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Molecular Diagnostics

SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer

Abstract

Background

Colorectal cancer (CRC) develops through chromosomal instability (CIN) or microsatellite instability (MSI) due to deficient mismatch-repair (dMMR). We aimed to characterise novel cancer-associated genes that are downregulated upon malignant transformation in microsatellite stable (MSS) CRCs, which typically exhibit CIN with proficient mismatch-repair (pMMR).

Methods

Comprehensive screening was conducted on adenomas, MSI/MSS CRCs and cell lines, followed by copy number analysis, and their genetic and prognostic relevance was confirmed in microarray and RNA-seq cohorts (n = 3262, in total). Immunohistochemistry for SH2D4A was performed in 524 specimens of adenoma, carcinoma in situ and dMMR/pMMR CRC. The functional role of SH2D4A was investigated using CRC cell lines.

Results

A set of 11 genes, including SH2D4A, was downregulated during the adenoma-carcinoma sequence in MSS/CIN CRCs, mainly due to chromosome 8p deletions, and their negative prognostic impact was validated in independent cohorts. All adenomas were SH2D4A positive, but a subset of CRCs (5.3%) lacked SH2D4A immunohistochemical staining, correlating with poor prognosis and scarce T cell infiltration. SH2D4A depletion did not affect cell proliferation or IL-6-induced STAT3 phosphorylation.

Conclusions

Our findings suggest that downregulation of multiple genes on chromosome 8p, including SH2D4A, cooperatively contribute to tumorigenesis, resulting in the immune cold tumour microenvironment and poor prognosis.

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Fig. 1: Identification of 11 genes on chromosome 8p, including SH2D4A, that were downregulated through the adenoma-carcinoma sequence particularly in microsatellite stable (MSS) colorectal cancer (CRC) compared to microsatellite unstable (MSI) CRC.
Fig. 2: Validation of clinical and prognostic association of SH2D4A and the 11-gene signature in multiple independent cohorts.
Fig. 3: The association of SH2D4A expression with genetic, epigenetic and clinical features.
Fig. 4: Immunohistochemistry for SH2D4A expression in adenoma and carcinoma specimens.
Fig. 5: SH2D4A depletion and IL-6-induced nuclear and cytoplasmic STAT3 phosphorylation in CRC cell lines.

Data availability

The public datasets used in this study are available from the GEO database (http://www.ncbi.nlm.nih.gov/geo).

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Funding

This work was supported by grants from Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 20K09061 and 20K08963.

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Authors

Contributions

HO and KK provided the study concept and design. HO, YK, HO, SH, SF, WS, MS, ZS and TM collected the data. TM, SN, KS, MI and AK performed the experiments. TM, HO, SN and KM interpret the data. TM, HO and KK wrote the paper.

Corresponding author

Correspondence to Hirokazu Okayama.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study was conducted in compliance with the declaration of Helsinki. The study was approved by the Institutional Review Board of Fukushima Medical University (No. 2289 and No. 2847), and samples were obtained with the patients’ informed consent.

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Matsumoto, T., Okayama, H., Nakajima, S. et al. SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer. Br J Cancer 126, 917–926 (2022). https://doi.org/10.1038/s41416-021-01660-y

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