| Title: |
Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer |
| Authors: |
Song, H; Dicks, EM; Tyrer, J; Intermaggio, M; Chenevix-Trench, G; Bowtell, DD; Traficante, N; Group, A; Brenton, J; Goranova, T; Hosking, K; Piskorz, A; Van Oudenhove, E; Doherty, J; Harris, HR; Rossing, MA; Duerst, M; Dork, T; Bogdanova, NV; Modugno, F; Moysich, K; Odunsi, K; Ness, R; Karlan, BY; Lester, J; Jensen, A; Krüger Kjaer, S; Høgdall, E; Campbell, IG; Lázaro, C; Pujara, MA; Cunningham, J; Vierkant, R; Winham, SJ; Hildebrandt, M; Huff, C; Li, D; Wu, X; Yu, Y; Permuth, JB; Levine, DA; Schildkraut, JM; Riggan, MJ; Berchuck, A; Webb, PM; Group, OS; Cybulski, C; Gronwald, J; Jakubowska, A; Lubinski, J; Alsop, J; Harrington, P; Chan, I; Menon, U; Pearce, CL; Wu, AH; De Fazio, A; Kennedy, CJ; Goode, E; Ramus, S; Gayther, S; Pharoah, P |
| Source: |
urn:ISSN:0022-2593 ; urn:ISSN:1468-6244 ; Journal of Medical Genetics, 58, 5, 305-313 |
| Publisher Information: |
BMJ |
| Publication Year: |
2021 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
31 Biological Sciences; 32 Biomedical and Clinical Sciences; 3105 Genetics; 3211 Oncology and Carcinogenesis; Prevention; Women's Health; Cancer; Genetics; Clinical Research; Genetic Testing; Human Genome; Ovarian Cancer; Rare Diseases; 2.1 Biological and endogenous factors; Case-Control Studies; Fanconi Anemia Complementation Group N Protein; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Ovarian Neoplasms; Risk Assessment; cancer: endocrine; genetic epidemiology; anzsrc-for: 31 Biological Sciences; anzsrc-for: 32 Biomedical and Clinical Sciences; anzsrc-for: 3105 Genetics; anzsrc-for: 3211 Oncology and Carcinogenesis; anzsrc-for: 06 Biological Sciences; anzsrc-for: 11 Medical and Health Sciences |
| Description: |
Purpose The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. Methods We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. Results The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. Conclusions We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling. |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| Relation: |
https://hdl.handle.net/1959.4/unsworks_71914 |
| DOI: |
10.1136/jmedgenet-2019-106739 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_71914; https://doi.org/10.1136/jmedgenet-2019-106739 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.DDB31ABE |
| Database: |
BASE |