大規(guī)模測序確定乳腺癌和卵巢癌與
已知和未知癌癥易感基因的相關性
自從乳腺癌易感基因BRCA1和BRCA2被發(fā)現(xiàn)之后，多種外顯率較高的基因相繼被報告為遺傳性乳腺癌或卵巢癌的風險因素；不過，這些發(fā)現(xiàn)能否代表乳腺癌或卵巢癌的完整基因譜？哪些非BRCA基因與乳腺癌或卵巢癌風險相關？風險大小如何？
2018年8月16日，《美國醫(yī)學會雜志》腫瘤學分冊在線發(fā)表安布瑞基因、先聲藥業(yè)、騰邦生物技術、英特利亞醫(yī)療、爾灣加利福尼亞大學的研究報告，通過大規(guī)模測序確定了乳腺癌或卵巢癌與已知和未知易感基因的相關性。
該研究標本來自2014～2015年美國各地1200家醫(yī)院診所轉診接受基因檢測的1萬1416例乳腺癌或卵巢癌患者、3988例無癌對照者，進行全外顯子組測序，并檢查基因與表型的相關性。此外，將《基因組聚集數(shù)據(jù)庫》作為參考對照進行病例對照分析。主要結局衡量指標：625個癌癥易感基因的乳腺癌風險相關致病變異、已知乳腺癌或卵巢癌易感基因與乳腺癌亞型（導管浸潤、小葉浸潤、激素受體陽性、激素受體陰性、男性、早發(fā)）的相關性。
結果發(fā)現(xiàn)，乳腺癌患者9639例，其中早發(fā)乳腺癌（診斷時≤45歲）3960例（41.1%）、男性乳腺癌123例（1.3%），男性與女性相比，診斷時年齡較大（平均年齡：61.8±12.8比48.6±11.4歲）。卵巢癌女性2051例，其中診斷時≤45歲445例（21.7%）。
以下4個非BRCA基因變異與乳腺癌風險增加相關：
PALB2（相對風險比：5.53，95%置信區(qū)間：2.24～17.65）
ATM（相對風險比：2.97，95%置信區(qū)間：1.67～5.68）
MSH6（相對風險比：2.59，95%置信區(qū)間：1.35～5.44）
CHEK2（相對風險比：2.19，95%置信區(qū)間：1.40～3.56）
以下4個非BRCA基因變異與卵巢癌風險增加相關：
TP53（相對風險比：18.50，95%置信區(qū)間：2.56～808.10）
MSH6（相對風險比：4.16，95%置信區(qū)間：1.95～9.47）
ATM（相對風險比：2.85，95%置信區(qū)間：1.30～6.32）
RAD51C（相對風險比：分母為零無法推算，假陽性率校正P=0.004）
MRN復合基因和CDKN2A均與乳腺癌或卵巢癌風險增加無關。該研究結果也不支持既往報告的乳腺癌與卵巢癌相關易感基因BRIP1、RAD51C、RAD51D或錯配修復基因MSH2和PMS2的相關性。
因此，該研究對患者和對照者進行的大規(guī)模外顯子組測序結果，揭示了迄今為止已知和未知非BRCA易感基因與乳腺癌或卵巢癌的相關性，以及其他可能參與DNA修復和基因組維護的乳腺癌或卵巢癌候選易感基因。
對此，英國南安普頓大學、南安普頓大學醫(yī)院、安妮公主醫(yī)院的腫瘤學和遺傳學專家發(fā)表特邀評論：基因時代的遺傳性乳腺癌和卵巢癌檢測。
JAMA Oncol. 2018 Aug 16. [Epub ahead of print]
Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing.
Hsiao-Mei Lu, Shuwei Li, Mary Helen Black, Shela Lee, Robert Hoiness, Sitao Wu, Wenbo Mu, Robert Huether, Jefferey Chen, Srijani Sridhar, Yuan Tian, Rachel McFarland, Jill Dolinsky, Brigette Tippin Davis, Sharon Mexal, Charles Dunlop, Aaron Elliott.
Ambry Genetics, Aliso Viejo, California; Simcere Pharmaceutical, Jiangsu, China; Tempus, Chicago, Illinois; Intellia Therapeutics, Cambridge, Massachusetts; University of California, Irvine.
This study of patients with breast cancer, ovarian cancer, or both compared with controls uses whole-exome sequencing to investigate whether non-BRCA genes are associated with an increased risk of those cancers.
QUESTION: Which non-BRCA genes are associated with breast or ovarian cancer and what are the magnitudes of those risks?
FINDINGS: In this study assessing whole-exome sequencing results from 11416 patients with breast cancer, ovarian cancer, or both and 3988 controls, an increased risk of breast cancer was associated with PALB2, ATM, CHEK2, and MSH6 genes, whereas MSH6, RAD51C, TP53, and ATM genes were associated with an increased risk of ovarian cancer.
MEANING: In addition to confirming several well-known breast or ovarian cancer gene associations, this study identified MSH6 and ATM as possible moderate-risk breast and ovarian cancer predisposition genes, respectively.
IMPORTANCE: Since the discovery of BRCA1 and BRCA2, multiple high- and moderate-penetrance genes have been reported as risk factors for hereditary breast cancer, ovarian cancer, or both; however, it is unclear whether these findings represent the complete genetic landscape of these cancers. Systematic investigation of the genetic contributions to breast and ovarian cancers is needed to confirm these findings and explore potentially new associations.
OBJECTIVE: To confirm reported and identify additional predisposition genes for breast or ovarian cancer.
DESIGN, SETTING, AND PARTICIPANTS: In this sample of 11416 patients with clinical features of breast cancer, ovarian cancer, or both who were referred for genetic testing from 1200 hospitals and clinics across the United States and of 3988 controls who were referred for genetic testing for noncancer conditions between 2014 and 2015, whole-exome sequencing was conducted and gene-phenotype associations were examined. Case-control analyses using the Genome Aggregation Database as a set of reference controls were also conducted.
MAIN OUTCOMES AND MEASURES: Breast cancer risk associated with pathogenic variants among 625 cancer predisposition genes; association of identified predisposition breast or ovarian cancer genes with the breast cancer subtypes invasive ductal, invasive lobular, hormone receptor-positive, hormone receptor-negative, and male, and with early-onset disease.
RESULTS: Of 9639 patients with breast cancer, 3960 (41.1%) were early-onset cases (≤45 years at diagnosis) and 123 (1.3%) were male, with men having an older age at diagnosis than women (mean [SD] age, 61.8 [12.8] vs 48.6 [11.4] years). Of 2051 women with ovarian cancer, 445 (21.7%) received a diagnosis at 45 years or younger. Enrichment of pathogenic variants were identified in 4 non-BRCA genes associated with breast cancer risk: ATM (odds ratio [OR], 2.97; 95% CI, 1.67-5.68), CHEK2 (OR, 2.19; 95% CI, 1.40-3.56), PALB2 (OR, 5.53; 95% CI, 2.24-17.65), and MSH6 (OR, 2.59; 95% CI, 1.35-5.44). Increased risk for ovarian cancer was associated with 4 genes: MSH6 (OR, 4.16; 95% CI, 1.95-9.47), RAD51C (OR, not estimable; false-discovery rate-corrected P=.004), TP53 (OR, 18.50; 95% CI, 2.56-808.10), and ATM (OR, 2.85; 95% CI, 1.30-6.32). Neither the MRN complex genes nor CDKN2A was associated with increased breast or ovarian cancer risk. The findings also do not support previously reported breast cancer associations with the ovarian cancer susceptibility genes BRIP1, RAD51C, and RAD51D, or mismatch repair genes MSH2 and PMS2.
CONCLUSIONS AND RELEVANCE: The results of this large-scale exome sequencing of patients and controls shed light on both well-established and controversial non-BRCA predisposition gene associations with breast or ovarian cancer reported to date and may implicate additional breast or ovarian cancer susceptibility gene candidates involved in DNA repair and genomic maintenance.
DOI: 10.1001/jamaoncol.2018.2956
JAMA Oncol. 2018 Aug 16. [Epub ahead of print]
Hereditary Breast and Ovarian Cancer Testing in the Genomic Era.
Stephanie L. Greville-Heygate, Diana M. Eccles, Lucy E. Side.
University of Southampton, University Hospital Southampton, Southampton, United Kingdom; Princess Anne Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
DOI: 10.1001/jamaoncol.2018.3034
聯(lián)系客服
