title: FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome.
abstract: 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)=1.66, 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 × 10-3). 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 = 1.50 × 10-3) 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Johanna I
authors.initials: JI
authors.lastname: Kiiski
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fagerholm
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre, NordLab, Oulu, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Tervasmäki
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Liisa M
authors.initials: LM
authors.lastname: Pelttari
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Maral
authors.initials: M
authors.lastname: Jamshidi
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre, NordLab, Oulu, Finland.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Mantere
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre, NordLab, Oulu, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Biochemistry and Biophysics, Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Biochemistry and Biophysics, Division of Translational Medicine and Chemical Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden.
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Imaging Center, Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Oncology, Kuopio, Finland.|Cancer Center, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Tengström
authors.affiliation: School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.|Imaging Center, Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.affiliation: Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.|Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre, NordLab, Oulu, Finland.
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
authors.affiliation: BioMediTech, University of Tampere and Fimlab Laboratories, Tampere, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Kallioniemi
authors.affiliation: Department of Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.affiliation: Department of Oncology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. heli.nevanlinna@hus.fi.
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D003131:Combined Modality Therapy; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010641:Phenotype; D017354:Point Mutation; D011159:Population Surveillance; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C518295:FANCM protein, human; D004265:DNA Helicases
keywords: DNA repair; FANCM; breast cancer; radiotherapy; survival