds a grant from Fondo de Investigacion Sanitaria /Plan Estatal de I + D + I 2013–2016/FEDER (PI14/00230). D.D.B. holds a Senior Research Fellowship from the University of Melbourne Research at Melbourne Accelerator Program (R@MAP) and a Fellowship from NHMRC R.D. Wright Career Development. I.P. and D.S. are supported by the Schroeder-Kurth Fund . I.G.C. and P.A.J. are supported by grants from the National Breast Cancer Foundation of Australia and Cancer Australia. L.V. and G.C. hold grants from the Spanish Ministry of Economy and Competitiveness , co-funded by FEDER funds – a way to build Europe ( SAF2016-80888-R and SAF2015-68016-R ). H.K.S. is supported by the Deutsche Krebshilfe . Publisher Copyright: © 2018 Elsevier Inc.
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 - adenomatous polyposis
KW - base excision repair
KW - breast cancer
KW - colorectal cancer
KW - DNA repair defect
KW - genetic predisposition
KW - multiple malignancies
KW - mutational signature
KW - NTHL1
KW - somatic mutation spectrum
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
AN - SCOPUS:85060026689
SN - 1535-6108
VL - 35
SP - 256-266.e5
JO - Cancer Cell
JF - Cancer Cell
IS - 2
ER -