A Large Case-Control Study Performed in Spanish Population Suggests That RECQL5 Is the Only RECQ Helicase Involved in Breast Cancer Susceptibility.

Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the role of the RECQ helicases, some of which have been studied in the past as candidates, with unclear results about their role in the disease. Using next-generation sequencing (NGS) technology, we analyzed the whole coding sequence of BLM, RECQL1, RECQL4, RECQL5, and WRN in almost 2000 index cases from BC Spanish families that had previously tested negative for the known BC susceptibility genes (BRCAX) and compared the results with the controls extracted from gnomAD. Our results suggest that BLM, RECQL1, RECQL4, and WRN do not play a major role in BC susceptibility. However, in the combined analysis, joining the present results with those previously reported in a series of 1334 BC Spanish patients and controls, we found a statistically significant association between Loss of Function (LoF) variants in RECQL5 and BC risk, with an OR of 2.56 (p = 0.009; 95% CI, 1.18-4.98). Our findings support our previous work and places the RECQL5 gene as a new moderate-risk BC gene.A.O. is partially funded by FIS PI19/00640 supported by FEDER funds and the Spanish Network on Rare Diseases (CIBERER). M.d.l.H. is partially funded by FIS PI20/00110 supported by FEDER funds.S

Caracterización molecular de cánceres de mama triple negativo mediante secuenciación masiva (NGS). Tipificación de variantes de significado incierto

El cáncer de mama triple negativo (CMTN) representa el 12-15% de los casos de cáncer de mama diagnosticados. Este subtipo de cáncer tan agresivo se ha relacionado con la presencia de variantes patogénicas en línea germinal en genes de predisposición a cáncer, diferentes a los genes de alta penetrancia BRCA1 y BRCA2. En este trabajo se ha evaluado la implementación de un panel Ion AmpliSeq On-Demand de 35 genes en 64 casos de CMTN, identificando variantes en el 14,06% de los casos (3,12% en los genes BRCA y 10,93% en otros genes de predisposición). Las variantes de significado incierto identificadas en este trabajo se evaluaron, demostrando que no afectan al proceso de splicing. Los resultados reflejan la contribución de otros genes de predisposición al desarrollo de este subtipo tumoral, así como la necesidad de realizar un estudio genético en línea germinal a las pacientes con CMTN, permitiendo la administración de los tratamientos más eficaces, y ampliar el estudio a familiares sanos, sobre los que aplicar las estrategias de prevención más adecuadas.Departamento de Bioquímica y Biología Molecular y FisiologíaMáster en Investigación Biomédic

Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?

The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both BRCA1/BRCA2, one ovarian cancer case DH for BRCA1/RAD51C, and another breast and colorectal cancer who is DH for BRCA2/PMS2 were identified in our cohort. Ages at diagnosis and severity of disease in BRCA1/BRCA2 DH resembled BRCA1 single-carrier features. Similarly, the co-existence of the BRCA2 and PMS2 mutations prompted the development of breast and colorectal cancer in the same patient. The first BRCA1/BRCA2 DH was identified by HA-based and Sanger sequencing (1 of 623 families with BRCA PVs). However, this ratio has increased up to 2.9% (1 DH carrier vs. 103 single PV carriers) since using a custom 35-cancer gene on-demand panel. The type of cancer developed in each DH patient was consistent with the independently inherited condition, and the clinical outcome was no worse than in patients with single BRCA1 mutations. Therefore, the clinical impact, especially in patients with two hereditary syndromes, lies in genetic counseling tailor-made for each family based on the clinical guidelines for each syndrome. The number of DH is expected to be increased in the future as a result of next generation sequencing routines