Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin.

Autor:	Rafnar T; deCODE Genetics/Amgen, Reykjavik, Iceland., Sigurjonsdottir GR; Department of Oncology, Landspitali-University Hospital, Reykjavik, Iceland., Stacey SN; deCODE Genetics/Amgen, Reykjavik, Iceland., Halldorsson G; deCODE Genetics/Amgen, Reykjavik, Iceland., Sulem P; deCODE Genetics/Amgen, Reykjavik, Iceland., Pardo LM; Department of Dermatology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., Helgason H; deCODE Genetics/Amgen, Reykjavik, Iceland.; Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavik, Iceland., Sigurdsson ST; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Gudjonsson T; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Tryggvadottir L; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.; Icelandic Cancer Registry, Reykjavik, Iceland., Olafsdottir GH; Icelandic Cancer Registry, Reykjavik, Iceland., Jonasson JG; Department of Pathology, Landspitali-University Hospital, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Alexiusdottir K; Department of Oncology, Landspitali-University Hospital, Reykjavik, Iceland.; Icelandic Cancer Registry, Reykjavik, Iceland., Sigurdsson A; deCODE Genetics/Amgen, Reykjavik, Iceland., Gudmundsson J; deCODE Genetics/Amgen, Reykjavik, Iceland., Saemundsdottir J; deCODE Genetics/Amgen, Reykjavik, Iceland., Sigurdsson JK; deCODE Genetics/Amgen, Reykjavik, Iceland., Johannsdottir H; deCODE Genetics/Amgen, Reykjavik, Iceland., Uitterlinden A; Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands., Vermeulen SH; Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands., Galesloot TE; Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands., Allain DC; Department of Internal Medicine.; The Ohio State University, Columbus, OH., Lacko M; Department of Otorhinolaryngology, Head and Neck Surgery, Maastricht University Medical Center, Maastricht, the Netherlands., Sigurgeirsson B; Department of Dermatology, Landspitali-University Hospital, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Thorisdottir K; Department of Dermatology, Landspitali-University Hospital, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Johannsson OT; Department of Oncology, Landspitali-University Hospital, Reykjavik, Iceland., Sigurdsson F; Department of Oncology, Landspitali-University Hospital, Reykjavik, Iceland., Ragnarsson GB; Department of Oncology, Landspitali-University Hospital, Reykjavik, Iceland., Isaksson H; Department of Pathology, Landspitali-University Hospital, Reykjavik, Iceland., Hardardottir H; Department of Medicine, Landspitali-University Hospital, Reykjavik, Iceland., Gudbjartsson T; Department of Surgery, Landspitali-University Hospital, Reykjavik, Iceland., Gudbjartsson DF; deCODE Genetics/Amgen, Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Masson G; deCODE Genetics/Amgen, Reykjavik, Iceland., Kiemeney LAML; Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands., Ewart Toland A; Department of Cancer Biology.; Department of Genetics and Internal Medicine.; Division of Human Genetics, and The Comprehensive Cancer Center., Nijsten T; Department of Dermatology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., Peters WHM; Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands., Olafsson JH; Department of Dermatology, Landspitali-University Hospital, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Jonsson S; Department of Medicine, Landspitali-University Hospital, Reykjavik, Iceland., Thorsteinsdottir U; deCODE Genetics/Amgen, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Thorleifsson G; deCODE Genetics/Amgen, Reykjavik, Iceland., Stefansson K; deCODE Genetics/Amgen, Reykjavik, Iceland.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Jazyk:	angličtina
Zdroj:	Journal of the National Cancer Institute [J Natl Cancer Inst] 2018 Sep 01; Vol. 110 (9), pp. 967-974.
DOI:	10.1093/jnci/djy002
Abstrakt:	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.
Databáze:	MEDLINE
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