Prevalence of tumor BRCA1 and BRCA2 dysfunction in unselected patients with ovarian cancer

被引：5

作者：

Kalachand, Roshni D. ^{[1
]}

O'Riain, Ciaran ^{[2
]}

Toomey, Sinead ^{[1
]}

Carr, Aoife

Timms, Kirsten M. ^{[3
]}

O'Toole, Sharon ^{[4
]}

Madden, Stephen ^{[5
]}

Bates, Mark ^{[4
]}

O'Leary, John J. ^{[2
]}

Gleeson, Noreen ^{[4
]}

O'Donnell, Dearbhaile ^{[6
]}

Grogan, Liam ^{[7
]}

Breathnach, Oscar ^{[7
]}

Farrelly, Angela ^{[1
]}

Stordal, Britta ^{[8
]}

Hennessy, Bryan T. ^{[1
,7
,9
]}

机构：

[1] Royal Coll Surgeons Ireland, Beaumont Hosp, Dept Mol Med, Med Oncol Grp, Smurfit Bldg, Dublin 9, Ireland

[2] Trinity Coll Dublin, St Jamess Hosp, Dept Histopathol, Cent Pathol Lab, Dublin, Ireland

[3] Myriad Genet Inc, Salt Lake City, UT USA

[4] Trinity Coll Dublin, St Jamess Hosp, Dept Obstet & Gynaecol, Trinity Ctr Hlth Sci, Dublin, Ireland

[5] Royal Coll Surgeons Ireland, Data Sci Ctr, Beaux Lane House, Dublin, Ireland

[6] Trinity Coll Dublin, St Jamess Hosp, Dept Clin Med, Dublin, Ireland

[7] Beaumont Hosp, Dept Med Oncol, Dublin, Ireland

[8] Middlesex Univ, Dept Nat Sci, London, England

[9] Our Lady Lourdes Hosp, Drogheda, Ireland

来源：

OBSTETRICS & GYNECOLOGY SCIENCE | 2020年 / 63卷 / 05期

关键词：

Ovarian cancer; BRCA1; methylation; mutation; BRCA2; PROMOTER METHYLATION; SOMATIC MUTATIONS; SURVIVAL; GENE; ASSOCIATION; GERMLINE; HYPERMETHYLATION; SENSITIVITY; PHENOTYPE; FREQUENCY;

D O I：

10.5468/ogs.20033

中图分类号：

R71 [妇产科学];

学科分类号：

100211 ;

摘要：

Objective The therapeutic benefits of poly(ADP-ribose) polymerase inhibitors highlight the need to evaluate BRCA1/2 defects in tubal/ovarian cancer (OC). We sought to determine the pattern and disease characteristics associated with tumor BRCA1/2 mutations and BRCA1 methylation in women with OC. Methods We obtained 111 OC specimens from 2 university hospitals and assessed BRCA1/2 mutations and BRCA1 methylation in tumor DNA. The frequency and pattern of BRCA1/2 defects were examined. Associations between patient/disease characteristics and BRCA1/2 defects were ascertained (Fisher's exact test). Platinum-free interval (PFI), progression-free survival (PFS), and overall survival (OS) based on the underlying BRCA1/2 defect were determined (Kaplan-Meier analysis [log-rank test]). Results We observed a BRCA1/2 dysfunction rate of 40% (28/70) in high-grade serous tubal/ovarian cancer (HGSC), including 14.3% BRCA1 methylation (n=10), 7.1% BRCA1 mutation (n=5), and 18.6% BRCA2 mutation (n=13). Defects in BRCA1/2 genes were associated with stage III/IV HGSC (BRCA1 methylation: P=0.005 [stage III/IV] and P=0.004 [HGSC]; BRCA1/2 mutation: P=0.03 [stage III/IV] and P<0.001 [HGSC]). Patients with BRCA1/2-mutated cancers showed improved OS (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.43-0.99; P=0.045) and a trend toward improved PFI (HR, 0.48; 95% CI, 0.22-1.06; P=0.07) and PFS (HR, 0.72; 95% CI, 0.51-1.03; P=0.07). No survival differences were observed between BRCA1-methylated and BRCA1/2 wild-type non-BRCA1-methylated cancers. Conclusion We observed a high tumor BRCA1/2 dysfunction rate in HGSC with a unique predominance of BRCA2 over BRCA1 mutations. While BRCA1/2 mutations conferred survival benefits in OC, no such association was observed with BRCA1 methylation.

引用

页码：643 / 654

页数：12

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