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

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 -