Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin
BACKGROUND: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer....
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Online Access: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136924/ http://www.ncbi.nlm.nih.gov/pubmed/29767749 https://doi.org/10.1093/jnci/djy002 |
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ftpubmed:oai:pubmedcentral.nih.gov:6136924 2023-05-15T16:51:50+02:00 Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin Rafnar, Thorunn Sigurjonsdottir, Gudbjorg R Stacey, Simon N Halldorsson, Gisli Sulem, Patrick Pardo, Luba M Helgason, Hannes Sigurdsson, Stefan T Gudjonsson, Thorkell Tryggvadottir, Laufey Olafsdottir, Gudridur H Jonasson, Jon G Alexiusdottir, Kristin Sigurdsson, Asgeir Gudmundsson, Julius Saemundsdottir, Jona Sigurdsson, Jon K Johannsdottir, Hrefna Uitterlinden, Andre Vermeulen, Sita H Galesloot, Tessel E Allain, Dawn C Lacko, Martin Sigurgeirsson, Bardur Thorisdottir, Kristin Johannsson, Oskar T Sigurdsson, Fridbjorn Ragnarsson, Gunnar B Isaksson, Helgi Hardardottir, Hronn Gudbjartsson, Tomas Gudbjartsson, Daniel F Masson, Gisli Kiemeney, Lambertus A M L Ewart Toland, Amanda Nijsten, Tamar Peters, Wilbert H M Olafsson, Jon H Jonsson, Steinn Thorsteinsdottir, Unnur Thorleifsson, Gudmar Stefansson, Kari 2018-05-14 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136924/ http://www.ncbi.nlm.nih.gov/pubmed/29767749 https://doi.org/10.1093/jnci/djy002 en eng Oxford University Press http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136924/ http://www.ncbi.nlm.nih.gov/pubmed/29767749 http://dx.doi.org/10.1093/jnci/djy002 © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com https://academic.oup.com/journals/pages/about_us/legal/notices This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) Articles Text 2018 ftpubmed https://doi.org/10.1093/jnci/djy002 2019-05-19T00:10:07Z BACKGROUND: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. METHODS: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database. RESULTS: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. CONCLUSIONS: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress. Text Iceland PubMed Central (PMC) JNCI: Journal of the National Cancer Institute 110 9 967 974 |
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Articles |
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Articles Rafnar, Thorunn Sigurjonsdottir, Gudbjorg R Stacey, Simon N Halldorsson, Gisli Sulem, Patrick Pardo, Luba M Helgason, Hannes Sigurdsson, Stefan T Gudjonsson, Thorkell Tryggvadottir, Laufey Olafsdottir, Gudridur H Jonasson, Jon G Alexiusdottir, Kristin Sigurdsson, Asgeir Gudmundsson, Julius Saemundsdottir, Jona Sigurdsson, Jon K Johannsdottir, Hrefna Uitterlinden, Andre Vermeulen, Sita H Galesloot, Tessel E Allain, Dawn C Lacko, Martin Sigurgeirsson, Bardur Thorisdottir, Kristin Johannsson, Oskar T Sigurdsson, Fridbjorn Ragnarsson, Gunnar B Isaksson, Helgi Hardardottir, Hronn Gudbjartsson, Tomas Gudbjartsson, Daniel F Masson, Gisli Kiemeney, Lambertus A M L Ewart Toland, Amanda Nijsten, Tamar Peters, Wilbert H M Olafsson, Jon H Jonsson, Steinn Thorsteinsdottir, Unnur Thorleifsson, Gudmar Stefansson, Kari Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin |
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description |
BACKGROUND: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. METHODS: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database. RESULTS: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. CONCLUSIONS: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress. |
format |
Text |
author |
Rafnar, Thorunn Sigurjonsdottir, Gudbjorg R Stacey, Simon N Halldorsson, Gisli Sulem, Patrick Pardo, Luba M Helgason, Hannes Sigurdsson, Stefan T Gudjonsson, Thorkell Tryggvadottir, Laufey Olafsdottir, Gudridur H Jonasson, Jon G Alexiusdottir, Kristin Sigurdsson, Asgeir Gudmundsson, Julius Saemundsdottir, Jona Sigurdsson, Jon K Johannsdottir, Hrefna Uitterlinden, Andre Vermeulen, Sita H Galesloot, Tessel E Allain, Dawn C Lacko, Martin Sigurgeirsson, Bardur Thorisdottir, Kristin Johannsson, Oskar T Sigurdsson, Fridbjorn Ragnarsson, Gunnar B Isaksson, Helgi Hardardottir, Hronn Gudbjartsson, Tomas Gudbjartsson, Daniel F Masson, Gisli Kiemeney, Lambertus A M L Ewart Toland, Amanda Nijsten, Tamar Peters, Wilbert H M Olafsson, Jon H Jonsson, Steinn Thorsteinsdottir, Unnur Thorleifsson, Gudmar Stefansson, Kari |
author_facet |
Rafnar, Thorunn Sigurjonsdottir, Gudbjorg R Stacey, Simon N Halldorsson, Gisli Sulem, Patrick Pardo, Luba M Helgason, Hannes Sigurdsson, Stefan T Gudjonsson, Thorkell Tryggvadottir, Laufey Olafsdottir, Gudridur H Jonasson, Jon G Alexiusdottir, Kristin Sigurdsson, Asgeir Gudmundsson, Julius Saemundsdottir, Jona Sigurdsson, Jon K Johannsdottir, Hrefna Uitterlinden, Andre Vermeulen, Sita H Galesloot, Tessel E Allain, Dawn C Lacko, Martin Sigurgeirsson, Bardur Thorisdottir, Kristin Johannsson, Oskar T Sigurdsson, Fridbjorn Ragnarsson, Gunnar B Isaksson, Helgi Hardardottir, Hronn Gudbjartsson, Tomas Gudbjartsson, Daniel F Masson, Gisli Kiemeney, Lambertus A M L Ewart Toland, Amanda Nijsten, Tamar Peters, Wilbert H M Olafsson, Jon H Jonsson, Steinn Thorsteinsdottir, Unnur Thorleifsson, Gudmar Stefansson, Kari |
author_sort |
Rafnar, Thorunn |
title |
Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin |
title_short |
Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin |
title_full |
Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin |
title_fullStr |
Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin |
title_full_unstemmed |
Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin |
title_sort |
association of brca2 k3326* with small cell lung cancer and squamous cell cancer of the skin |
publisher |
Oxford University Press |
publishDate |
2018 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136924/ http://www.ncbi.nlm.nih.gov/pubmed/29767749 https://doi.org/10.1093/jnci/djy002 |
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Iceland |
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Iceland |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136924/ http://www.ncbi.nlm.nih.gov/pubmed/29767749 http://dx.doi.org/10.1093/jnci/djy002 |
op_rights |
© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com https://academic.oup.com/journals/pages/about_us/legal/notices This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) |
op_doi |
https://doi.org/10.1093/jnci/djy002 |
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JNCI: Journal of the National Cancer Institute |
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110 |
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9 |
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967 |
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974 |
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1766041954595897344 |