TP53 Mutational Spectrum in Endometrioid and Serous Endometrial Cancers

Abstract

Endometrial carcinomas (ECs) are heterogeneous at the genetic level. Although TP53 mutations are highly recurrent in serous endometrial carcinomas (SECs), these are also present in a subset of endometrioid endometrial carcinomas (EECs). Here, we sought to define the frequency, pattern, distribution, and type of TP53 somatic mutations in ECs by performing a reanalysis of the publicly available data from The Cancer Genome Atlas (TCGA). A total of 228 EECs (n=186) and SECs (n=42) from the TCGA data set, for which an integrated genomic characterization was performed, were interrogated for the presence and type of TP53 mutations, and for mutations in genes frequently mutated in ECs. TP53 mutations were found in 15% of EECs and 88% of SECs, and in 91% of copy-number-high and 35% of polymerase (DNA directed), epsilon, catalytic subunit (POLE) integrative genomic subtypes. In addition to differences in prevalence, variations in the type and pattern of TP53 mutations were observed between histologic types and between integrative genomic subtypes. TP53 hotspot mutations were significantly more frequently found in SECs (46%) than in EECs (15%). TP53-mutant EECs significantly more frequently harbored a co-occurring PTEN mutation than TP53-mutant SECs. Finally, a subset of TP53-mutant ECs (22%) was found to harbor frameshift or nonsense mutations. Given that nonsense and frameshift TP53 mutations result in distinct p53 immunohistochemical results that require careful interpretation, and that EECs and SECs display different patterns, types, and distributions of TP53 mutations, the use of the TP53/p53 status alone for the differential diagnosis of EECs and SECs may not be sufficient.

Figures

Fig. 1. Distribution and spectrum of TP53 mutations in endometrial cancer

(A) Distribution and spectrum of TP53 mutations in endometrioid endometrial cancer (top) and serous endometrial cancer (bottom). Diagrams represent the protein domains of p53 encoded by TP53. The presence of a mutation is shown on the x-axis (‘lollipop’), the frequency of mutations is shown on the y-axis. Missense mutations are presented as green circles, truncating mutations (i.e. nonsense, frameshift, splice-site) are depicted in red circles, in-frame insertions and deletions are shown in black circles, and circles colored in purple indicate residues affected by different types of mutation at the same proportion. Plots were generated using cBioPortal (www.cBioPortal.org) and manually curated. Note that mutations affecting the hotspots R175, R248 and R273 are more frequent in serous than in endometrioid endometrial cancers. (B) Prevalence of ARID1A, PTEN, FBXW7 and PPP2R1A mutations in TP53-mutant endometrioid endometrial cancers (EECs; left), and prevalence of ARID1A, PTEN, FBXW7 and PPP2R1A mutations in TP53-mutant serous endometrial cancers (SECs; right). Mutation types/ color-codes as depicted in the legend. Plots were generated using cBioPortal (www.cBioPortal.org) and manually curated.

Fig. 2. A combination of immunohistochemical and mutational analysis may aid in the distinction of sporadic high-grade TP53-mutant endometrial carcinomas of serous endometrial and FIGO grade 3 endometrioid histologic subtypes

Histologic features characteristic of MSI endometrial cancers or endometrial carcinomas harboring POLE hotspot mutations include enrichment in tumor-infiltrating lymphocytes and/or peri-tumoral lymphocytes, among others. *DNA MMR markers may be limited to MLH1 immunohistochemistry and/or MLH1 promoter methylation analysis. DNA MMR, DNA mismatch repair; IHC, immunohistochemistry; MSI, microsatellite instability.