A comprehensive study evaluating germline FANCG variants in predisposition to breast and ovarian cancer

Author:

Soukupova Jana1,Stastna Barbora123,Kanwal Madiha2,Hojny Jan4,Zemankova Petra15,Borecka Marianna1,Cerna Leona6,Cerna Marta1,Cerna Monika7,Curtisova Vaclava8,Dolezalova Tatana1,Duskova Petra9,Foretova Lenka10,Havranek Ondrej1112,Horackova Klara1,Hovhannisyan Milena1,Hruskova Lucie13,Chvojka Stepan6,Janatova Marketa1,Janikova Maria8,Jelinkova Sandra1,Just Pavel1,Kalousova Marta1,Kleiblova Petra111,Kosarova Marcela14,Koudova Monika6,Kral Jan1,Krausova Michaela4,Krutilkova Vera15,Machackova Eva10,Matejkova Katerina116,Michalovska Renata13,Nehasil Petr1517,Nemcova Barbora1,Novotny Jan1118,Palek Matous2,Pesek Pavel1,Safarikova Marketa1,Scheinost Ondrej9,Springer Drahomira1,Stolarova Lenka2,Stranecky Viktor17,Subrt Ivan7,Tavandzis Spiros15,Tureckova Eva1,Vesela Kamila11,Vlckova Zdenka13,Vocka Michal19,Zima Tomas1,Macurek Libor2ORCID,Kleibl Zdenek15ORCID,

Affiliation:

1. Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague Prague Czech Republic

2. Laboratory of Cancer Cell Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

3. Department of Biochemistry, Faculty of Science Charles University Prague Czech Republic

4. Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague Prague Czech Republic

5. Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague Czech Republic

6. Centre for Medical Genetics and Reproductive Medicine, GENNET Prague Czech Republic

7. Institute of Medical Genetics, University Hospital Pilsen Pilsen Czech Republic

8. Department of Medical Genetics Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc Czech Republic

9. Hospital Ceske Budejovice Ceske Budejovice Czech Republic

10. Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

11. Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague Prague Czech Republic

12. BIOCEV, First Faculty of Medicine Charles University Vestec Czech Republic

13. Department of Medical Genetics GHC Genetics Prague Czech Republic

14. Department of Medical Genetics Pronatal Prague Czech Republic

15. Department of Medical Genetics, AGEL Laboratories AGEL Research and Training Institute Novy Jicin Czech Republic

16. Department of Genetics and Microbiology, Faculty of Science Charles University in Prague Prague Czech Republic

17. Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine Charles University and General University Hospital in Prague Prague Czech Republic

18. Institute for Clinical and Experimental Medicine Prague Czech Republic

19. Department of Oncology, First Faculty of Medicine Charles University and General University Hospital in Prague Prague Czech Republic

Abstract

AbstractBackgroundMonoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear.MethodsHere, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk.ResultsThe frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss‐of‐heterozygosity of the wild‐type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations.ConclusionOur study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.

Funder

Ministerstvo Školství, Mládeže a Tělovýchovy

Ministerstvo Zdravotnictví Ceské Republiky

Grantová Agentura, Univerzita Karlova

Publisher

Wiley

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