Dumont, Martine ORCID: 0000-0002-5488-4839, Weber-Lassalle, Nana, Joly-Beauparlant, Charles, Ernst, Corinna ORCID: 0000-0001-7756-8815, Droit, Arnaud, Feng, Bing-Jian, Dubois, Stephane, Collin-Deschesnes, Annie-Claude, Soucy, Penny, Vallee, Maxime, Fournier, Frederic, Lemacon, Audrey, Adank, Muriel A., Allen, Jamie, Altmueller, Janine, Arnold, Norbert, Ausems, Margreet G. E. M., Berutti, Riccardo, Bolla, Manjeet K., Bull, Shelley ORCID: 0000-0002-3280-7154, Carvalho, Sara, Cornelissen, Sten, Dufault, Michael R., Dunning, Alison M., Engel, Christoph ORCID: 0000-0002-7247-282X, Gehrig, Andrea, Geurts-Giele, Willemina R. R., Gieger, Christian, Green, Jessica, Hackmann, Karl, Helmy, Mohamed, Hentschel, Julia, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hooning, Maartje J., Horvath, Judit, Ikram, M. Arf An, Kaulfuss, Silke ORCID: 0000-0003-2577-9711, Keeman, Renske, Kuang, Da, Luccarini, Craig, Maier, Wolfgang, Martens, John W. M., Niederacher, Dieter, Nurnberg, Peter ORCID: 0000-0002-7228-428X, Ott, Claus-Eric, Peters, Annette ORCID: 0000-0001-6645-0985, Pharoah, Paul D. P., Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Ramser, Juliane, Riedel-Heller, Steffi, Schmidt, Gunnar, Shah, Mitul, Scherer, Martin, Stabler, Antje, Strom, Tim M., Sutter, Christian, Thiele, Holger, van Asperen, Christi J., van der Kolk, Lizet, van der Luijt, Rob B., Volk, Alexander E., Wagner, Michael ORCID: 0000-0003-2589-6440, Waisfisz, Quinten, Wang, Qin, Wang-Gohrke, Shan, Weber, Bernhard H. F., Devilee, Peter ORCID: 0000-0002-8023-2009, Tavtigian, Sean, Bader, Gary D., Meindl, Alfons, Goldgar, David E., Andrulis, Irene L., Schmutzler, Rita K., Easton, Douglas F., Schmidt, Marjanka K., Hahnen, Eric and Simard, Jacques ORCID: 0000-0001-6906-3390 (2022). Uncovering the Contribution of Moderate-Penetrance Susceptibility Genes to Breast Cancer by Whole-Exome Sequencing and Targeted Enrichment Sequencing of Candidate Genes in Women of European Ancestry. Cancers, 14 (14). BASEL: MDPI. ISSN 2072-6694

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Abstract

Simple Summary Genetic variants explaining approximately 40% of familial breast cancer risk have been identified, thus leaving a significant fraction of the heritability of this disease still unexplained. The exact nature of this missing fraction is unknown; more extensive sequencing efforts could potentially identify new moderate-penetrance breast cancer risk alleles. The aim of this study was to perform a large-scale whole-exome sequencing study, followed by a targeted validation, in breast cancer patients and healthy women of European descent. We identified 20 novel genes with modest evidence of association (p-value < 0.05) for either overall or subtype-specific breast cancer; however, much larger studies are needed to confirm the exact role of these genes in susceptibility to breast cancer. Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dumont, MartineUNSPECIFIEDorcid.org/0000-0002-5488-4839UNSPECIFIED
Weber-Lassalle, NanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joly-Beauparlant, CharlesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ernst, CorinnaUNSPECIFIEDorcid.org/0000-0001-7756-8815UNSPECIFIED
Droit, ArnaudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Feng, Bing-JianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dubois, StephaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collin-Deschesnes, Annie-ClaudeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soucy, PennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vallee, MaximeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fournier, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemacon, AudreyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adank, Muriel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allen, JamieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arnold, NorbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ausems, Margreet G. E. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berutti, RiccardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolla, Manjeet K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bull, ShelleyUNSPECIFIEDorcid.org/0000-0002-3280-7154UNSPECIFIED
Carvalho, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cornelissen, StenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dufault, Michael R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dunning, Alison M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel, ChristophUNSPECIFIEDorcid.org/0000-0002-7247-282XUNSPECIFIED
Gehrig, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geurts-Giele, Willemina R. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gieger, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Green, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hackmann, KarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helmy, MohamedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hentschel, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hogervorst, Frans B. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hollestelle, AntoinetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hooning, Maartje J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horvath, JuditUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ikram, M. Arf AnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaulfuss, SilkeUNSPECIFIEDorcid.org/0000-0003-2577-9711UNSPECIFIED
Keeman, RenskeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuang, DaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luccarini, CraigUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maier, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martens, John W. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niederacher, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nurnberg, PeterUNSPECIFIEDorcid.org/0000-0002-7228-428XUNSPECIFIED
Ott, Claus-EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, AnnetteUNSPECIFIEDorcid.org/0000-0001-6645-0985UNSPECIFIED
Pharoah, Paul D. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramirez, AlfredoUNSPECIFIEDorcid.org/0000-0003-4991-763XUNSPECIFIED
Ramser, JulianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riedel-Heller, SteffiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, GunnarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shah, MitulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scherer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stabler, AntjeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strom, Tim M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sutter, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Asperen, Christi J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Kolk, LizetUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Luijt, Rob B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volk, Alexander E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, MichaelUNSPECIFIEDorcid.org/0000-0003-2589-6440UNSPECIFIED
Waisfisz, QuintenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, QinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang-Gohrke, ShanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weber, Bernhard H. F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devilee, PeterUNSPECIFIEDorcid.org/0000-0002-8023-2009UNSPECIFIED
Tavtigian, SeanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bader, Gary D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meindl, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldgar, David E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Easton, Douglas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Marjanka K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simard, JacquesUNSPECIFIEDorcid.org/0000-0001-6906-3390UNSPECIFIED
URN: urn:nbn:de:hbz:38-699052
DOI: 10.3390/cancers14143363
Journal or Publication Title: Cancers
Volume: 14
Number: 14
Date: 2022
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2072-6694
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RECEPTOR TYROSINE KINASES; ASSOCIATION ANALYSIS; RISK; FRAMEWORK; VARIANTS; MUTATIONS; SURVIVAL; PROFILE; DESIGNMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69905

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