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- Title
SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer.
- Authors
Matsumoto, Takuro; Okayama, Hirokazu; Nakajima, Shotaro; Saito, Katsuharu; Ito, Misato; Kaneta, Akinao; Kanke, Yasuyuki; Onozawa, Hisashi; Hayase, Suguru; Fujita, Shotaro; Sakamoto, Wataru; Saito, Motonobu; Seze, Zenichiro; Momma, Tomoyuki; Mimura, Kosaku; Kono, Koji
- Abstract
<bold>Background: </bold>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).<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
British Journal of Cancer, 2022, Vol 126, Issue 6, p917
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-021-01660-y