Prevalence of Homologous Recombination-Related Gene Mutations Across Multiple Cancer Types.

Autor:	Heeke AL; Arielle L. Heeke, Michael J. Pishvaian, Filipa Lynce, John L. Marshall, Claudine Isaacs, Georgetown University, Washington, DC, Joanne Xiu, Wang-Juh Chen, Tabari M. Baker, Caris Life Sciences, Inc., Phoenix, AZ; and Jonathan R. Brody, Thomas Jefferson University, Philadelphia, PA., Pishvaian MJ; Arielle L. Heeke, Michael J. Pishvaian, Filipa Lynce, John L. Marshall, Claudine Isaacs, Georgetown University, Washington, DC, Joanne Xiu, Wang-Juh Chen, Tabari M. Baker, Caris Life Sciences, Inc., Phoenix, AZ; and Jonathan R. Brody, Thomas Jefferson University, Philadelphia, PA., Lynce F; Arielle L. Heeke, Michael J. Pishvaian, Filipa Lynce, John L. Marshall, Claudine Isaacs, Georgetown University, Washington, DC, Joanne Xiu, Wang-Juh Chen, Tabari M. Baker, Caris Life Sciences, Inc., Phoenix, AZ; and Jonathan R. Brody, Thomas Jefferson University, Philadelphia, PA., Xiu J; Arielle L. Heeke, Michael J. Pishvaian, Filipa Lynce, John L. Marshall, Claudine Isaacs, Georgetown University, Washington, DC, Joanne Xiu, Wang-Juh Chen, Tabari M. Baker, Caris Life Sciences, Inc., Phoenix, AZ; and Jonathan R. Brody, Thomas Jefferson University, Philadelphia, PA., Brody JR; Arielle L. Heeke, Michael J. Pishvaian, Filipa Lynce, John L. Marshall, Claudine Isaacs, Georgetown University, Washington, DC, Joanne Xiu, Wang-Juh Chen, Tabari M. Baker, Caris Life Sciences, Inc., Phoenix, AZ; and Jonathan R. Brody, Thomas Jefferson University, Philadelphia, PA., Chen WJ; Arielle L. Heeke, Michael J. Pishvaian, Filipa Lynce, John L. Marshall, Claudine Isaacs, Georgetown University, Washington, DC, Joanne Xiu, Wang-Juh Chen, Tabari M. Baker, Caris Life Sciences, Inc., Phoenix, AZ; and Jonathan R. Brody, Thomas Jefferson University, Philadelphia, PA., Baker TM; Arielle L. Heeke, Michael J. Pishvaian, Filipa Lynce, John L. Marshall, Claudine Isaacs, Georgetown University, Washington, DC, Joanne Xiu, Wang-Juh Chen, Tabari M. Baker, Caris Life Sciences, Inc., Phoenix, AZ; and Jonathan R. Brody, Thomas Jefferson University, Philadelphia, PA., Marshall JL; Arielle L. Heeke, Michael J. Pishvaian, Filipa Lynce, John L. Marshall, Claudine Isaacs, Georgetown University, Washington, DC, Joanne Xiu, Wang-Juh Chen, Tabari M. Baker, Caris Life Sciences, Inc., Phoenix, AZ; and Jonathan R. Brody, Thomas Jefferson University, Philadelphia, PA., Isaacs C; Arielle L. Heeke, Michael J. Pishvaian, Filipa Lynce, John L. Marshall, Claudine Isaacs, Georgetown University, Washington, DC, Joanne Xiu, Wang-Juh Chen, Tabari M. Baker, Caris Life Sciences, Inc., Phoenix, AZ; and Jonathan R. Brody, Thomas Jefferson University, Philadelphia, PA.
Jazyk:	angličtina
Zdroj:	JCO precision oncology [JCO Precis Oncol] 2018; Vol. 2018. Date of Electronic Publication: 2018 Jul 23.
DOI:	10.1200/PO.17.00286
Abstrakt:	Purpose: The prevalence of homologous recombination DNA damage repair (HR-DDR) deficiencies among all tumor lineages is not well characterized. Therapy directed toward homologous recombination DDR deficiency (HRD) is now approved in ovarian and breast cancer, and there may be additional opportunities for benefit for patients with other cancers. Comprehensive evaluations for HRD are limited in part by the lack of a uniform, cost-effective method for testing and defining HRD. Methods: Molecular profiles of 52,426 tumors were reviewed to identify pathogenic mutations in the HR-DDR genes ARID1A , ATM , ATRX , BAP1 , BARD1 , BLM , BRCA1/2 , BRIP1 , CHEK1/2 , FANCA/C/D2/E/F/G/L , MRE11A , NBN , PALB2 , RAD50 , RAD51 , RAD51B , or WRN . From solid tumors submitted to Caris Life Sciences, molecular profiles were generated using next-generation sequencing (NGS; average read depth, 500×). A total of 17,566 tumors were sequenced with NGS600 (n = 592 genes), and 34,860 tumors underwent hotspot Illumina MiSeq platform testing (n = 47 genes). Results: Of the tumors that underwent NGS600 testing, the overall frequency of HRDDR mutations detected was 17.4%, and the most commonly mutated lineages were endometrial (34.4%; n = 1,475), biliary tract (28.9%; n = 343), bladder (23.9%; n = 201), hepatocellular (20.9%; n = 115), gastroesophageal (20.8%; n = 619), and ovarian (20.0%; n = 2,489). Least commonly mutated lineages included GI stromal (3.7%; n = 108), head and neck (6.8%; n = 206), and sarcoma (9.3%; n = 592). ARID1A was the most commonly mutated gene (7.2%), followed by BRCA2 (3.0%), BRCA1 (2.8%), ATM (1.3%), ATRX (1.3%), and CHEK2 (1.3%). Conclusions: HR-DDR mutations were seen in 17.4% of tumors across 21 cancer lineages, providing a path to explore the role of HRD-directed therapies, including poly-ADP ribose polymerase inhibitors, DNA-damaging chemotherapies, and newer agents such as ATR inhibitors. Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Arielle L. Heeke No relationship to disclose Michael J. Pishvaian Stock and Other Ownership Interests: Perthera Honoraria: Caris Life Sciences, Celgene, Sirtex Medical, Merrimack Consulting or Advisory Role: Caris Life Sciences, Perthera, Celgene, Sirtex Medical, AstraZeneca/MedImmune, RenovoRx Travel, Accommodations, Expenses: Caris Life Sciences, Sirtex Medical, Perthera, AstraZeneca/MedImmune Filipa Lynce Joanne Xiu Employment: Caris Life Sciences Jonathan R. Brody Consulting or Advisory Role: Perthera Travel, Accommodations, Expenses: Perthera Wang-Juh Chen Employment: Caris Life Sciences Tabari M. Baker Employment: Caris Life Sciences, Roche Travel, Accommodations, Expenses: Caris Life Sciences, Roche John L. Marshall Employment: Caris Life Sciences Honoraria: Roche, Amgen, Bayer/Onyx, Taiho Pharmaceutical, Caris Life Sciences, Celgene Consulting or Advisory Role: Roche, Amgen, Bayer/Onyx, Taiho Pharmaceutical, Caris Life Sciences, Celgene Speakers’ Bureau: Roche, Amgen, Bayer/Onyx, Celgene, Taiho Pharmaceutical Claudine Isaacs Honoraria: Roche, AstraZeneca, Pfizer, Novartis, Syndax, NanoString Technologies Consulting or Advisory Role: Pfizer, Roche, Novartis, AstraZeneca, Medivation, NanoString Technologies, Syndax Speakers’ Bureau: Genentech, Pfizer, AstraZeneca Patents, Royalties, Other Intellectual Property: UpToDate, McGraw Hill Publishing
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