Germline mutations in cancer susceptibility genes in high grade serous ovarian cancer in Serbia

PurposeThe known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

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Genetic testing and clinical management practices for variants in non-BRCA1/2 breast (and/or ovarian) cancer susceptibility genes: An international survey by the Enigma Clinical Working Group.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.1539 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 1539-1539 ◽

Cited By ~ 3

Author(s):

Sarah Nielsen ◽

Arcangela De Nicolo ◽

Diana Eccles ◽

Iris L Romero ◽

Susan M. Domchek ◽

...

Keyword(s):

Ovarian Cancer ◽

Genetic Testing ◽

Clinical Management ◽

Working Group ◽

Management Practices ◽

Cancer Susceptibility ◽

Susceptibility Genes ◽

International Survey ◽

Cancer Susceptibility Genes

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Comparison of risk-reducing surgery in women with BRCA and non-BRCA ovarian cancer susceptibility genes.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1547 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1547-1547

Author(s):

Zachary Phillip Schwartz ◽

Mae Zakhour ◽

Andrew John Li ◽

Christine S. Walsh ◽

Bj Rimel ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Susceptibility ◽

Brca Mutation ◽

Susceptibility Genes ◽

Brca Mutations ◽

Cancer Susceptibility Genes ◽

Mutation Carriers ◽

Brca Mutation Carriers ◽

History Of ◽

Risk Reducing

1547 Background: Risk reducing gynecologic surgery (RRSO) is standard of care for women with BRCA mutations. The optimal management for women with non-BRCA ovarian cancer susceptibility mutations remains unclear. We sought to characterize the practice patterns for these women at our two institutions. Methods: Women with germline ovarian cancer susceptibility genes who had a RRSO were identified from 1/2000-1/2019 in an IRB approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. Continuous variables were analyzed with Kruskal-Wallis and categorical variables analyzed with chi square and t-tests. Results: 152 BRCA1, 95 BRCA2, and 63 Non-BRCA mutation carriers were identified—50 Lynch (22 MLH1, 13 MSH2, 13 MSH6, 2 PMS2) and 13 Other (6 BRIP1, 2 RAD51C, 5 RAD51D). There was no difference between age at testing, age at RRSO, and interval between testing and RRSO between groups. Genetic counseling was higher in Non-BRCA patients. Family history of ovarian cancer was more common in women with BRCA1 and Other germline mutations compared to BRCA2 and Lynch. Family and personal history of breast cancer was high in all groups except Lynch carriers. Prophylactic mastectomy was seen mostly in BRCA mutation carriers. Concomitant hysterectomy was performed in the majority of women (BRCA1 59%, BRCA2 57%, and Other 62%), with the highest frequency in Lynch carriers (86%, p<.01). Occult cancer was only seen in BRCA mutation carriers: BRCA1 (7%), BRCA2 (2%), Lynch (0%), Other (0%). Conclusions: In this cohort, women with Non-BRCA mutations are managed similarly to women with BRCA mutations. We observed no occult cancers in Non-BRCA patients. The optimal role of surgery as a risk reducing strategy in this group requires further study. [Table: see text]

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BRCA 1/2 mutations in high-grade serous ovarian cancer (HGS-OC) patients of three Latin American countries: Report of 412 cases.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14288 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14288-e14288

Author(s):

Juan Molina ◽

Omar Orlando Castillo Fernandez ◽

Maria Lim ◽

Luis Mas ◽

Ignacio Fernando Veliz ◽

...

Keyword(s):

Ovarian Cancer ◽

Costa Rica ◽

Latin American ◽

Positive Family History ◽

Germline Mutations ◽

High Grade ◽

Serous Ovarian Cancer ◽

Brca 1 ◽

Brca 2 ◽

Latin American Countries

e14288 Background: Ovarian Cancer (OC) is the most common gynecologic cancer in women in the World and with elevated mortality. High Grade Serous Ovarian Cancer (HGS-OC) is a common histotype and closely related with the presence of BCRA abnormalities. This is to our knowledge the first report of a large series of patients with HGS-OC evaluated in Latin-American countries. The study aim was to present the data obtained from Perú, Costa Rica and Panamá from January 2016 to December 2018. Methods: A cross-sectional evaluation was performed in patients diagnosed between 2016 and 2018 with HGS-OC in three countries in Latin America. The patients were selected from Cancer National Reference Centers in Perú, Panamá and Costa Rica. Germline BRCA 1 / 2 mutations were evaluated through Next Generation Sequencing (NGS) in blood samples. Results: During the period 412 HGS-OC were studied. The mean age at diagnosis was 56.55(SD:12.21) years for all the evaluated patients and 55.42(SD:8.60) years in the mutated cases. Pathogenic HGS-OC mutations in germline BRCA 1 / 2 were diagnosed in 72 cases. Germline BRCA 2 mutations were the most frequent abnormality detected in Panama and in Costa Rica with 70.0 %(7/10) and 77.8%(14/18), respectively. However in Perú, germline mutations in BRCA 1 represents the majority of the mutations with 79.3%(35/44). Variants of uncertain significance (VUS) were detected in 3.64 %(15/412). Positive family history for breast or ovarian cancer were detected in 13.8% of patients with pathogenic mutations(10/72). Specific mutation distribution evidenced in Perú that 6 of 44(13.6%) mutated patients had the mutation in BRCA 1 c.2105dupT; 6 patients of 18(33.3%) had the mutation in BRCA 2 c.5303_5304delTT in Costa Rica and 2 cases had the mutation in BRCA1 c.5186C > A in Panama. The rest of mutations were less common. Conclusions: The frequency of Germline mutations BRCA 1 and BRCA 2 in patients with HSG-OC is similar to the reported in developed nations. However, the different mutation profile between the studied countries could be explained by the Latin-American genetic diversity. Most of the mutations we report were not described in previous studies evaluating breast cancer susceptibility.

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