期刊
BREAST CANCER RESEARCH
卷 18, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s13058-016-0758-5
关键词
Breast cancer; CHEK2; CHK2; I157T; 1100delC; Survival; Pathology; Gene expression
类别
资金
- Cancer Research UK [C1287/A10118, C1287/A12014, C490/A10124, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565]
- European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]
- ELAN-Fond of the University Hospital of Erlangen
- Helsinki University Central Hospital Research Fund
- Academy of Finland [266528, 250083, 122715]
- Finnish Cancer Society
- Nordic Cancer Union
- Sigrid Juselius Foundation
- Finnish Cultural Foundation
- Orion Research Foundation
- Cancer Society of Finland
- Ida Montin Foundation
- UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge
- Marit and Hans Rausings Initiative Against Breast Cancer
- Deutsche Krebshilfe e.V. [70-2892-BR I, 106332, 108253, 108419]
- Hamburg Cancer Society
- German Cancer Research Center (DKFZ)
- Federal Ministry of Education and Research (BMBF) Germany [01KH0402]
- Chief Physician Johan Boserup and Lise Boserup Fund
- Danish Medical Research Council and Herlev Hospital
- NIH grantsan NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA192393, CA116167, CA176785, CA116201]
- Breast Cancer Research Foundation
- Intramural Research Funds of the National Cancer Institute
- Department of Health and Human Services, USA
- Agency for Science, Technology and Research of Singapore (A*STAR)
- US National Institute of Health (NIH)
- Susan G. Komen Breast Cancer Foundation
- National Cancer Institute (USA) [UM1 CA164920]
- Finnish Cancer Foundation
- University of Oulu
- University of Oulu Support Foundation
- special Governmental EVO funds for Oulu University Hospital-based research activities
- special Government Funding (EVO) of Kuopio University Hospital grants
- Cancer Fund of North Savo
- Finnish Cancer Organizations
- strategic funding of the University of Eastern Finland
- Stockholm County Council
- Karolinska Institutet
- Swedish Cancer Society
- Gustav V Jubilee foundation
- Bert von Kantzows foundation
- SZBCS [PBZ_KBN_122/P05/2004]
- intramural grant from Hannover Medical School
- National Institutes of Health [CA128978]
- Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]
- Department of Defence [W81XWH-10-1-0341]
- Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer
- Komen Foundation for the Cure
- Ovarian Cancer Research Fund
- Cancer Foundation Finland sr [140146, 150147, 110135] Funding Source: researchfish
- Cancer Research UK [16561, 16565, 10118] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10124] Funding Source: researchfish
- Academy of Finland (AKA) [122715, 122715] Funding Source: Academy of Finland (AKA)
Background: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. Methods: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO:GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. Results: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors. Conclusions: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2: p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据