The aim of the study was to assess the efficacy of pegylated liposomal doxorubicin (PLD) and oxaliplatin in patients affected by relapsed epithelial ovarian cancer with a family history of BRCA and p53 mutations.
We analyzed mRNA expression of <i>PD-1</i>, <i>PD-L1</i> and <i>IFNG</i> by quantitative real-time PCR in tissue of 170 patients with low grade-serous (LGSOC), high-grade serous (HGSOC), endometrioid and clear cell OC compared to 28 non-diseased tissues (ovaries and fallopian tubes) in relation to tumor protein 53 (<i>TP53</i>) and breast cancer gene 1/2 (<i>BRCA1/2</i>) mutation status.
Our study provides evidence that both germ line and somatic alterations of the p53 pathway influence the incidence and survival of ovarian carcinoma, and it underscores the importance of assessing the functionality of p53 in order to predict the sensitivity of platinum-based chemotherapies and patient outcome.
Missense mutations in the TP53 gene resulting in the accumulation of mutant proteins are extremely common in advanced ovarian cancer, which is characterised by peritoneal metastasis.
A high frequency of p53 mutations in ovarian cancers and lack of mutation in 6 benign ovarian tumors and 2 normal ovaries suggested that the mutation of the p53 gene was associated with the genesis and/or progression of ovarian cancer.
The most frequent type of ovarian cancer is high grade serous that often displays p53 mutation and its precursor lesions may originate from normal-appearing fallopian tube epithelium that contains a p53 "signature".
According to the International Agency for Research on Cancer TP53 mutation database, this type of p53 mutation in colorectal cancer and ovarian cancer is 0.13% (5/3,693) and 0% (0/1,494), respectively.
In TP53, CGA codons comprise <3% of the total 393 codons but they account for 72% and 39% of the mutations in CRC and ovarian cancer OVC, respectively.
Inhibition of PARP or homologous recombination (HR) repair mediated by Chk1 (checkpoint kinase 1) would selectively sensitize p53 mutation, BRCAness phenotype (serous type ovarian cancer) or HNF (hepatocyte nuclear factor)-1β-overexpressing tumor cells (clear cell type ovarian cancer) to chemotherapeutic agents.
Thus, considering the susceptibility to spontaneous mutations of the p53 gene in advanced ovarian carcinoma, the selection process resulting in emergence of p53 mutant tumors is a possible origin of resistance of ovarian carcinoma to DNA-damaging agents.
Other high-risk cancer genes that confer increased risks of breast or ovarian cancer in addition to other cancers include the hereditary non-polyposis colorectal cancer genes and the TP53 gene, which causes breast cancer as part of the Li-Fraumeni syndrome.