Germline and somatic variants in ovarian carcinoma: A next-generation sequencing (NGS) analysis

Abstract

BackgroundGermline BRCA1/2 mutations are identified in 13-15% of ovarian cancers, while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations. Beyond these mutations, germline or somatic aberrations in genes of the homologous recombination (HR) pathway such as RAD51B/C/D, PALB2, ATM, BRIP1 may confer an HR deficiency in up to 50% of ovarian tumors. Next-generation sequencing (NGS) is a high-throughput massive parallel sequencing method that enables the simultaneous detection of several mutations in entire genomes.MethodsWe performed NGS analysis in 86 patients with ovarian cancer treated in the Oncology Department of Alexandra University Hospital in order to identify the molecular landscape of germline and somatic mutations in ovarian cancer.ResultsThe genes with the highest number of pathogenic somatic mutations in high grade serous carcinoma (HGSC) patients were TP53 [68%; 34/50] and BRCA1 [22%; 11/50] followed by somatic mutations in RB1 [2%; 1/50], NF1 [2%; 1/50], BRCA2 [2%; 1/50], AKT1 [2%; 1/50], RAD50 [2%; 1/50], PIK3CA [2%; 1/50] genes. Of note, the most common TP53 genetic polymorphism was c.524G>A p.Arg175His in exon 5. Variants of unknown significance (VUS) detected in HGSC included ROS1 [26%; 13/50], RAD50 [6%; 3/50], BRCA2 [6%; 3/50], NOTCH1 [6%; 3/50], TP53 [6%; 3/50], AR [6%; 3/50]. As for germline mutations, BRCA1 [8/30; 27%] and BRCA2 [4/30; 13%] were the most common genes bearing pathogenic alterations in HGSC, while VUS germline mutations commonly affected HRR-related genes, including ATM (c.7816A>G), BRIP (c.2327 C>A), CHEK2 (c.320-5T>A).ConclusionOverall, genetic testing should be offered in most patients with ovarian cancer to identify mutations in HRR genes and determine the population that would be susceptible to poly ADP ribose polymerase (PARP) inhibitors.

BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer

“…The prevalence of TP53 somatic variants categorized as non‐functional or likely non‐functional, which may disturb p53 function, was 62.5% (35/56) of all patients, and 64.7% (22/34) of HGSOC patients. The frequency of TP53 somatic variants in the present study was lower than the 68%–96% frequency found in other studies 82–85 . Most TP53 somatic variants found here were missense substitutions spanning exons 5 to 8, which correspond to the DNA‐binding domain (amino acid residues 95–288) 86,87 .…”

“…The frequency of TP53 somatic variants in the present study was lower than the 68%-96% frequency found in other studies. [82][83][84][85] Most TP53 somatic variants found here were missense substitutions spanning exons 5 to 8, which correspond to the DNA-binding domain (amino acid residues 95-288). 86,87 Nineteen of these missense somatic variants are frequently reported in ovarian tumors, occurring at codons considered cancer hotspots, 88,89 and presented VAFadjusted ranging from to 100%.…”

Next-generation sequencing-based analysis of homologous recombination repair gene variant in ovarian cancer

“…Moreover, figuring out the alterations of BRCA1/2 , especially germline mutation, is an effective way to identify the inherited risk of cancer and take preventive measures. Previous studies showed that about 8.6–24.5 % patients harbored g BRCA1/2 mutations, while 3.7–7.1 % patients presented s BRCA1/2 mutations [ 10 , [31] , [32] , [33] , [34] , [35] ]. Our study excluded the benign mutations and found the frequencies of g/s BRCA1/2 mutation were 18.55 % and 9.68 %.…”

Biomarkers in Ovarian Cancer: Towards Personalized Medicine

“…Also, it has been observed that those patients presenting germline BRCA1 and BRCA2 pathogenic variants show a better response to platinum-based treatments [ 57 ]. As for the somatic mutations, they are detected in 5–7% of OC cases [ 58 ]. Of note, better short-term survival rates have been observed in those patients carrying BRCA mutations; however, there are some contradictory observations at longer times, with studies reporting conflicting mortality rates for BRCA-mutated carriers vs. noncarriers [ 59 , 60 , 61 ].…”