N94: Uruguayan Hereditary Breast and Ovarian Cancer Syndrome Registry: BRCA and Non-BRCA pathogenic variants

P. Esperon1,2, F. Neffa1, C. Acevedo1, G. Santander1, M. Sapone1, C. Vergara1, F. Carusso1, A.Della Valle1

1 – Grupo Colaborativo Uruguayo. 2 – Facultad de Química. UDELAR Montevideo, Uruguay

Introduction: Mutations in BRCA1 or BRCA2 genes are considered the most prevalent cause of hereditary breast and ovarian cancer syndrome (HBOC), although other genes also explain this kind of affection. Since 2014, the Uruguayan Collaborative Group (UCG), a nonprofit organization is devoted to the registry, diagnosis, management and research of hereditary cancer, has been recruiting high-risk family groups with HBOC.

Objective: To report about pathogenic variants in BRCA and non-BRCA genes detected in Uruguayan high-risk for HBOC population.

Methodology: From the UCG registry, 592 non-related are defined as HBOC-high risk population following the National Comprehensive Cancer Network 2018 guidelines. Selected probands for genetic testing signed informed consent prior to obtain saliva or blood samples. Different approaches for searching gene mutations have been employed. At first, Next Generation Sequencing of BRCA1 and BRCA2, then large rearrangements detection methods were used, and lately multigene panels have been employed.

Results: 330 (56%) HBOC-high risk, non-related probands were tested, 56 were found positives and 49 different pathogenic variants identified. BRCA1-2 accounted for 31 (66%) pathogenic mutations (14 BRCA1 and 17 BRCA2) while mutations in non-BRCA genes were: PALB2(3) ATM(1) CHEK2(3) BARD1(3), TP53(6), CHD1(1), NBN(1).

Conclusion: Even though only HBOC high risk probands were selected, a relatively high proportion of non-BRCA genes presented with pathogenic variants. Although multigene panels can give unexpected and uninformative results, when used with thoughtfulness, they can be a valuable tool capable of diagnose beyond the traditional boundaries of BRCA genes. Despite technological improvements, a high number of families with no molecular diagnosis still remains. Since the role of constitutive epimutations in cancer development can be underestimated, future approaches will include a methylation screening.

Acknowledgement: Fundación Génesis Uruguay. Laboratorio Genia Uruguay.