期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 42, 页码 15172-15177出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1407909111
关键词
breast cancer; DNA repair; FANCM; exome sequencing; triple-negative breast cancer
资金
- Helsinki University Central Hospital Research Fund
- Academy of Finland [266528]
- Sigrid Juselius Foundation
- Nordic Cancer Union
- Finnish Cancer Society
- Alfred Kordelin Foundation
- Orion-Farmos Research Foundation
- Emil Aaltonen Foundation
- Maud Kuistila Foundation
- Breast Cancer Research Foundation
- National Institutes of Health [CA176785, CA116167]
- National Cancer Institute Specialized Program of Research Excellence Award in Breast Cancer [P50 CA116201]
- Landspitali University Hospital
- Gongum saman Research Fund
- Academy of Finland (AKA) [266528, 266528] Funding Source: Academy of Finland (AKA)
Inherited predisposition to breast cancer is known to be caused by loss-of-function mutations in BRCA1, BRCA2, PALB2, CHEK2, and other genes involved in DNA repair. However, most families severely affected by breast cancer do not harbor mutations in any of these genes. In Finland, founder mutations have been observed in each of these genes, suggesting that the Finnish population may be an excellent resource for the identification of other such genes. To this end, we carried out exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. In Fanconi anemia complementation gene M (FANCM), nonsense mutation c.5101C>T (p.Q1701X) was significantly more frequent among breast cancer patients than among controls [odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; P = 0.0018], with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, P = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM p.Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. These findings identify FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC.
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