Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype
NTHL1 authors
(2019) Cancer Cell, volume 35, issue 2, pp. 256 - 266.e5
(Article)
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
... read more
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.
show less
Download/Full Text
The full text of this publication is not available.
Keywords: adenomatous polyposis, base excision repair, breast cancer, colorectal cancer, DNA repair defect, genetic predisposition, multiple malignancies, mutational signature, NTHL1, somatic mutation spectrum, Oncology, Cell Biology, Cancer Research
ISSN: 1535-6108
Publisher: Cell Press
Note: 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.
(Peer reviewed)