Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2

Since the approval of PARP inhibitors for the treatment of high-grade serous ovarian cancer, in addition to cancer risk assessment, BRCA1 and BRCA2 genetic testing also has therapeutic implications (germline and somatic variants) and should be offered to these patients at diagnosis, irrespective of family history. However, variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which would be missed by a genetic testing aimed only at indication for PARP inhibitor treatment. In this study, we aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of formalin-fixed paraffin-embedded samples from 96 ovarian carcinomas, a strategy that allows the detection of both somatic and germline variants in a single test. In addition to 13.7% of deleterious germline BRCA1/BRCA2 carriers, we identified 7.4% additional patients with pathogenic germline variants in other genes predisposing for ovarian cancer, namely RAD51C, RAD51D, and MSH6, representing 35% of all pathogenic germline variants. We conclude that the strategy of reflex gene-panel tumor testing enables the identification of clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients, which may be valuable information in patients with advanced disease that have run out of approved therapeutic options. Furthermore, this approach increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants.

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Low rates of BRCA1 and BRCA2 testing for patients with ovarian cancer in ASCO's CancerLinQ, a real-world database.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6041 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6041-6041 ◽

Cited By ~ 1

Author(s):

Summer Dewdney ◽

Danielle Potter ◽

Joy Larsen Haidle ◽

Peter J Hulick ◽

Mark Riffon ◽

...

Keyword(s):

Ovarian Cancer ◽

Genetic Testing ◽

Cancer Prevention ◽

Real World ◽

Gynecological Cancer ◽

Brca2 Mutation ◽

Transitional Cell ◽

Genetic Mutations ◽

Brca1 And Brca2 ◽

Number Of Patients

6041 Background: Ovarian cancer is the deadliest gynecological cancer and has limited screening options for early stage diagnosis. Genetic mutations in genes such as BRCA1 and BRCA2 increase the risk of ovarian cancer, and if identified, patients can undergo risk-reducing surgery. It is recommended and well accepted to test any new ovarian cancer patient for genetic mutations, particulary BRCA1 and BRCA2. If a BRCA1/2 mutation is found in a patient (somatic or germ line), this information can be used to guide therapy. We sought to analyze the characteristics of genetic testing in a real-world database, ASCO’s CancerLinQ. Methods: We performed a retrospective cohort study using the CancerLinQ Discovery database. Women with ovarian, fallopian tube, or primary peritoneal cancer were identified using ICD9 and ICD10 codes. We included patients diagnosed between 1/1/11 to 12/31/18 and age >18. We included all epithelial histologies including carcinosarcomas and excluded patients without a known histology. Results: Of the 2654 patients meeting inclusion criteria, 600 had been tested for a BRCA1/2 mutation (22.6%). Of those tested, 63% were stage III/IV, 14% stage I/II, and 21.8% an unknown stage. The majority of the histologies were serous (76%), followed by undifferentiated (21.2%). The majority of patients tested were white (69.9%), with 18.8% unknown, and 9.9% black. The rate of a positive BRCA1 or BRCA2 mutation in this population was 17.2%. Of the patients with a BRCA1/2 mutation, the majority had serous histology (87%), followed by 18.5% undifferentiated, and 3.9% transitional cell. The majority of the patients found to have a BRCA1/2 mutation were age >50 (57.3%). Conclusions: Since 2008 evidence-based guidelines have recommended that all ovarian cancer patients be tested for BRCA1 and BRCA2 mutations, but in this real-world database only 22.6% have a recorded test. Of those tested, we found a BRCA1 or BRCA2 mutation rate of 17.2%. Our data is limited by what is recorded in the database and may not represent the true number of patients tested because of data missing from the EHR; however, these percentages appear similar to previous studies. Not only is testing important for cancer prevention for family members of patients, it now impacts the type of treatments for which these patients are eligible. Since genetic testing remains low at only 22.6% in this population, significant opportunities exist to impact cancer prevention and treatment.

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Mainstreaming genetic counselling for genetic testing of BRCA1 and BRCA2 in ovarian cancer patients in Malaysia (MaGiC study)

Annals of Oncology ◽

10.1093/annonc/mdx729.004 ◽

2017 ◽

Vol 28 ◽

pp. x187 ◽

Cited By ~ 3

Author(s):

S.Y. Yoon ◽

N.S.Ahmad. Bashah ◽

S.W. Wong ◽

S. Mariapun ◽

T. Hassan ◽

...

Keyword(s):

Ovarian Cancer ◽

Genetic Testing ◽

Cancer Patients ◽

Genetic Counselling ◽

Brca1 And Brca2

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Mainstreaming genetic counselling for genetic testing of BRCA1 and BRCA2 in ovarian cancer patients in Malaysia (MaGiC study)

Annals of Oncology ◽

10.1093/annonc/mdy483.004 ◽

2018 ◽

Vol 29 ◽

pp. ix176

Author(s):

S.Y.Y. Yoon ◽

N.S. Ahmad Bashah ◽

S.W. Wong ◽

S. Mariapun ◽

H. Padmanabhan ◽

...

Keyword(s):

Ovarian Cancer ◽

Genetic Testing ◽

Cancer Patients ◽

Genetic Counselling ◽

Brca1 And Brca2

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Frequency of BRCA1 and BRCA2 Germline Variants in Women With Ovarian Cancer in Malaysia

Journal of Global Oncology ◽

10.1200/jgo.18.50600 ◽

2018 ◽

Vol 4 (Supplement 2) ◽

pp. 47s-47s

Author(s):

J. Lim ◽

S.Y. Lau ◽

N.S. Ahmad Bashah ◽

K.N. Lai ◽

W.X. Wen ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Cancer Control ◽

Control Program ◽

Population Based ◽

Brca1 And Brca2 ◽

Germline Variants ◽

Pathogenic Variants ◽

Brca1 And Brca2 Genes ◽

Cancer Control Program

Background: Germline BRCA1 or BRCA2 pathogenic variants in ovarian cancer patients may be informative in risk management and treatment, with the advent of poly(ADP-ribose) polymerase inhibitors. In the era of precision medicine, companion diagnostics for BRCA1 and BRCA2 genes have been featured as a strategy in the Malaysia National Strategic Plan for Cancer Control Program (2016-2020). To facilitate this strategy, frequency data from Malaysia's understudied multiethnic population will be required. Aim: To determine the prevalence of BRCA1 and BRCA2 germline variants in a population-based cohort of ovarian cancer patients in Malaysia. Methods: From August 2016, women with nonmucinous epithelial ovarian, peritoneal or fallopian tube carcinoma are prospectively recruited to the Malaysia-wide population-based MaGiC Observational Study. DNA were tested using a Hi-Plex next generation sequencing method and multiplex ligation-dependent probe amplification to detect < 10 bp alterations and exon deletions or duplications in the BRCA1 and BRCA2 genes. Results: Interim results from 325 patients tested until March 2018 have identified BRCA1 and BRCA2 pathogenic variants in 9.8% (32/325) and 3.1% (10/325) patients, respectively. Variants of uncertain significance were detected in 13.2% (43/325) patients and no pathogenic variants were detected in 73.8% (240/325) patients. Taken together, the frequency of BRCA1/2 pathogenic variants in ovarian cancer patients is approximately 12.9% (42/325). Conclusion: The identification of BRCA1 or BRCA2 carriers across the country have enabled the concentration of efforts from limited genetic counseling resources to high risk families. Results arising from the completion of this study will supplement cancer control programs and genetic services in Malaysia.

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Fas gene promoter –670 polymorphism in gynecological cancer

International Journal of Gynecological Cancer ◽

10.1136/ijgc-00009577-200602001-00028 ◽

2006 ◽

Vol 16 (Suppl 1) ◽

pp. 179-182 ◽

Cited By ~ 2

Author(s):

M. Ueda ◽

Y. Terai ◽

K. Kanda ◽

M. Kanemura ◽

M. Takehara ◽

...

Keyword(s):

Ovarian Cancer ◽

Cervical Cancer ◽

Cancer Patients ◽

Germ Line ◽

Gynecological Cancer ◽

Gene Promoter ◽

Single Nucleotide ◽

Increased Risk ◽

Significant Difference ◽

Germ Line Polymorphism

Single-nucleotide polymorphism at −670 of Fas gene promoter (A/G) was examined in a total of 354 blood samples from normal healthy women and gynecological cancer patients. They consisted of 95 normal, 83 cervical, 108 endometrial, and 68 ovarian cancer cases. Eighty-three patients with cervical cancer had statistically higher frequency of GG genotype and G allele than 95 controls (P= 0.0353 and 0.0278, respectively). There was no significant difference in the genotype or allele prevalence between control subjects and endometrial or ovarian cancer patients. The Fas −670 GG genotype was associated with an increased risk for the development of cervical cancer (OR = 2.56, 95% CI = 1.08–6.10) compared with the AA genotype. The G allele also increased the risk of cervical cancer (OR = 1.60, 95% CI = 1.05–2.43) compared with the A allele. Germ-line polymorphism of Fas gene promoter −670 may be associated with the risk of cervical cancer in a Japanese population.

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Extended gene panel testing in lobular breast cancer

Familial Cancer ◽

10.1007/s10689-021-00241-5 ◽

2021 ◽

Author(s):

Elke M. van Veen ◽

D. Gareth Evans ◽

Elaine F. Harkness ◽

Helen J. Byers ◽

Jamie M. Ellingford ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Testing ◽

Detection Rate ◽

Gene Panel ◽

Lobular Breast Cancer ◽

Germline Variants ◽

Panel Testing ◽

Pathogenic Variants ◽

Gene Panel Testing ◽

Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

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A MOLECULAR-BASED APPROACH TO INVESTIGATE BREAST CANCER 1 AND BREAST CANCER 2 STATUS IN OVARIAN CANCER AMONG IRAQI WOMEN

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i7.25217 ◽

2018 ◽

Vol 11 (7) ◽

pp. 199

Author(s):

Muhannad Shweash ◽

Saddam Jumaa Naseer ◽

Maisam Khider Al-anii ◽

Thulfiqar Fawwaz Mutar

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Cancer Patients ◽

Gene Mutations ◽

Healthy Controls ◽

Brca1 And Brca2 ◽

First Degree Relatives ◽

Brca Gene ◽

Brca2 Mutations ◽

Brca1 And Brca2 Mutations

Objective: Cancer ovary is one of the fatal gynecologic malignancies worldwide. Since breast cancer (BRCA) genes are considered tumor suppressor genes and play important roles in cancer by repairing of chromosomal damage with the error repair of DNA breaks. Therefore, breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations strongly enhance the development of ovarian cancer risk among women. Here, we report that both genes are an essential mediator of progress ovarian cancer, to determine the influence of BRCA1 and BRCA2 mutations in the improvement of ovarian cancer.Methods: A total of 25 subjects were chosen for the genetic studies, and three groups were recruited: fifteen ovarian cancer patients group, five healthy controls, and five first-degree relatives to a known case of ovarian cancer patients.Results: A genetic analysis revealed that a strong correlation exists between both gene mutations’ status in ovarian cancer, and BRCA gene mutations (185delAG, 5382insC, and 4153delA in BRCA1 and 6174delT in BRCA2) remained to establish to have a relatively high frequency among people in this study among ovarian cancer patients. Furthermore, seven patients with ovarian cancer carried all of the four investigated mutations, and five had three mutations.Conclusion: Otherwise, BRCA gene frequency showed low prevalence among first-degree relatives, and to a lesser extent among healthy controls, with only a few had all of the mutations combined. These data demonstrate for the first time a molecular link between BRCA1 and BRCA2 mutations in ovarian cancer progression in Iraq.

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Management of hereditary ovarian cancer

Orvosi Hetilap ◽

10.1556/oh.2011.29218 ◽

2011 ◽

Vol 152 (40) ◽

pp. 1596-1608 ◽

Cited By ~ 2

Author(s):

József Gábor Joó ◽

Szabolcs Ládi ◽

B. Zsolt Nagy ◽

Zoltán Langmár

Keyword(s):

Ovarian Cancer ◽

Hereditary Ovarian Cancer ◽

Brca1 And Brca2 ◽

Ovarian Cancers ◽

Brca2 Mutations ◽

Histological Phenotype ◽

Brca1 Brca2 ◽

Brca1 And Brca2 Mutations ◽

High Level ◽

Associated Tumors

Mutations in BRCA1 and BRCA2 genes account for the majority of hereditary breast and ovarian cancers. Approximately 10% of cases of ovarian cancer are due to germline mutations in BRCA1 and BRCA2. Ovarian cancer associated with BRCA1 and BRCA2 mutations has a distinct histological phenotype. This type of cancer is predominantly of serous or endometrioid histology and is high grade. Patients with BRCA1 or BRCA2 mutations should be offered risk-reducing salpingo-oophorectomy by age 40 years, or when childbearing is complete. Nowadays there are no differences between the treatments provided for sporadic and hereditary ovarian cancer, although there are indications that targeted therapy is effective in women with BRCA1/BRCA2-associated tumors. Retrospective studies reveal a high level of sensitivity to platinum agents in BRCA-associated tumors and initial trials show good efficacy and tolerability for polyADP-ribose polymerase inhibitors in mutation carriers with advanced ovarian cancers. These agents might also potentially be used in chemoprevention. Authors review the current management of hereditary ovarian cancer. Orv. Hetil., 2011, 152, 1596–1608.

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Prevalence of BRCA1 and BRCA2 Mutations Among Patients With Ovarian, Primary Peritoneal, and Fallopian Tube Cancer in India: A Multicenter Cross-Sectional Study

JCO Global Oncology ◽

10.1200/go.21.00051 ◽

2021 ◽

pp. 849-861

Author(s):

Sudeep Gupta ◽

Senthil Rajappa ◽

Suresh Advani ◽

Amit Agarwal ◽

Shyam Aggarwal ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Family History ◽

Newly Diagnosed ◽

Brca1 And Brca2 ◽

Brca Mutations ◽

Fallopian Tube Cancer ◽

Cross Sectional ◽

Brca2 Mutations ◽

Brca1 Brca2

PURPOSE There are deficient data on prevalence of germline mutations in breast cancer susceptibility genes 1 and 2 ( BRCA1/ BRCA2) in Indian patients with ovarian cancer who are not selected by clinical features. METHODS This prospective, cross-sectional, noninterventional study in nine Indian centers included patients with newly diagnosed or relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer. The primary objective was to assess the prevalence of BRCA1/ BRCA2 mutations, and the secondary objective was to correlate BRCA1/ BRCA2 status with clinicopathologic characteristics. Mutation testing was performed by a standard next-generation sequencing assay. RESULTS Between March 2018 and December 2018, 239 patients with a median age of 53.0 (range, 23.0-86.0 years) years were included, of whom 203 (84.9%) had newly diagnosed disease, 36 (15.1%) had family history of ovarian or breast cancer, and 159 (66.5%) had serous subtype of epithelial ovarian cancer. Germline pathogenic or likely pathogenic mutations in BRCA1 and BRCA2 were detected in 37 (15.5%; 95% CI, 11.1 to 20.7) and 14 (5.9%; 95% CI, 3.2 to 9.6) patients, respectively, whereas variants of uncertain significance in these genes were seen in four (1.7%; 95% CI, 0.5 to 4.2) and six (2.5%; 95% CI, 0.9 to 5.4) patients, respectively. The prevalence of pathogenic or likely pathogenic BRCA mutations in patients with serous versus nonserous tumors, with versus without relevant family history, and ≤ 50 years versus > 50 years, were 40 of 159 (25.2%; 95% CI, 18.6 to 32.6) versus 11 of 80 (13.8%; 95% CI, 7.1 to 23.3; P = .0636), 20 of 36 (55.6%; 95% CI, 38.1 to 72.1) versus 41 of 203 (20.2%; 95% CI, 14.9 to 26.4; P < .0001), and 20 of 90 (22.2%; 95% CI, 14.1 to 32.2) versus 31 of 149 (20.8%; 95% CI, 14.6 to 28.2; P = .7956), respectively. CONCLUSION There is a high prevalence of pathogenic or likely pathogenic germline BRCA mutations in Indian patients with ovarian cancer.

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