FANCM mutation c.5791C>T is a risk factor for triple-negative breast cancer in the Finnish population

• Published in: Breast cancer research and treatment 2017-11, Vol.166 (1), p.217-226
• Main Authors: Kiiski, Johanna I., Tervasmäki, Anna, Pelttari, Liisa M., Khan, Sofia, Mantere, Tuomo, Pylkäs, Katri, Mannermaa, Arto, Tengström, Maria, Kvist, Anders, Borg, Åke, Kosma, Veli-Matti, Kallioniemi, Anne, Schleutker, Johanna, Bützow, Ralf, Blomqvist, Carl, Aittomäki, Kristiina, Winqvist, Robert, Nevanlinna, Heli
• Format: Article
• Language: English
• Subjects: Alleles; BRCA1 protein; Breast cancer; Cancer research; Case-Control Studies; DNA Helicases - genetics; DNA Repair; Epidemiology; Female; Finland - epidemiology; Gene Duplication; Gene Frequency; Genetic Predisposition to Disease; Genotype; Health risk assessment; Humans; Invasiveness; Medicine; Medicine & Public Health; Mutation; Nonsense mutation; Odds Ratio; Oncology; Ovarian cancer; Population Surveillance; Risk Assessment; Risk Factors; Sequence Deletion; Statistical analysis; Triple Negative Breast Neoplasms - epidemiology; Triple Negative Breast Neoplasms - genetics
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-017-4388-0

Purpose The FANCM c.5101C>T nonsense mutation was previously found to associate with breast cancer in the Finnish population, especially among triple-negative cases. Here, we studied the prevalence of three other FANCM variants: c.5791C>T, which has been reported to predispose to familial breast cancer, and the c.4025_4026delCT and c.5293dupA variants recently identified in Finnish cancer patients. Methods We genotyped the FANCM c.5791C>T mutation in 4806 invasive breast cancer patients, including BRCA1/2 mutation negative familial cases and unselected cases, and in 2734 healthy population controls from four different geographical areas of Finland. The association of the mutation with breast cancer risk among patient subgroups was statistically evaluated. We further analyzed the combined risk associated with c.5101C>T and c.5791C>T mutations. We also genotyped 526 unselected ovarian cancer patients for the c.5791C>T mutation and 862 familial breast cancer patients for the c.4025_4026delCT and c.5293dupA variants. Results The frequency of the FANCM c.5791C>T mutation was higher among breast cancer cases than in controls (OR 1.94, 95% CI 0.87–4.32, P  = 0.11), with a statistically significant association with triple-negative breast cancer (OR 5.14, 95% CI 1.65–16.0, P  = 0.005). The combined analysis for c.5101C>T and c.5791C>T carriers confirmed a strong association with breast cancer (OR 1.86, 95% CI 1.32–2.49, P  = 0.0002), especially among the triple-negative patients (OR 3.08, 95% CI 1.77–5.35, P  = 0.00007). For the other variants, only one additional c.4025_4026delCT carrier and no c.5293dupA carriers were observed. Conclusions These results support the role of FANCM as a breast cancer susceptibility gene, particularly for triple-negative breast cancer.