Abstract
High-grade serous carcinoma (HGSCa) of the ovary is featured by TP53 gene mutation. Missense or nonsense mutation types accompany most cases of HGSCa that correlate well with immunohistochemical (IHC) staining results—an all (missense) or none (nonsense) pattern. However, some IHCs produce subclonal or mosaic patterns from which TP53 mutation types, including the wild type of the gene, cannot be clearly deduced. We analyzed a total of 236 cases of ovarian HGSCa and tumors of other histology by matching the results of p53 IHC staining and targeted next-generation sequencing (TruSight Tumor 170 panel). Ambiguous IHCs that do not belong to the conventional “all or none” groups were reviewed to distinguish the true wild type (WT) from potentially pathogenic subclonal or mosaic patterns. There were about 9% of sequencing-IHC mismatching cases, which were enriched by the p53 c-terminal encoding nuclear localization signal and oligomerization domain, in which the subcellular locations of p53 protein were affected. Indeed, mutations in the oligomerization domain of the p53 protein frequently revealed an unmatched signal or cytosolic staining (L289Ffs*57 (Ins), and R342*). We conclude that both mutation types and IHC patterns of p53 are important sources of information to provide a precise diagnosis of HGSCa.
Highlights
The tumor suppressor gene TP53 is one of the most frequently altered genes in human cancers [1]
Low-grade serous carcinoma (LGSCa) (n = 1), carcinosarcoma (CS) (n = 9), endometrioid carcinoma (EMC) (n = 9), mucinous carcinoma (MuC) (n = 8), clear cell carcinoma (CCC) (n = 3), and unclassified metastatic carcinoma (n = 4) samples were included for comparative analysis
We report that the mutation types of the TP53 gene in ovarian High-grade serous carcinoma (HGSCa) generally matched the IHC results
Summary
The tumor suppressor gene TP53 is one of the most frequently altered genes in human cancers [1]. The most common type of TP53 mutations in HGSCa is missense mutation (MM, ~70%) which results in p53 protein accumulation in the cell (gain-of-function or dominant-negative), while some occur as nonsense mutation (NM, ~10%) leading to a truncated p53 protein with reduced activity [4]. The p53 protein consists of a transactivation domain, DNA-binding domain, nuclear localization site, and oligomerization domain (From N-terminal to C-terminal). It is possible that mutations occurring in different domains lead to different biological consequences in terms of protein degradation or intracellular location. Most of the TP53 missense mutations (MM) are found in the DNA binding domain (DBD) encoded by amino acid (AA) residues 102 to 292. The transactivation domain, proline-rich domain, or oligomerization domain are enriched with NM or frameshift alterations (40–70% of cases) [5]
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