Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families

Abstract

RAD51C was defined by Meindl et al. in 2010 as a high-risk gene involved in hereditary breast and ovarian cancers. Although this role seems to be clear, nowadays there is controversy about the indication of including the gene in routine clinical genetic testing, due to the lower prevalence or the absence of mutations found in subsequent studies. Here, we present the results of a comprehensive mutational screening of the RAD51C gene in a large series of 785 Spanish breast and/or ovarian cancer families, which, in contrast to the various subsequent studies published to date, includes the functional characterization of suspicious missense variants as reported in the initial study. We have detected 1.3% mutations of RAD51C in breast and ovarian cancer families, while mutations in breast cancer only families seem to be very rare. More than half of the deleterious variants detected were of missense type, which highlights their significance in the gene, and suggest that RAD51C mutations may have been so far partially disregarded and their prevalence underestimated due to the lack of functional complementation assays. Our results provide new evidences, suggesting that the genetic testing of RAD51C should be considered for inclusion into the clinical setting, at least for breast and ovarian cancer families, and encourage re-evaluating its role incorporating functional assays.

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

“…Thus, we recommend excluding FANCM as an FA gene, although, together with FAAP100, FAAP25, and other FA-core complex interacting proteins, FANCM is involved in the FA ICL repair (ICLR) pathway (see below). Similarly, whole genome exon sequencing (WES) detected biallelic XRCC2 mutations in a consanguineous FA family [9]; however, because of FA genes that predispose to breast and ovarian cancer influence ovarian cancers more than breast cancer [18,19], and are linked to other tumors such as head and neck cancer [20,21]. RAD51C and FANCM were initially associated to FA before they were candidates for FBOC in monoallelic carriers [22,23] highlighting the role of FA research in molecular oncology.…”

Diseases Associated with Defective Responses to DNA Damage

“…Multiple mutations in RAD51C and RAD51D have been found in breast and ovarian cancer cohorts prompting some to call for screening for these genes in breast and ovarian cancer (Meindl et al 2010;Loveday et al 2011;Osorio et al 2012). The difficulty in assigning pathogenicity for some missense variants, in the absence of functional evaluation has, however, led to some debate here (Loveday et al 2012).…”

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.…”