研究發現32個新型乳腺癌易感基因座

研究發現32個新型乳腺癌易感基因座

作者：

小柯機器人

發布時間：2020/5/20 21:14:19

2020年5月18日，美國約翰霍普金斯大學Nilanjan Chatterjee等研究人員在《自然—遺傳學》雜誌發表論文，他們利用全基因組關聯研究鑑定出32個新型乳腺癌易感基因座。

乳腺癌易感性變異通常在腫瘤亞型之間表現出異質性。為了確定新的基因座，研究人員進行了全基因組關聯研究，包括133384例乳腺癌病例和113789例對照，以及18908例歐洲血統的BRCA1突變攜帶者（9 414例患有乳腺癌）。通過使用標準方法和新的方法，研究人員分析了腫瘤異質性背後雌激素受體、孕激素受體和人表皮生長因子受體2的狀態以及腫瘤的等級。

 

研究人員確定了32個新的易感基因座（P<5.0×10-8），其中15個至少與一個腫瘤特徵相關（假髮現率<0.05）。5個基因座在管腔和非管腔亞型之間顯示出相反的關聯（P<0.05）。在計算分析中，這五個基因座包含的細胞特異性增強子在正常腔和基底乳腺細胞之間有所不同。五個亞型之間的遺傳相關性介於0.35至0.80之間。由所有已知的敏感性位點解釋的全基因組晶片遺傳力比例對於管腔A型疾病為54.2％，對於三陰性疾病為37.6％。與管腔A類和三陰性病例相比，最高1％分位數的多基因風險評分（包括330個變異）的比值比分別為5.63和3.02。

 

這些發現為乳腺癌亞型遺傳易感性提供了更好的理解，並將為亞型特異性多基因風險評分的發展提供信息。

 

Title: Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Haoyu Zhang, Thomas U. Ahearn, Julie Lecarpentier, Daniel Barnes, Jonathan Beesley, Guanghao Qi, Xia Jiang, Tracy A. OMara, Ni Zhao, Manjeet K. Bolla, Alison M. Dunning, Joe Dennis, Qin Wang, Zumuruda Abu Ful, Kristiina Aittomki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Paul L. Auer, Jacopo Azzollini, Daniel Barrowdale, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna Bialkowska, Ana Blanco, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Davide Bondavalli, Ake Borg, Hiltrud Brauch, Hermann Brenner, Ignacio Briceno, Annegien Broeks, Sara Y. Brucker, Thomas Brning, Barbara Burwinkel, Saundra S. Buys, Helen Byers, Trinidad Calds, Maria A. Caligo, Mariarosaria Calvello, Daniele Campa, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Melissa Christiaens, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Susan M. Domchek, Thilo Drk

Issue&Volume: 2020-05-18

Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1,2,3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P<5.0×108), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate<0.05). Five loci showed associations (P<0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

DOI: 10.1038/s41588-020-0609-2

Source: https://www.nature.com/articles/s41588-020-0609-2