Two truncating variants in FANCC and breast cancer risk

doi:10.1038/s41598-019-48804-y

Two truncating variants in FANCC and breast cancer risk

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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.

Original language	English
Article number	12524
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-48804-y
Publication status	Published - 1 Dec 2019

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University of Sydney, & Department of Cancer Genetics University of Oslo Institute of Clinical Medicine Department of Research Vestre Viken Hospital iFIT Cluster of Excellence University of Tübingen Section for Breast- and Endocrine Surgery Department of Radiology and Nuclear Medicine Department of Pathology Department of Tumor Biology Department of Oncology National Advisory Unit on Late Effects after Cancer Treatment Department of Oncology Breast Cancer Research Consortium (2019). Two truncating variants in FANCC and breast cancer risk. Scientific Reports, 9(1), Article 12524. https://doi.org/10.1038/s41598-019-48804-y

University of Sydney ; Department of Cancer Genetics University of Oslo Institute of Clinical Medicine Department of Research Vestre Viken Hospital iFIT Cluster of Excellence University of Tübingen Section for Breast- and Endocrine Surgery Department of Radiology and Nuclear Medicine Department of Pathology Department of Tumor Biology Department of Oncology National Advisory Unit on Late Effects after Cancer Treatment Department of Oncology Breast Cancer Research Consortium. / Two truncating variants in FANCC and breast cancer risk. In: Scientific Reports. 2019 ; Vol. 9, No. 1.

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title = "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.",

author = "Thilo D{\"o}rk and Paolo Peterlongo and Arto Mannermaa and Bolla, {Manjeet K.} and Qin Wang and Joe Dennis and Thomas Ahearn and Andrulis, {Irene L.} and Hoda Anton-Culver and Volker Arndt and Aronson, {Kristan J.} and Annelie Augustinsson and Freeman, {Laura E.Beane} and Beckmann, {Matthias W.} and Alicia Beeghly-Fadiel and Sabine Behrens and Marina Bermisheva and Carl Blomqvist and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Hiltrud Brauch and Hermann Brenner and Barbara Burwinkel and Federico Canzian and Chan, {Tsun L.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Choi, {Ji Yeob} and Hans Christiansen and Clarke, {Christine L.} and Couch, {Fergus J.} and Kamila Czene and Daly, {Mary B.} and Isabel dos-Santos-Silva and Miriam Dwek and Eccles, {Diana M.} and Ekici, {Arif B.} and Mikael Eriksson and Evans, {D. Gareth} and Fasching, {Peter A.} and Jonine Figueroa and Henrik Flyger and Lin Fritschi and Marike Gabrielson and Manuela Gago-Dominguez and Chi Gao and Gapstur, {Susan M.} and Montserrat Garc{\'i}a-Closas and Jane Dahlstrom and Adrienne Morey",

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year = "2019",

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doi = "10.1038/s41598-019-48804-y",

language = "English",

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University of Sydney & Department of Cancer Genetics University of Oslo Institute of Clinical Medicine Department of Research Vestre Viken Hospital iFIT Cluster of Excellence University of Tübingen Section for Breast- and Endocrine Surgery Department of Radiology and Nuclear Medicine Department of Pathology Department of Tumor Biology Department of Oncology National Advisory Unit on Late Effects after Cancer Treatment Department of Oncology Breast Cancer Research Consortium 2019, 'Two truncating variants in FANCC and breast cancer risk', Scientific Reports, vol. 9, no. 1, 12524. https://doi.org/10.1038/s41598-019-48804-y

Two truncating variants in FANCC and breast cancer risk. / University of Sydney; Department of Cancer Genetics University of Oslo Institute of Clinical Medicine Department of Research Vestre Viken Hospital iFIT Cluster of Excellence University of Tübingen Section for Breast- and Endocrine Surgery Department of Radiology and Nuclear Medicine Department of Pathology Department of Tumor Biology Department of Oncology National Advisory Unit on Late Effects after Cancer Treatment Department of Oncology Breast Cancer Research Consortium.
In: Scientific Reports, Vol. 9, No. 1, 12524, 01.12.2019.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Two truncating variants in FANCC and breast cancer risk

AU - Dörk, Thilo

AU - Peterlongo, Paolo

AU - Mannermaa, Arto

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dennis, Joe

AU - Ahearn, Thomas

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Aronson, Kristan J.

AU - Augustinsson, Annelie

AU - Freeman, Laura E.Beane

AU - Beckmann, Matthias W.

AU - Beeghly-Fadiel, Alicia

AU - Behrens, Sabine

AU - Bermisheva, Marina

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Burwinkel, Barbara

AU - Canzian, Federico

AU - Chan, Tsun L.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Choi, Ji Yeob

AU - Christiansen, Hans

AU - Clarke, Christine L.

AU - Couch, Fergus J.

AU - Czene, Kamila

AU - Daly, Mary B.

AU - dos-Santos-Silva, Isabel

AU - Dwek, Miriam

AU - Eccles, Diana M.

AU - Ekici, Arif B.

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Fasching, Peter A.

AU - Figueroa, Jonine

AU - Flyger, Henrik

AU - Fritschi, Lin

AU - Gabrielson, Marike

AU - Gago-Dominguez, Manuela

AU - Gao, Chi

AU - Gapstur, Susan M.

AU - García-Closas, Montserrat

AU - Dahlstrom, Jane

AU - Morey, Adrienne

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41598-019-48804-y

DO - 10.1038/s41598-019-48804-y

M3 - Article

SN - 2045-2322

VL - 9

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 12524

ER -

University of Sydney, Department of Cancer Genetics University of Oslo Institute of Clinical Medicine Department of Research Vestre Viken Hospital iFIT Cluster of Excellence University of Tübingen Section for Breast- and Endocrine Surgery Department of Radiology and Nuclear Medicine Department of Pathology Department of Tumor Biology Department of Oncology National Advisory Unit on Late Effects after Cancer Treatment Department of Oncology Breast Cancer Research Consortium. Two truncating variants in FANCC and breast cancer risk. Scientific Reports. 2019 Dec 1;9(1):12524. doi: 10.1038/s41598-019-48804-y

Two truncating variants in FANCC and breast cancer risk

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