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Two truncating variants in FANCC and breast cancer risk.

ABSTRACT: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p?=?0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

SUBMITTER: Dork T

PROVIDER: S-EPMC6715680 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Two truncating variants in FANCC and breast cancer risk.

Dörk Thilo T Peterlongo Paolo P Mannermaa Arto A Bolla Manjeet K MK Wang Qin Q Dennis Joe J Ahearn Thomas T Andrulis Irene L IL Anton-Culver Hoda H Arndt Volker V Aronson Kristan J KJ Augustinsson Annelie A Freeman Laura E Beane LEB Beckmann Matthias W MW Beeghly-Fadiel Alicia A Behrens Sabine S Bermisheva Marina M Blomqvist Carl C Bogdanova Natalia V NV Bojesen Stig E SE Brauch Hiltrud H Brenner Hermann H Burwinkel Barbara B Canzian Federico F Chan Tsun L TL Chang-Claude Jenny J Chanock Stephen J SJ Choi Ji-Yeob JY Christiansen Hans H Clarke Christine L CL Couch Fergus J FJ Czene Kamila K Daly Mary B MB Dos-Santos-Silva Isabel I Dwek Miriam M Eccles Diana M DM Ekici Arif B AB Eriksson Mikael M Evans D Gareth DG Fasching Peter A PA Figueroa Jonine J Flyger Henrik H Fritschi Lin L Gabrielson Marike M Gago-Dominguez Manuela M Gao Chi C Gapstur Susan M SM García-Closas Montserrat M García-Sáenz José A JA Gaudet Mia M MM Giles Graham G GG Goldberg Mark S MS Goldgar David E DE Guénel Pascal P Haeberle Lothar L Haiman Christopher A CA Håkansson Niclas N Hall Per P Hamann Ute U Hartman Mikael M Hauke Jan J Hein Alexander A Hillemanns Peter P Hogervorst Frans B L FBL Hooning Maartje J MJ Hopper John L JL Howell Tony T Huo Dezheng D Ito Hidemi H Iwasaki Motoki M Jakubowska Anna A Janni Wolfgang W John Esther M EM Jung Audrey A Kaaks Rudolf R Kang Daehee D Kapoor Pooja Middha PM Khusnutdinova Elza E Kim Sung-Won SW Kitahara Cari M CM Koutros Stella S Kraft Peter P Kristensen Vessela N VN Kwong Ava A Lambrechts Diether D Marchand Loic Le LL Li Jingmei J Lindström Sara S Linet Martha M Lo Wing-Yee WY Long Jirong J Lophatananon Artitaya A Lubiński Jan J Manoochehri Mehdi M Manoukian Siranoush S Margolin Sara S Martinez Elena E Matsuo Keitaro K Mavroudis Dimitris D Meindl Alfons A Menon Usha U Milne Roger L RL Mohd Taib Nur Aishah NA Muir Kenneth K Mulligan Anna Marie AM Neuhausen Susan L SL Nevanlinna Heli H Neven Patrick P Newman William G WG Offit Kenneth K Olopade Olufunmilayo I OI Olshan Andrew F AF Olson Janet E JE Olsson Håkan H Park Sue K SK Park-Simon Tjoung-Won TW Peto Julian J Plaseska-Karanfilska Dijana D Pohl-Rescigno Esther E Presneau Nadege N Rack Brigitte B Radice Paolo P Rashid Muhammad U MU Rennert Gad G Rennert Hedy S HS Romero Atocha A Ruebner Matthias M Saloustros Emmanouil E Schmidt Marjanka K MK Schmutzler Rita K RK Schneider Michael O MO Schoemaker Minouk J MJ Scott Christopher C Shen Chen-Yang CY Shu Xiao-Ou XO Simard Jacques J Slager Susan S Smichkoska Snezhana S Southey Melissa C MC Spinelli John J JJ Stone Jennifer J Surowy Harald H Swerdlow Anthony J AJ Tamimi Rulla M RM Tapper William J WJ Teo Soo H SH Terry Mary Beth MB Toland Amanda E AE Tollenaar Rob A E M RAEM Torres Diana D Torres-Mejía Gabriela G Troester Melissa A MA Truong Thérèse T Tsugane Shoichiro S Untch Michael M Vachon Celine M CM Ouweland Ans M W van den AMWVD Veen Elke M van EMV Vijai Joseph J Wendt Camilla C Wolk Alicja A Yu Jyh-Cherng JC Zheng Wei W Ziogas Argyrios A Ziv Elad E Dunning Alison M AM Pharoah Paul D P PDP Schindler Detlev D Devilee Peter P Easton Douglas F DF

Scientific reports 20190829 1

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 ...[more]

PMID: 31467304

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Project description:BackgroundInherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon.MethodsWe used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways.ResultsPatients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00-27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05.ConclusionsTo our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results.

Project description:INTRODUCTION: Recently, several genome-wide association studies (GWAS) have identified novel single nucleotide polymorphisms (SNPs) associated with breast cancer risk. However, most of the studies were conducted among Caucasians and only one from Chinese. METHODS: In the current study, we first tested whether 15 SNPs identified by previous GWAS were also breast cancer marker SNPs in this Chinese population. Then, we grouped the marker SNPs, and modeled them with clinical risk factors, to see the usage of these factors in breast cancer risk assessment. Two methods (risk factors counting and odds ratio (OR) weighted risk scoring) were used to evaluate the cumulative effects of the five significant SNPs and two clinical risk factors (age at menarche and age at first live birth). RESULTS: Five SNPs located at 2q35, 3p24, 6q22, 6q25 and 10q26 were consistently associated with breast cancer risk in both testing set (878 cases and 900 controls) and validation set (914 cases and 967 controls) samples. Overall, all of the five SNPs contributed to breast cancer susceptibility in a dominant genetic model (2q35, rs13387042: adjusted OR = 1.26, P = 0.006; 3q24.1, rs2307032: adjusted OR = 1.24, P = 0.005; 6q22.33, rs2180341: adjusted OR = 1.22, P = 0.006; 6q25.1, rs2046210: adjusted OR = 1.51, P = 2.40 × 10-8; 10q26.13, rs2981582: adjusted OR = 1.31, P = 1.96 × 10-4). Risk score analyses (area under the curve (AUC): 0.649, 95% confidence interval (CI): 0.631 to 0.667; sensitivity = 62.60%, specificity = 57.05%) presented better discrimination than that by risk factors counting (AUC: 0.637, 95% CI: 0.619 to 0.655; sensitivity = 62.16%, specificity = 60.03%) (P < 0.0001). Absolute risk was then calculated by the modified Gail model and an AUC of 0.658 (95% CI = 0.640 to 0.676) (sensitivity = 61.98%, specificity = 60.26%) was obtained for the combination of five marker SNPs, age at menarche and age at first live birth. CONCLUSIONS: This study shows that five GWAS identified variants were also consistently validated in this Chinese population and combining these genetic variants with other risk factors can improve the risk predictive ability of breast cancer. However, more breast cancer associated risk variants should be incorporated to optimize the risk assessment.

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Two truncating variants in FANCC and breast cancer risk.

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Two truncating variants in FANCC and breast cancer risk.

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