Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing

Abstract

Despite extensive analysis of the BRCA1 and BRCA2 genes, germline mutations are detected in <20% of families with a presumed genetic predisposition for breast and ovarian cancer. Recent literature reported RAD51C as a new breast cancer susceptibility gene. In this study, we report the analysis of 410 patients from 351 unrelated pedigrees. All were referred for genetic testing and we selected families with at least one reported case of ovarian cancer in which BRCA1&2 mutations were previously ruled out. We analyzed the coding exons, intron-exons boundaries, and UTRs of RAD51C. Our mutation analysis did not reveal any unequivocal deleterious mutation. In total 12 unique sequence variations were identified of which two were novel. Our study and others suggest a low prevalence of RAD51C mutations with an exception for some founder populations. This observation is in favor of the rare allele hypothesis in the debate over the nature of the genetic contribution to individual susceptibility to breast and ovarian cancer and further genome-wide studies in high risk families are warranted.

Genetic testing for RAD51C mutations: in the clinic and community

“…Several studies from various countries and ethnic groups have attempted to confirm these findings. Eleven studies have reported mutations with varying frequencies (0.4 -2.9%; summarized in table 1) [13][14][15][16][17][18][19][20][21][22][23][24], but eight studies failed to detect any clearly pathogenic mutation [25][26][27][28][29][30][31]. Of all families with an identified mutation in the 11 studies, only one mutation was found in a family without ovarian cancer (prevalence 0.2%) [18,21].…”

Mutaciones del gen RAD51 en el cáncer familiar de ovario: revisión de la literatura

“…Evaluaron 277 pacientes con cáncer familiar de mama/ovario, donde reportan la mutación en el 2% de las familias con cáncer mama/ovario (23 Por otro lado, Lu y cols en el 2012, reportan un estudio de cohorte, donde se analizan los resultados del análisis mutacional de RAD51C en 192 familias con alto riesgo de carcinoma mama y/u ovario; este estudio no logró identificar ninguna mutación, atribuyendo este resultado al número limitado de familias con cáncer de mama y ovario (n=35) (24). Para los artículos de calidad aceptable, cuatro no mostraron una relación directa entre la mutación del gen y la enfermedad (25)(26)(27)(28), los restantes encontraron mutaciones en las familias con carcinoma de mama y ovario, pero no en los casos exclusivos de carcinoma de mama (11,(19)(20)(21)(22)(29)(30)(31)(32)(33)(34), relacionando la presencia de mutaciones en los casos con historia familiar de por lo menos un caso de carcinoma de ovario: OR: 13,59; IC95% 1,89-97,6; p=0,026 en los casos de cáncer familiar de mama y ovario, y OR: 213; IC95% 25,6-1769; p=0,0002 en casos de cáncer familiar de ovario en ausencia de cáncer de mama (23).…”

“…Caracterización de la población estudiada. Los 17 artículos incluidos y revisados, incluyeron poblaciones de diversas etnias; Finlandia (22,23,28,33), Estados Unidos (24,27,30,34), España (19,31), Reino Unido (21), Alemania (11), Australia (32), Francia (20), Israel (26), Canadá, Bélgica y Países bajos (25). Esta diversidad poblacional, se plantea como la causa principal del amplio rango de prevalencias reportada.…”

“…Otros cánceres encontrados en familias con mutaciones en RAD51. Nueve de los diecisiete estudios incluidos, reportan carcinomas diferentes al de mama y/u ovario presentes en familias portadoras de mutaciones en genes del complejo RAD51 (11,(19)(20)(21)23,29,(31)(32)(33), uno descarta la asociación entre mutaciones a otro tipo de cáncer (22), los restantes, no aportan información (24)(25)(26)(27)(28)30,34). Entre las neoplasias encontradas se incluyen: carcinoma colo-rectal, pulmón, próstata, linfoma no Hodgkin, riñón, páncreas, primario desconocido, laringe, sistema nervioso central, endometrio, leucemia, hí-gado, melanoma, y lengua.…”

Genetic and Genomic Factors in Breast Cancer

“…Despite the initial scienti fi c and clinical support for RAD51C as a cancer susceptibility gene, others have not found a high prevalence of RAD51C mutations in at-risk breast-ovarian cancer cohorts [ 38 ] or may not be as highly penetrant as has been demonstrated in some studies [ 39 ] . As the actual frequency of RAD51C has not yet been precisely delineated as well as the effect of the various identi fi ed germline mutations on the risk of breast and ovarian cancers in women and men carrying such mutations, further studies are needed in order to determine whether RAD51C should be included in a universal or targeted genetic screening panel for women with family histories of breast and ovarian cancer.…”