Clinical significance of SPOP and APC gene alterations in colorectal cancer in Indian population.
Chemoradiotherapy
Colorectal cancer
Gene expression
Methylation
Mutation
SPOP
Journal
Molecular genetics and genomics : MGG
ISSN: 1617-4623
Titre abrégé: Mol Genet Genomics
Pays: Germany
ID NLM: 101093320
Informations de publication
Date de publication:
Sep 2023
Sep 2023
Historique:
received:
16
11
2022
accepted:
29
04
2023
medline:
24
7
2023
pubmed:
8
6
2023
entrez:
8
6
2023
Statut:
ppublish
Résumé
Speckle-Type Poz Protein (SPOP) involved in the regulation of proteasome-mediated degradation of several oncoproteins, resulting in cancer initiation and progression. Mutations in Adenomatous Polyposis Coli (APC) gene is reported in most sporadic and hereditary colorectal cancer (CRC). Identifying the cellular changes involved in carcinogenesis when APC is mutated is an important issue that needs attention. The tumor suppressive function of SPOP and APC has long been a major focus in the research field of colorectal cancer. However, the clinical significance of SPOP and APC gene alteration in CRC has not been established to date. Mutational analysis was performed by single-strand conformational polymorphism followed by Sanger sequencing, methylation status by methylation-specific PCR, and protein expression by immunohistochemistry on 142 tumor tissues along with their adjacent non-cancerous specimens. The overall survival (OS) and recurrence free survival (RFS) were estimated by Kaplan-Meier Curve. Mutation rates of APC and SPOP gene were 2.8% and 11.9% while that of promoter hypermethylation were 37% and 47%, respectively. The grade of differentiation and Lymph node metastasis were significantly correlated with APC methylation pattern (p ≤ 0.05). The down regulation of APC was more often seen in colonic cancer compared to rectal cancer (p = 0.07) and more commonly in T3-4 depth of invasion (p = 0.07) and in patients without lymphovascular and perineural invasion (p = 0.007, p = 0.08 respectively). The median overall survival and recurrence free survival (RFS) was 67 & 36 months while 3-yr and 5-yr OS and RFS were 61.1% & 56.4% and 49.2% & 44.8%, respectively. APC promoter methylation had a better overall survival (p = 0.035) while loss of SPOP expression had a worse survival (p = 0.09). Our findings reveal high percentage of SPOP gene mutations in CRC. A significant link is found between promoter hyper methylation and protein expression in all mutant cases of APC and SPOP, suggesting that both genes may be associated in the development of colorectal cancer in people of Indian decent. Hypermethylation of APC gene and loss of SPOP expression have shown an association with disease prognosis and could be further studied looking at its potential role in planning adjuvant treatment in CRC patients.
Identifiants
pubmed: 37289229
doi: 10.1007/s00438-023-02029-x
pii: 10.1007/s00438-023-02029-x
doi:
Substances chimiques
SPOP protein, human
0
Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1087-1105Subventions
Organisme : Indian Council of Medical Research
ID : 2013-1129
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Ali A, Mishra PKPK, Sharma S, Arora A, Saluja SSSS (2015) Effects of PTEN gene alteration in patients with gallbladder cancer. Cancer Genet 208:587–594. https://doi.org/10.1016/j.cancergen.2015.09.007
doi: 10.1016/j.cancergen.2015.09.007
pubmed: 26586294
Alwers E, Jia M, Kloor M, Bläker H, Brenner H, Hoffmeister M (2019) Associations between molecular classifications of colorectal cancer and patient survival: a systematic review. Clin Gastroenterol Hepatol 17:402–410. https://doi.org/10.1016/j.cgh.2017.12.038
doi: 10.1016/j.cgh.2017.12.038
pubmed: 29306042
Androvic P, Valihrach L, Elling J, Sjoback R, Kubista M (2017) Two-tailed RT-qPCR: a novel method for highly accurate miRNA quantification. Nucl Acids Res. https://doi.org/10.1093/nar/gkx588
doi: 10.1093/nar/gkx588
pubmed: 28911110
pmcid: 5587787
Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY, Sboner A, Esgueva R, Pflueger D, Sougnez C, Onofrio R, Carter SL, Park K, Habegger L, Ambrogio L, Fennell T, Parkin M, Saksena G, Voet D, Ramos AH, Pugh TJ, Wilkinson J, Fisher S, Winckler W, Mahan S, Ardlie K, Baldwin J, Simons JW, Kitabayashi N, MacDonald TY, Kantoff PW, Chin L, Gabriel SB, Gerstein MB, Golub TR, Meyerson M, Tewari A, Lander ES, Getz G, Rubin MA, Garraway LA (2011) The genomic complexity of primary human prostate cancer. Nature 470:214–220. https://doi.org/10.1038/nature09744
doi: 10.1038/nature09744
pubmed: 21307934
pmcid: 3075885
Bishehsari F, Mahdavinia M, Vacca M, Malekzadeh R, Mariani-Costantini R (2014) Epidemiological transition of colorectal cancer in developing countries: environmental factors, molecular pathways, and opportunities for prevention. World J Gastroenterol 20:6055–6072. https://doi.org/10.3748/wjg.v20.i20.6055
doi: 10.3748/wjg.v20.i20.6055
pubmed: 24876728
pmcid: 4033445
Bo BL, Eun JL, Eun HJ, Chun HK, Dong KC, Sang YS, Park J, Kim DH (2009) Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer. Clin Cancer Res 15:6185–6191. https://doi.org/10.1158/1078-0432.CCR-09-0111
doi: 10.1158/1078-0432.CCR-09-0111
Bode AM, Dong Z (2004) Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4:793–805. https://doi.org/10.1038/nrc1455
doi: 10.1038/nrc1455
pubmed: 15510160
Cao Q, Bai P (2019) Role of autophagy in renal cancer. J Cancer 10:2501–2509. https://doi.org/10.7150/jca.29285
doi: 10.7150/jca.29285
pubmed: 31258756
pmcid: 6584354
Chen SP, Chiu SC, Wu CC, Lin SZ, Kang JC, Chen YL, Lin PC, Pang CY, Harn HJ (2009) The association of methylation in the promoter of APC and MGMT and the prognosis of Taiwanese CRC patients. Genet Test Mol Biomarkers 13:67–71. https://doi.org/10.1089/gtmb.2008.0045
doi: 10.1089/gtmb.2008.0045
pubmed: 19309276
Chen X, Liu L, Mims J, Punska EC, Williams KE, Zhao W, Arcaro KF, Tsang AW, Zhou X, Furdui CM (2015) Analysis of DNA methylation and gene expression in radiation-resistant head and neck tumors. Epigenetics 10:545–561. https://doi.org/10.1080/15592294.2015.1048953
doi: 10.1080/15592294.2015.1048953
pubmed: 25961636
pmcid: 4622425
Clark A, Burleson M (2020) SPOP and cancer: a systematic review. Am J Cancer Res 10:704–726
pubmed: 32266086
pmcid: 7136909
Coppedè F, Lopomo A, Spisni R, Migliore L (2014) Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer. World J Gastroenterol 20:943–956. https://doi.org/10.3748/wjg.v20.i4.943
doi: 10.3748/wjg.v20.i4.943
pubmed: 24574767
pmcid: 3921546
DeLair DF, Burke KA, Selenica P, Lim RS, Scott SN, Middha S, Mohanty AS, Cheng DT, Berger MF, Soslow RA, Weigelt B (2017) The genetic landscape of endometrial clear cell carcinomas. Journal of Pathology 243:230–241. https://doi.org/10.1002/path.4947
doi: 10.1002/path.4947
pubmed: 28718916
Ding D, Song T, Jun W, Tan Z, Fang J (2015) Decreased expression of the SPOP gene is associated with poor prognosis in glioma. Int J Oncol 46:333–341. https://doi.org/10.3892/ijo.2014.2729
doi: 10.3892/ijo.2014.2729
pubmed: 25351530
Jones S, Stransky N, McCord CL, Cerami E, Lagowski J, Kelly D, Angiuoli SV, Sausen M, Kann L, Shukla M, Makar R, Wood LD, Diaz LA, Lengauer C, Velculescu VE (2014) Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes. Nat Commun. https://doi.org/10.1038/ncomms6006
doi: 10.1038/ncomms6006
pubmed: 25523894
Kim YS, Deng G (2007) Epigenetic changes (aberrant DNA methylation) in colorectal neoplasia. Gut Liver 1:1–11. https://doi.org/10.5009/gnl.2007.1.1.1
doi: 10.5009/gnl.2007.1.1.1
pubmed: 20485652
pmcid: 2871659
Kim MS, Je EM, Oh JE, Yoo NJ, Lee SH (2013) Mutational and expressional analyses Of SPOP, a candidate tumor suppressor gene, in prostate, gastric and colorectal cancers. APMIS 121:626–633. https://doi.org/10.1111/apm.12030
doi: 10.1111/apm.12030
pubmed: 23216165
Klaus A, Birchmeier W (2008) Wnt signalling and its impact on development and cancer. Nat Rev Cancer 8:387–398. https://doi.org/10.1038/nrc2389
doi: 10.1038/nrc2389
pubmed: 18432252
Le Gallo M, Bell DW (2014) The emerging genomic landscape of endometrial cancer. Clin Chem 60:98–110. https://doi.org/10.1373/clinchem.2013.205740
doi: 10.1373/clinchem.2013.205740
pubmed: 24170611
Li G, Ci W, Karmakar S, Chen K, Dhar R, Fan Z, Guo Z, Zhang J, Ke Y, Wang L, Zhuang M, Hu S, Li X, Zhou L, Li X, Calabrese MF, Watson ER, Prasad SM, Rinker-Schaeffer C, Eggener SE, Stricker T, Tian Y, Schulman BA, Liu J, White KP (2014) SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer. Cancer Cell 25:455–468. https://doi.org/10.1016/j.ccr.2014.02.007
doi: 10.1016/j.ccr.2014.02.007
pubmed: 24656772
pmcid: 4443692
Liang TJ, Wang HX, Zheng YY, Cao YQ, Wu X, Zhou X, Dong SX (2017) APC hypermethylation for early diagnosis of colorectal cancer: a meta-analysis and literature review. Oncotarget 8:46468–46479. https://doi.org/10.18632/oncotarget.17576
doi: 10.18632/oncotarget.17576
pubmed: 28515349
pmcid: 5542282
Merlo A, Herman JG, Mao L, Lee DJ, Gabrielson E, Burger PC, Baylin SB, Sidransky D (1995) 5’ CpG Island méthylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1:686–692. https://doi.org/10.1038/nm0795-686
doi: 10.1038/nm0795-686
pubmed: 7585152
Munteanu I, Mastalier B (2014) Genetics of colorectal cancer. J Med Life 7:507–511. https://doi.org/10.1016/b978-0-12-091075-5.50016-0
doi: 10.1016/b978-0-12-091075-5.50016-0
pubmed: 25713610
pmcid: 4316127
Nakayama KI, Nakayama K (2006) Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6:369–381. https://doi.org/10.1038/nrc1881
doi: 10.1038/nrc1881
pubmed: 16633365
Shi D, Grossman SR (2010) Ubiquitin becomes ubiquitous in cancer: emerging roles of ubiquitin ligases and deubiquitinases in tumorigenesis and as therapeutic targets. Cancer Biol Ther 10:737–747. https://doi.org/10.4161/cbt.10.8.13417
doi: 10.4161/cbt.10.8.13417
pubmed: 20930542
pmcid: 3023568
Wei X, Fried J, Li Y, Hu L, Gao M, Zhang S, Xu B (2018) Functional roles of speckle-type PoZ (SPOP) protein in genomic stability. Jo Cancer 9:3257–3262. https://doi.org/10.7150/jca.25930
doi: 10.7150/jca.25930
Xu Y, Pasche B (2007) TGF-β signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet 16:14–20. https://doi.org/10.1093/hmg/ddl486
doi: 10.1093/hmg/ddl486
Zhang L, Shay JW (2017) Multiple roles of APC and its therapeutic implications in colorectal cancer. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djw332
doi: 10.1093/jnci/djw332
pubmed: 29117356
pmcid: 6037061
Zhang P, Gao K, Jin X, Ma J, Peng J, Wumaier R, Tang Y, Zhang Y, An J, Yan Q, Dong Y, Huang H, Yu L, Wang C (2015) Endometrial cancer-associated mutants of SPOP are defective in regulating estrogen receptor-α protein turnover. Cell Death Dis 6:e1687. https://doi.org/10.1038/cddis.2015.47
doi: 10.1038/cddis.2015.47
pubmed: 25766326
pmcid: 4385925
Zhi X, Tao J, Zhang L, Tao R, Ma L, Qin J (2016) Silencing speckle-type POZ protein by promoter hypermethylation decreases cell apoptosis through upregulating hedgehog signaling pathway in colorectal cancer. Cell Death Dis 7:1–11. https://doi.org/10.1038/cddis.2016.435
doi: 10.1038/cddis.2016.435