Dataset Information

Histopathological and genotypic characterization of metastatic colorectal carcinoma with PD-L1 (CD274)-expression: Possible roles of tumour micro environmental factors for CD274 expression.

ABSTRACT: Aberrant PD-L1 (CD274) expression has been described in different types of tumour and linked to tumour aggressiveness and a poor prognosis. In primary colorectal carcinomas (CRCs), CD274 expression was reported to be associated with mismatch repair (MMR)-deficiency, BRAF mutation, and "stem-like" immunophenotype defined by down-regulation of homeobox protein CDX2 and membranous expression of activated leukocyte cell adhesion molecule (ALCAM). However, the immunophenotype and genotype of CD274-positive metastatic CRC have not been extensively analysed. In this study, 189 CRC metastases were evaluated immunohistochemically for CD274, MMR proteins, CDX2, and ALCAM expression. Immunostaining for CD4, CD8, and FOXP3 was also performed to characterize tumour-associated immune cells. In addition, 34 arbitrarily selected lesions were genotyped using Sanger- and next-generation sequencing. Univariate analyses showed no clear association between CD274 expression and clinicopathological parameters including MMR-deficiency or "stem-like" immunophenotype after adjustment for multiple testing. Comparison of the clinicopathological profiles of CD274-positive primary and metastatic tumours revealed in the latter younger age of occurrence (60.9?±?13.3 versus 72.6?±?13.1 years, p?=?0.001), cytoplasm-dominant CD274 expression (p?

SUBMITTER: Inaguma S

PROVIDER: S-EPMC5653930 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Histopathological and genotypic characterization of metastatic colorectal carcinoma with PD-L1 (CD274)-expression: Possible roles of tumour micro environmental factors for CD274 expression.

Inaguma Shingo S Lasota Jerzy J Felisiak-Golabek Anna A Kowalik Artur A Wang Zengfeng Z Zieba Sebastian S Kalisz Joanna J Ikeda Hiroshi H Miettinen Markku M

The journal of pathology. Clinical research 20171007 4

Aberrant PD-L1 (CD274) expression has been described in different types of tumour and linked to tumour aggressiveness and a poor prognosis. In primary colorectal carcinomas (CRCs), CD274 expression was reported to be associated with mismatch repair (MMR)-deficiency, <i>BRAF</i> mutation, and "stem-like" immunophenotype defined by down-regulation of homeobox protein CDX2 and membranous expression of activated leukocyte cell adhesion molecule (ALCAM). However, the immunophenotype and genotype of C ...[more]

PMID: 29085667

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Project description:The effects of non-amplification short variant (SV) mutations in CD274 (programmed death-ligand 1 (PD-L1)) on PD-L1 protein expression and immune checkpoint inhibitors (ICPIs) therapy are unknown. Here, we present a retrospective analysis of CD274 mutations detected by comprehensive genomic profiling (CGP) and correlate these results with tumor-cell PD-L1 immunohistochemistry (IHC)-based expression assessment to better understand the relationship between mutations and protein expression of PD-L1. CGP was performed on hybridization-captured, adaptor ligation-based libraries using DNA and/or RNA extracted from 314,631 tumor samples that were sequenced for up to 406 cancer-related genes and select gene rearrangements. PD-L1 IHC was performed on a subset of cases (n=58,341) using the DAKO 22C3 PD-L1 IHC assay and scored with the tumor proportion score (TPS). Overall, the prevalence of CD274 SV mutations was low (0.3%, 1081/314,631) with 577 unique variants. The most common CD274 SV mutations were R260H (n=51), R260C (n=18), R125Q (n=12), C272fs*13 (n=11), R86W (n=10), and R113H (n=10). The prevalence of CD274 mutations varied depending on tumor type with diffuse large B-cell lymphoma (1.9%, 19/997), cutaneous squamous cell carcinoma (1.6%, 14/868), endometrial adenocarcinoma (1.0%, 36/3740), unknown primary melanoma (0.9%, 33/3679), and cutaneous melanoma (0.8%, 32/3874) having the highest frequency of mutations. Of the R260H cases concurrently tested with PD-L1 IHC, most (81.8%, 9/11) had no PD-L1 expression, which contrasts to the five E237K cases where most (80%, 4/5) had PD-L1 expression. In addition, we saw a significantly lower level of PD-L1 expression in samples with a clonal truncating variant (nonsense or frameshift indel) when compared with samples with a subclonal truncating variants (mean: TPS=1 vs TPS=38; p<0.001), and also in clonal versus subclonal missense mutations (mean: TPS=11 vs TPS=22, respectively; p=0.049) CONCLUSIONS: We defined the landscape of CD274 mutations in a large cohort of tumor types that can be used as a reference for examining CD274 mutations as potential resistance biomarkers for ICPI. Furthermore, we presented novel data on the correlation of CD274 mutations and PD-L1 protein expression, providing important new information on the potential functionality of these mutations and can serve as a basis for future research.

Dataset Information

Histopathological and genotypic characterization of metastatic colorectal carcinoma with PD-L1 (CD274)-expression: Possible roles of tumour micro environmental factors for CD274 expression.

Publications

Histopathological and genotypic characterization of metastatic colorectal carcinoma with PD-L1 (CD274)-expression: Possible roles of tumour micro environmental factors for CD274 expression.

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