Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 139, Issue 12, Pages 2760-2770Publisher
WILEY
DOI: 10.1002/ijc.30394
Keywords
FANCM; breast cancer; survival; DNA repair; radiotherapy
Categories
Funding
- Helsinki University Central Hospital Research Fund
- Academy of Finland [132473, 284605, 250083]
- Sigrid Juselius Foundation
- Cancer Society of Finland
- Finnish Cultural Foundation
- Paulo Foundation
- Bio-medicum Helsinki Foundation
- University of Oulu
- University of Oulu Support Foundation
- special Governmental EVO funds for Oulu University Hospital-based research activities
- special Government Funding of Kuopio University Hospital Grants
- University of Eastern Finland
- Novo Nordisk Foundation
- Danish Cancer Society
- Danish National Research Foundation (Center of Excellence CARD) [DNRF125]
- Swedish Research Council
- CancerFonden
- Cancer Foundation Finland sr [140146, 110135, 150147, 150100] Funding Source: researchfish
- Novo Nordisk Fonden [NNF15OC0016584, NNF12OC0002290] Funding Source: researchfish
- The Danish Cancer Society [R124-A7785] Funding Source: researchfish
- Academy of Finland (AKA) [284605, 284605] Funding Source: Academy of Finland (AKA)
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Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C> T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple-negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3,933 invasive breast cancer patients, including 101 FANCM c.5101C> T mutation carriers and 3,832 non-carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1,240 breast tumors. The FANCM c.5101C>T mutation associated with poor 10-year breast cancer-specific survival (hazard ratio (HR) 51.66, 95% confidence interval (CI) 1.09-2.52, p=0.018), with a more pronounced survival effect among familial cases (HR=2.93, 95% CI 1.5-5.76, p=1.80 x 10 23). Poor disease outcome of the carriers was also found among the estrogen receptor (ER) positive subgroup of patients (HR=1.8, 95% CI 1.09-2.98, p=0.021). Reduced survival was seen especially among patients who had not received radiotherapy (HR=3.43, 95% CI 1.6-7.34, p=1.50x10(-3)) but not among radiotherapy treated patients (HR=1.35, 95% CI 0.82-2.23, p=0.237). Significant interaction was found between the mutation and radiotherapy (p=0.040). Immunohistochemical analyses show that c.5101C> T carriers have reduced PAR-activity. Our results suggest that FANCM c.5101C>T nonsense mutation carriers have a reduced breast cancer survival but postoperative radiotherapy may diminish this survival disadvantage.
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