Accurate interpretation of p53 immunohistochemical patterns is a surrogate biomarker for TP53 alterations in large B-cell lymphoma

Abstract

Background: To clarify the relationship between p53 immunohistochemistry (IHC) staining and TP53 alterations (including mutations and deletions) in large B-cell lymphomas (LBCLs) and to explore the possibility of p53 IHC expression patterns as surrogate markers for TP53 alterations.

Methods: A total of 95 patients diagnosed with LBCLs were selected, and paraffin samples were taken for TP53 gene sequencing, fluorescence in situ hybridization and p53 IHC staining. The results were interpreted by experienced pathologists and molecular pathologists.

Results: Forty-three nonsynonymous TP53 mutations and p53 deletions were detected in 40 cases, whereas the remaining 55 cases had wild-type TP53 genes. The majority of TP53 mutations (34/43, 79.1%) occurred in exons 4-8, and R248Q was the most common mutation codon (4/43, 9.3%). The highest frequency single nucleotide variant was C > T (43.6%). p53 expression was interpreted as follows: Pattern A: p53 staining was positive in 0%-3% of tumor cells, Pattern B: p53 staining was positive in 4-65% of tumor cells, Pattern C: more than 65% of tumor cells were stained positive for p53. The p53 IHC expression patterns were associated with TP53 alterations. Gain of function variants and wild-type TP53 tended to exhibit type C and B p53 expression patterns, but loss of function variants were exclusively seen in type A cases. Additionally, interpretation of the staining by various observers produced significant reproducibility.

Conclusions: The p53 IHC expression patterns can be used to predict TP53 alterations and are reliable for diverse alteration types, making them possible surrogate biomarkers for TP53 alterations in LBCLs.

Keywords: Large B-cell lymphoma; Lymphoma; Surrogate marker; TP53 alterations; p53 immunohistochemistry.

Fig. 1

A. The “lollipop” plot of the TP53 gene, as well as the frequency and position of TP53 mutations in LBCLs in our study. B. Percentage of the 6 possible mutation classes. AD: transactivation domain; DBD: DNA binding domain; TD: tetramerization domain

Fig. 2

Different patterns of p53 expression in LBCLs. A. Representative hematoxylin and eosin (HE) image of Pattern A (left) and representative p53 IHC staining image of Pattern A (right). B. Representative HE image of Pattern B (left) and representative p53 IHC staining image of Pattern B (right). C. Representative HE image of Pattern C (left) and representative p53 IHC staining image of Pattern C (right)

Fig. 3

The Pearson analysis showed a strong correlation between the p53 percentage scores by different pathologists (R = 0.989, p < 0.001)

Fig. 4

Schematic diagram of research ideas and results