p53 immunohistochemistry in endometrial cancer: clinical and molecular correlates in the PORTEC-3 trial

TransPORTEC consortium

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Abstract

Standard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to benefit from adjuvant chemo(radio)therapy. P53abn EC are POLE wildtype, mismatch repair proficient and show abnormal immunohistochemical (IHC) staining for p53. Correct interpretation of routinely performed p53 IHC has therefore become of paramount importance. We aimed to comprehensively investigate abnormal p53 IHC patterns and their relation to clinicopathological and molecular features. Tumour material of 411 molecularly classified high-risk EC from consenting patients from the PORTEC-3 clinical trial were collected. p53 IHC was successful in 408 EC and was considered abnormal when the tumour showed (subclonal) overexpression, null mutant or cytoplasmic p53 expression. The presence of pathogenic mutations was determined by next generation sequencing. Abnormal p53 expression was observed in 131/408 (32%) tumours. The most common abnormal p53 IHC pattern was mutant overexpression (n=89, 68%), followed by null mutant (n=12, 9%) and cytoplasmic (n=3, 2%) p53 expression. Subclonal abnormal p53 staining was observed in 27 cases (21%), which was frequently but not exclusively, associated with POLE mutations and/or MMRd (n=22/27; p<0.001). Agreement between p53 IHC and TP53 NGS was observed in 90.7%, resulting in a sensitivity and specificity of 83.6% and 94.3%, respectively. Risk of recurrence was similar across the different abnormal p53 IHC patterns. Our data shows that quality-assured p53 IHC protocols and awareness of the abnormal p53 IHC patterns are prerequisites for correct EC molecular classification. Subclonal abnormal p53 expression is a strong indicator for POLEmut and/or MMRd EC (also referred to as ‘double classifier’ EC). No significant differences in clinical outcomes were observed among the abnormal p53 IHC patterns, which supports combining the different abnormal p53 IHC patterns into one diagnostic entity (p53abn EC).


Original languageEnglish
JournalModern Pathology
Early online date25 Jun 2022
DOIs
Publication statusPublished - 25 Jun 2022

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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