外显子测序鉴定乳腺癌易感基因并确定编码变异对乳腺癌风险的贡献。
Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.
发表日期：2023 Aug 17
作者：
Naomi Wilcox, Martine Dumont, Anna González-Neira, Sara Carvalho, Charles Joly Beauparlant, Marco Crotti, Craig Luccarini, Penny Soucy, Stéphane Dubois, Rocio Nuñez-Torres, Guillermo Pita, Eugene J Gardner, Joe Dennis, M Rosario Alonso, Nuria Álvarez, Caroline Baynes, Annie Claude Collin-Deschesnes, Sylvie Desjardins, Heiko Becher, Sabine Behrens, Manjeet K Bolla, Jose E Castelao, Jenny Chang-Claude, Sten Cornelissen, Thilo Dörk, Christoph Engel, Manuela Gago-Dominguez, Pascal Guénel, Andreas Hadjisavvas, Eric Hahnen, Mikael Hartman, Belén Herráez, , Audrey Jung, Renske Keeman, Marion Kiechle, Jingmei Li, Maria A Loizidou, Michael Lush, Kyriaki Michailidou, Mihalis I Panayiotidis, Xueling Sim, Soo Hwang Teo, Jonathan P Tyrer, Lizet E van der Kolk, Cecilia Wahlström, Qin Wang, John R B Perry, Javier Benitez, Marjanka K Schmidt, Rita K Schmutzler, Paul D P Pharoah, Arnaud Droit, Alison M Dunning, Anders Kvist, Peter Devilee, Douglas F Easton, Jacques Simard
来源：
NATURE GENETICS
摘要：
连锁和候选基因研究已鉴定出一些乳腺癌易感基因，但编码变异对乳腺癌的整体贡献尚不清楚。为了更全面地评估罕见编码变异的作用，我们对三个大型全外显子测序数据集进行了荟萃分析，含有26,368个女性病例和217,673个女性对照。对15,616个基因的蛋白截短变异和18,601个基因的罕见错义变异进行了负荷测试。我们确定了以下六个基因在全外显子范围内与乳腺癌的关联(P < 2.5 × 10-6)：五个已知易感基因ATM、BRCA1、BRCA2、CHEK2和PALB2，以及MAP3K1。我们还观察到LZTR1、ATR和BARD1与乳腺癌的关联，P值小于1 × 10-4。此外，我们还发现CDKN2A在全外显子范围内与预测有害罕见错义或蛋白截短变异的乳腺癌的关联。估计除前述已知基因之外的基因的编码变异对乳腺癌的整体贡献较小。© 2023。作者。
Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10-6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10-4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.© 2023. The Author(s).