Prevalence of BRCA1/2 mutations in sporadic breast/ovarian cancer patients and identification of a novel de novo BRCA1 mutation in a patient diagnosed with late onset breast and ovarian cancer: implications for genetic testing

Abstract

In order to adequately evaluate the clinical relevance of genetic testing in sporadic breast and ovarian cancer patients, we offered comprehensive BRCA1/2 mutation analysis in patients without a family history for the disease. We evaluated the complete coding and splice site regions of BRCA1/2 in 193 sporadic patients. In addition, a de novo mutation was further investigated with ultra deep sequencing and microsatellite marker analysis. In 17 patients (8.8%), a deleterious germline BRCA1/2 mutation was identified. The highest mutation detection ratio (3/7 = 42.9%) was obtained in sporadic patients diagnosed with breast and ovarian cancer after the age of 40. In 21 bilateral breast cancer patients, two mutations were identified (9.5%). Furthermore, 140 sporadic patients with unilateral breast cancer were investigated. Mutations were only identified in patients diagnosed with breast cancer before the age of 40 (12/128 = 9.4% vs. 0/12 with Dx > 40). No mutations were detected in 17 sporadic male breast cancer and 6 ovarian cancer patients. BRCA1 c.3494_3495delTT was identified in a patient diagnosed with breast and ovarian cancer at the age of 52 and 53, respectively, and was proven to have occurred de novo at the paternal allele. Our study shows that the mutation detection probability in specific patient subsets can be significant, therefore mutation analysis should be considered in sporadic patients. As a consequence, a family history for the disease and an early age of onset should not be used as the only criteria for mutation analysis of BRCA1/2. The relatively high mutation detection ratio suggests that the prevalence of BRCA1/2 may be underestimated, especially in sporadic patients who developed breast and ovarian cancer. In addition, although rare, the possibility of a de novo occurrence in a sporadic patient should be considered.

BRCA1 Promotes Unloading of the CMG Helicase from a Stalled DNA Replication Fork

“…Growing evidence also indicates that BRCA1 loss plays an important role in the development of sporadic cancers (Chalasani and Livingston, 2013; Leeneer et al, 2011). In the absence of BRCA1, cells develop multiple chromosomal abnormalities, implicating genome maintenance in tumor suppression (Zhang, 2013).…”

Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells

“…However, the frequency of Polθ overexpression, especially in sporadic breast cancer, suggests that Polθ is not only involved in a compensatory mechanism that rescues HR deficiency, but is likely to provide HR-proficient tumours with a growth advantage. Indeed, while the proportion of HR-proficiency in sporadic cancers is difficult to quantify, somatic mutations in BRCA genes in sporadic breast cancer is estimated to be around 10% (Futreal et al, 1994; De Leeneer et al, 2012). To obtain new insights regarding the contextual relevance of Polθ overexpression in tumours, and identify possible mechanisms associated with its mode-of-action, we initially studied the correlation between the expression of POLQ and that of the genes involved either in DNA repair or replication.…”

Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations

“…However, in this study, only one out of four cases had a negative family history (case 2). The presence of a breast cancer family history has also been described in 5 of the 11 cases of de novo BRCA1/2 mutations reported in the literature [5][6][7][8][9][10][11][12][13][14][15] (Table 1). Breast cancer family history for de novo BRCA1/2 mutation carriers can have several origins: the high frequency of breast cancer in the general population; the strong impact of family history in the inclusion criteria for BRCA1/2 genetic testing, resulting in a bias for family cancer cases; and finally, genetic heterogeneity in breast cancer.…”

“…[1][2][3] More than 3000 distinct genetic variants have been reported in these genes (BRCA1 and BRCA2 Universal Mutation Databases 4 ). Despite the large number of mutation carriers identified by means of the large number of genetic tests conducted worldwide, only six BRCA1 and five BRCA2 de novo mutations have been reported [5][6][7][8][9][10][11][12][13][14][15] (Table 1). This small number is surprising, as the de novo mutation rate can be as high as 11-25% in APC, 74% in NF1 and up to 90% in RB1.…”