SH2D4A downregulation due to loss of chromosome 8p is associated with poor prognosis and low T cell infiltration in colorectal cancer.
Chromosomes, Human, Pair 8
/ genetics
Colorectal Neoplasms
/ genetics
DNA Mismatch Repair
Down-Regulation
Humans
Intracellular Signaling Peptides and Proteins
/ genetics
Lymphocytes, Tumor-Infiltrating
/ immunology
Microsatellite Instability
Monosomy
/ genetics
Prognosis
T-Lymphocytes
Tumor Microenvironment
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
11
06
2021
accepted:
30
11
2021
revised:
21
11
2021
pubmed:
12
12
2021
medline:
6
4
2022
entrez:
11
12
2021
Statut:
ppublish
Résumé
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). 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 34893760
doi: 10.1038/s41416-021-01660-y
pii: 10.1038/s41416-021-01660-y
pmc: PMC8927606
doi:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
SH2D4A protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
917-926Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021. https://doi.org/10.3322/caac.21660.
doi: 10.3322/caac.21660.
pubmed: 33538338
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.
doi: 10.1126/science.1235122
Sansregret L, Vanhaesebroeck B, Swanton C. Determinants and clinical implications of chromosomal instability in cancer. Nat Rev Clin Oncol. 2018;15:139–50.
doi: 10.1038/nrclinonc.2017.198
Nguyen LH, Goel A, Chung DC. Pathways of Colorectal Carcinogenesis. Gastroenterology. 2020;158:291–302.
doi: 10.1053/j.gastro.2019.08.059
Network, T. C. G. A. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.
doi: 10.1038/nature11252
Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138:2059–72.
doi: 10.1053/j.gastro.2009.12.065
Shih IM, Zhou W, Goodman SN, Lengauer C, Kinzler KW, Vogelstein B. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res. 2001;61:818–22.
pubmed: 11221861
Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394:1467–80.
doi: 10.1016/S0140-6736(19)32319-0
Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, Shia J, Segal NH, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019;16:361–75.
doi: 10.1038/s41575-019-0126-x
Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6.
doi: 10.1038/nm.3967
Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science. 2017;355:eaaf8399.
doi: 10.1126/science.aaf8399
Taylor AM, Shih J, Ha G, Gao GF, Zhang X, Berger AC, et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell. 2018;33:676–89 e673.
doi: 10.1016/j.ccell.2018.03.007
Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, et al. The immune landscape of cancer. Immunity. 2018;48:812–30 e814.
doi: 10.1016/j.immuni.2018.03.023
Bakhoum SF, Cantley LC. The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell. 2018;174:1347–60.
doi: 10.1016/j.cell.2018.08.027
Kwon J, Bakhoum SF. The cytosolic DNA-sensing cGAS-STING pathway in cancer. Cancer Discov. 2020;10:26–39.
doi: 10.1158/2159-8290.CD-19-0761
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.
doi: 10.1126/scisignal.2004088
Liu Y, Sethi NS, Hinoue T, Schneider BG, Cherniack AD, Sanchez-Vega F, et al. Comparative molecular analysis of gastrointestinal adenocarcinomas. Cancer Cell. 2018;33:721–35 e728.
doi: 10.1016/j.ccell.2018.03.010
Endo E, Okayama H, Saito K, Nakajima S, Yamada L, Ujiie D, et al. A TGFbeta-dependent stromal subset underlies immune checkpoint inhibitor efficacy in DNA mismatch repair-deficient/microsatellite instability-high colorectal cancer. Mol Cancer Res. 2020;18:1402–13.
doi: 10.1158/1541-7786.MCR-20-0308
Vasaikar S, Huang C, Wang X, Petyuk VA, Savage SR, Wen B, et al. Proteogenomic analysis of human colon cancer reveals new therapeutic opportunities. Cell. 2019;177:1035–49 e1019.
doi: 10.1016/j.cell.2019.03.030
Sheffer M, Bacolod MD, Zuk O, Giardina SF, Pincas H, Barany F, et al. Association of survival and disease progression with chromosomal instability: a genomic exploration of colorectal cancer. Proc Natl Acad Sci USA. 2009;106:7131–6.
doi: 10.1073/pnas.0902232106
Medico E, Russo M, Picco G, Cancelliere C, Valtorta E, Corti G, et al. The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets. Nat Commun. 2015;6:7002.
doi: 10.1038/ncomms8002
Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.
doi: 10.1038/ncomms3612
Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.
doi: 10.1038/nprot.2008.211
Japanese Society for Cancer of the Colon and Rectum. Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma: the 3d English Edition [Secondary Publication]. J Anus Rectum Colon. 2019;3:175–95.
Noda M, Okayama H, Tachibana K, Sakamoto W, Saito K, Thar Min AK, et al. Glycosyltransferase gene expression identifies a poor prognostic colorectal cancer subtype associated with mismatch repair deficiency and incomplete glycan synthesis. Clin Cancer Res. 2018;24:4468–81.
doi: 10.1158/1078-0432.CCR-17-3533
Roessler S, Long EL, Budhu A, Chen Y, Zhao X, Ji J, et al. Integrative genomic identification of genes on 8p associated with hepatocellular carcinoma progression and patient survival. Gastroenterology. 2012;142:957–66 e912.
doi: 10.1053/j.gastro.2011.12.039
Quagliata L, Andreozzi M, Kovac M, Tornillo L, Makowska Z, Moretti F, et al. SH2D4A is frequently downregulated in hepatocellular carcinoma and cirrhotic nodules. Eur J Cancer. 2014;50:731–8.
doi: 10.1016/j.ejca.2013.11.018
Ploeger C, Waldburger N, Fraas A, Goeppert B, Pusch S, Breuhahn K, et al. Chromosome 8p tumor suppressor genes SH2D4A and SORBS3 cooperate to inhibit interleukin-6 signaling in hepatocellular carcinoma. Hepatology. 2016;64:828–42.
doi: 10.1002/hep.28684
Birnbaum D, Adelaide J, Popovici C, Charafe-Jauffret E, Mozziconacci MJ, Chaffanet M. Chromosome arm 8p and cancer: a fragile hypothesis. Lancet Oncol. 2003;4:639–42.
doi: 10.1016/S1470-2045(03)01225-7
Cai Y, Crowther J, Pastor T, Abbasi Asbagh L, Baietti MF, De Troyer M, et al. Loss of chromosome 8p governs tumor progression and drug response by altering lipid metabolism. Cancer Cell. 2016;29:751–66.
doi: 10.1016/j.ccell.2016.04.003
Lebok P, Mittenzwei A, Kluth M, Ozden C, Taskin B, Hussein K, et al. 8p deletion is strongly linked to poor prognosis in breast cancer. Cancer Biol Ther. 2015;16:1080–7.
doi: 10.1080/15384047.2015.1046025
Kluth M, Amschler NN, Galal R, Moller-Koop C, Barrow P, Tsourlakis MC, et al. Deletion of 8p is an independent prognostic parameter in prostate cancer. Oncotarget. 2017;8:379–92.
doi: 10.18632/oncotarget.13425
El Gammal AT, Bruchmann M, Zustin J, Isbarn H, Hellwinkel OJ, Kollermann J, et al. Chromosome 8p deletions and 8q gains are associated with tumor progression and poor prognosis in prostate cancer. Clin Cancer Res. 2010;16:56–64.
doi: 10.1158/1078-0432.CCR-09-1423
Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179.
doi: 10.1038/srep15179
Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, et al. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med. 2016;22:679–84.
doi: 10.1038/nm.4086
Saleh R, Elkord E. FoxP3(+) T regulatory cells in cancer: prognostic biomarkers and therapeutic targets. Cancer Lett. 2020;490:174–85.
doi: 10.1016/j.canlet.2020.07.022
Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463:899–905.
doi: 10.1038/nature08822
Xue W, Kitzing T, Roessler S, Zuber J, Krasnitz A, Schultz N, et al. A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions. Proc Natl Acad Sci USA. 2012;109:8212–7.
doi: 10.1073/pnas.1206062109
Muleris M, Chalastanis A, Meyer N, Lae M, Dutrillaux B, Sastre-Garau X, et al. Chromosomal instability in near-diploid colorectal cancer: a link between numbers and structure. PLoS ONE. 2008;3:e1632.
doi: 10.1371/journal.pone.0001632