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
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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. / Dumont, Martine; Weber-Lassalle, Nana; Joly-Beauparlant, Charles; Ernst, Corinna; Droit, Arnaud; Feng, Bing-Jian; Dubois, Stéphane; Collin-Deschesnes, Annie-Claude; Soucy, Penny; Vallée, Maxime; Fournier, Frédéric; Lemaçon, Audrey; Adank, Muriel A; Allen, Jamie; Altmüller, Janine; Arnold, Norbert; Ausems, Margreet G E M; Berutti, Riccardo; Bolla, Manjeet K; Bull, Shelley; Carvalho, Sara; Cornelissen, Sten; Dufault, Michael R; Dunning, Alison M; Engel, Christoph; 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; Horváth, Judit; Ikram, M Arfan; Kaulfuß, Silke; Keeman, Renske; Kuang, Da; Luccarini, Craig; Maier, Wolfgang; Martens, John W M; Niederacher, Dieter; Nürnberg, Peter; Ott, Claus-Eric; Peters, Annette; Pharoah, Paul D P; Ramirez, Alfredo; Ramser, Juliane; Riedel-Heller, Steffi; Schmidt, Gunnar; Shah, Mitul; Scherer, Martin; Stäbler, Antje; Strom, Tim M; Sutter, Christian; Thiele, Holger; van Asperen, Christi J; van der Kolk, Lizet; van der Luijt, Rob B; Volk, Alexander E; Waisfisz, Quinten; Wang, Qin; Wang-Gohrke, Shan; Weber, Bernhard H F; Genome Of The Netherlands Project; Ghs Study Group; Devilee, Peter; Tavtigian, Sean; Bader, Gary D; Meindl, Alfons; Goldgar, David E; Andrulis, Irene L; Schmutzler, Rita K; Easton, Douglas F; Schmidt, Marjanka K; Hahnen, Eric; Simard, Jacques.
In: CANCERS, Vol. 14, No. 14, 3363, 11.07.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - 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
AU - Dumont, Martine
AU - Weber-Lassalle, Nana
AU - Joly-Beauparlant, Charles
AU - Ernst, Corinna
AU - Droit, Arnaud
AU - Feng, Bing-Jian
AU - Dubois, Stéphane
AU - Collin-Deschesnes, Annie-Claude
AU - Soucy, Penny
AU - Vallée, Maxime
AU - Fournier, Frédéric
AU - Lemaçon, Audrey
AU - Adank, Muriel A
AU - Allen, Jamie
AU - Altmüller, Janine
AU - Arnold, Norbert
AU - Ausems, Margreet G E M
AU - Berutti, Riccardo
AU - Bolla, Manjeet K
AU - Bull, Shelley
AU - Carvalho, Sara
AU - Cornelissen, Sten
AU - Dufault, Michael R
AU - Dunning, Alison M
AU - Engel, Christoph
AU - Gehrig, Andrea
AU - Geurts-Giele, Willemina R R
AU - Gieger, Christian
AU - Green, Jessica
AU - Hackmann, Karl
AU - Helmy, Mohamed
AU - Hentschel, Julia
AU - Hogervorst, Frans B L
AU - Hollestelle, Antoinette
AU - Hooning, Maartje J
AU - Horváth, Judit
AU - Ikram, M Arfan
AU - Kaulfuß, Silke
AU - Keeman, Renske
AU - Kuang, Da
AU - Luccarini, Craig
AU - Maier, Wolfgang
AU - Martens, John W M
AU - Niederacher, Dieter
AU - Nürnberg, Peter
AU - Ott, Claus-Eric
AU - Peters, Annette
AU - Pharoah, Paul D P
AU - Ramirez, Alfredo
AU - Ramser, Juliane
AU - Riedel-Heller, Steffi
AU - Schmidt, Gunnar
AU - Shah, Mitul
AU - Scherer, Martin
AU - Stäbler, Antje
AU - Strom, Tim M
AU - Sutter, Christian
AU - Thiele, Holger
AU - van Asperen, Christi J
AU - van der Kolk, Lizet
AU - van der Luijt, Rob B
AU - Volk, Alexander E
AU - Waisfisz, Quinten
AU - Wang, Qin
AU - Wang-Gohrke, Shan
AU - Weber, Bernhard H F
AU - Genome Of The Netherlands Project, null
AU - Ghs Study Group, null
AU - Devilee, Peter
AU - Tavtigian, Sean
AU - Bader, Gary D
AU - Meindl, Alfons
AU - Goldgar, David E
AU - Andrulis, Irene L
AU - Schmutzler, Rita K
AU - Easton, Douglas F
AU - Schmidt, Marjanka K
AU - Hahnen, Eric
AU - Simard, Jacques
PY - 2022/7/11
Y1 - 2022/7/11
N2 - 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.
AB - 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.
U2 - 10.3390/cancers14143363
DO - 10.3390/cancers14143363
M3 - SCORING: Journal article
C2 - 35884425
VL - 14
JO - CANCERS
JF - CANCERS
SN - 2072-6694
IS - 14
M1 - 3363
ER -