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Published in: World Journal of Surgical Oncology 1/2015

Open Access 01-12-2015 | Research

A comprehensive analysis of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss in colorectal cancer

Authors: Pei-Ching Lin, Jen-Kou Lin, Hung-Hsin Lin, Yuan-Tzu Lan, Chun-Chi Lin, Shung-Haur Yang, Wei-Shone Chen, Wen-Yi Liang, Jeng-Kai Jiang, Shih-Ching Chang

Published in: World Journal of Surgical Oncology | Issue 1/2015

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Abstract

Background

Alterations of PTEN, regulator of the PTEN/PI3K-AKT pathway, are common in several types of cancer. This study aimed to do comprehensive analysis of PTEN in colorectal cancer patients.

Methods

Totally, 198 colorectal cancer patients who received surgery at Taipei Veterans General Hospital from 2006 to 2008 were enrolled. Mutations, loss of protein expression, promoter hypermethylation, and DNA copy number of PTEN were analyzed by sequencing, immunohistochemistry, methylation-specific polymerase chain reaction PCR, and quantitative (QPCR), respectively, and correlated with clinicopathological features and patients’ outcome.

Results

Genomic mutations, loss of protein expression, promoter hypermethylation, and decreased DNA copy number of PTEN were found in 4 (2.02 %), 68 (34.3 %), 54 (27.3 %), and 36 (18.2 %) tumors, respectively. Of these 68 tumors with loss expression of PTEN, 34 (50 %) tumors had promoter methylation and 18 (26.5 %) had decreased DNA copy number. All four tumors with PTEN mutations demonstrated loss of PTEN expression. In the stage I disease, frequency of loss of PTEN expression was 20 % and significantly increased to 56.9 % in stage IV disease. Either loss expression of PTEN, PTEN hypermethylation or decreased PTEN copy number was not associated with colorectal cancer (CRC) patients’ outcome.

Conclusions

PTEN alterations were found in up to one-third of colorectal cancers but did not impact CRC patients’ prognosis.
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Literature
1.
go back to reference Healthy statistics: cancer registry annual report in Taiwan area. The Ministry of Health and Welfare, the Executive Yuan, Taiwan; 2007. Healthy statistics: cancer registry annual report in Taiwan area. The Ministry of Health and Welfare, the Executive Yuan, Taiwan; 2007.
2.
3.
go back to reference Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319(9):525–32. doi:10.1056/nejm198809013190901.CrossRefPubMed Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319(9):525–32. doi:10.1056/nejm198809013190901.CrossRefPubMed
4.
go back to reference Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4(12):988–1004. doi:10.1038/nrd1902.CrossRefPubMed Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4(12):988–1004. doi:10.1038/nrd1902.CrossRefPubMed
5.
go back to reference Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27(13):2278–87. doi:10.1200/jco.2008.20.0766.CrossRefPubMedCentralPubMed Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27(13):2278–87. doi:10.1200/jco.2008.20.0766.CrossRefPubMedCentralPubMed
6.
go back to reference Agarwal R, Carey M, Hennessy B, Mills GB. PI3K pathway-directed therapeutic strategies in cancer. Curr Opin Investig Drugs. 2010;11(6):615–28.PubMed Agarwal R, Carey M, Hennessy B, Mills GB. PI3K pathway-directed therapeutic strategies in cancer. Curr Opin Investig Drugs. 2010;11(6):615–28.PubMed
7.
go back to reference Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997;57(11):2124–9.PubMed Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997;57(11):2124–9.PubMed
8.
go back to reference Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. 2009;16(2):115–25. doi:10.1016/j.ccr.2009.06.006.CrossRefPubMedCentralPubMed Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. 2009;16(2):115–25. doi:10.1016/j.ccr.2009.06.006.CrossRefPubMedCentralPubMed
9.
go back to reference Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, et al. Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 2009;69(10):4192–201. doi:10.1158/0008-5472.can-09-0042.CrossRefPubMedCentralPubMed Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, et al. Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 2009;69(10):4192–201. doi:10.1158/0008-5472.can-09-0042.CrossRefPubMedCentralPubMed
10.
go back to reference Naguib A, Cooke JC, Happerfield L, Kerr L, Gay LJ, Luben RN, et al. Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors. BMC Cancer. 2011;11:123. doi:10.1186/1471-2407-11-123.CrossRefPubMedCentralPubMed Naguib A, Cooke JC, Happerfield L, Kerr L, Gay LJ, Luben RN, et al. Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors. BMC Cancer. 2011;11:123. doi:10.1186/1471-2407-11-123.CrossRefPubMedCentralPubMed
11.
go back to reference Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004;64(9):3014–21.CrossRefPubMed Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004;64(9):3014–21.CrossRefPubMed
12.
go back to reference Nassif NT, Lobo GP, Wu X, Henderson CJ, Morrison CD, Eng C, et al. PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene. 2004;23(2):617–28. doi:10.1038/sj.onc.1207059.CrossRefPubMed Nassif NT, Lobo GP, Wu X, Henderson CJ, Morrison CD, Eng C, et al. PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene. 2004;23(2):617–28. doi:10.1038/sj.onc.1207059.CrossRefPubMed
13.
go back to reference Zhou XP, Loukola A, Salovaara R, Nystrom-Lahti M, Peltomaki P, de la Chapelle A, et al. PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am J Pathol. 2002;161(2):439–47. doi:10.1016/s0002-9440(10)64200-9.CrossRefPubMedCentralPubMed Zhou XP, Loukola A, Salovaara R, Nystrom-Lahti M, Peltomaki P, de la Chapelle A, et al. PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am J Pathol. 2002;161(2):439–47. doi:10.1016/s0002-9440(10)64200-9.CrossRefPubMedCentralPubMed
14.
go back to reference Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006;31(2):89–97. doi:10.1016/j.tibs.2005.12.008.CrossRefPubMed Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006;31(2):89–97. doi:10.1016/j.tibs.2005.12.008.CrossRefPubMed
15.
go back to reference Garcia JM, Rodriguez R, Silva J, Munoz C, Dominguez G, Silva JM, et al. Intratumoral heterogeneity in microsatellite alterations in BRCA1 and PTEN regions in sporadic colorectal cancer. Ann Surg Oncol. 2003;10(8):876–81.CrossRefPubMed Garcia JM, Rodriguez R, Silva J, Munoz C, Dominguez G, Silva JM, et al. Intratumoral heterogeneity in microsatellite alterations in BRCA1 and PTEN regions in sporadic colorectal cancer. Ann Surg Oncol. 2003;10(8):876–81.CrossRefPubMed
16.
go back to reference Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, et al. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000;124(7):979–94. doi:10.1043/0003-9985(2000)124<0979:pficc>2.0.co;2.PubMed Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, et al. Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med. 2000;124(7):979–94. doi:10.1043/0003-9985(2000)124<0979:pficc>2.0.co;2.PubMed
17.
go back to reference Lin JK, Lin AJ, Lin CC, Lan YT, Yang SH, Li AF, et al. The status of EGFR-associated genes could predict the outcome and tumor response of chemo-refractory metastatic colorectal patients using cetuximab and chemotherapy. J Surg Oncol. 2011;104(6):661–6. doi:10.1002/jso.21993.CrossRefPubMed Lin JK, Lin AJ, Lin CC, Lan YT, Yang SH, Li AF, et al. The status of EGFR-associated genes could predict the outcome and tumor response of chemo-refractory metastatic colorectal patients using cetuximab and chemotherapy. J Surg Oncol. 2011;104(6):661–6. doi:10.1002/jso.21993.CrossRefPubMed
18.
go back to reference Price TJ, Hardingham JE, Lee CK, Townsend AR, Wrin JW, Wilson K, et al. Prognostic impact and the relevance of PTEN copy number alterations in patients with advanced colorectal cancer (CRC) receiving bevacizumab. Cancer Med. 2013;2(3):277–85. doi:10.1002/cam4.75.CrossRefPubMedCentralPubMed Price TJ, Hardingham JE, Lee CK, Townsend AR, Wrin JW, Wilson K, et al. Prognostic impact and the relevance of PTEN copy number alterations in patients with advanced colorectal cancer (CRC) receiving bevacizumab. Cancer Med. 2013;2(3):277–85. doi:10.1002/cam4.75.CrossRefPubMedCentralPubMed
19.
go back to reference Jones N, Bonnet F, Sfar S, Lafitte M, Lafon D, Sierankowski G, et al. Comprehensive analysis of PTEN status in breast carcinomas. Int J Cancer. 2013;133(2):323–34. doi:10.1002/ijc.28021.CrossRefPubMed Jones N, Bonnet F, Sfar S, Lafitte M, Lafon D, Sierankowski G, et al. Comprehensive analysis of PTEN status in breast carcinomas. Int J Cancer. 2013;133(2):323–34. doi:10.1002/ijc.28021.CrossRefPubMed
20.
go back to reference Danielsen SA, Lind GE, Bjornslett M, Meling GI, Rognum TO, Heim S, et al. Novel mutations of the suppressor gene PTEN in colorectal carcinomas stratified by microsatellite instability- and TP53 mutation- status. Hum Mutat. 2008;29(11):E252–62. doi:10.1002/humu.20860.CrossRefPubMed Danielsen SA, Lind GE, Bjornslett M, Meling GI, Rognum TO, Heim S, et al. Novel mutations of the suppressor gene PTEN in colorectal carcinomas stratified by microsatellite instability- and TP53 mutation- status. Hum Mutat. 2008;29(11):E252–62. doi:10.1002/humu.20860.CrossRefPubMed
21.
go back to reference Guanti G, Resta N, Simone C, Cariola F, Demma I, Fiorente P, et al. Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis. Hum Mol Genet. 2000;9(2):283–7.CrossRefPubMed Guanti G, Resta N, Simone C, Cariola F, Demma I, Fiorente P, et al. Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis. Hum Mol Genet. 2000;9(2):283–7.CrossRefPubMed
22.
go back to reference Chang JG, Chen YJ, Perng LI, Wang NM, Kao MC, Yang TY, et al. Mutation analysis of the PTEN/MMAC1 gene in cancers of the digestive tract. Eur J Cancer. 1999;35(4):647–51.CrossRefPubMed Chang JG, Chen YJ, Perng LI, Wang NM, Kao MC, Yang TY, et al. Mutation analysis of the PTEN/MMAC1 gene in cancers of the digestive tract. Eur J Cancer. 1999;35(4):647–51.CrossRefPubMed
23.
go back to reference Dicuonzo G, Angeletti S, Garcia-Foncillas J, Brugarolas A, Okrouzhnov Y, Santini D, et al. Colorectal carcinomas and PTEN/MMAC1 gene mutations. Clin Cancer Res. 2001;7(12):4049–53.PubMed Dicuonzo G, Angeletti S, Garcia-Foncillas J, Brugarolas A, Okrouzhnov Y, Santini D, et al. Colorectal carcinomas and PTEN/MMAC1 gene mutations. Clin Cancer Res. 2001;7(12):4049–53.PubMed
24.
go back to reference Bamford S, Dawson E, Forbes S, Clements J, Pettett R, Dogan A, et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer. 2004;91(2):355–8. doi:10.1038/sj.bjc.6601894.PubMedCentralPubMed Bamford S, Dawson E, Forbes S, Clements J, Pettett R, Dogan A, et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer. 2004;91(2):355–8. doi:10.1038/sj.bjc.6601894.PubMedCentralPubMed
25.
go back to reference Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007;97(8):1139–45. doi:10.1038/sj.bjc.6604009.CrossRefPubMedCentralPubMed Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007;97(8):1139–45. doi:10.1038/sj.bjc.6604009.CrossRefPubMedCentralPubMed
26.
go back to reference Molinari F, Martin V, Saletti P, De Dosso S, Spitale A, Camponovo A, et al. Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br J Cancer. 2009;100(7):1087–94. doi:10.1038/sj.bjc.6604848.CrossRefPubMedCentralPubMed Molinari F, Martin V, Saletti P, De Dosso S, Spitale A, Camponovo A, et al. Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br J Cancer. 2009;100(7):1087–94. doi:10.1038/sj.bjc.6604848.CrossRefPubMedCentralPubMed
27.
go back to reference Hsu CP, Kao TY, Chang WL, Nieh S, Wang HL, Chung YC. Clinical significance of tumor suppressor PTEN in colorectal carcinoma. Eur J Surg Oncol. 2011;37(2):140–7. doi:10.1016/j.ejso.2010.12.003.CrossRefPubMed Hsu CP, Kao TY, Chang WL, Nieh S, Wang HL, Chung YC. Clinical significance of tumor suppressor PTEN in colorectal carcinoma. Eur J Surg Oncol. 2011;37(2):140–7. doi:10.1016/j.ejso.2010.12.003.CrossRefPubMed
28.
go back to reference Jang KS, Song YS, Jang SH, Min KW, Na W, Jang SM, et al. Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma. Histopathology. 2010;56(2):229–39. doi:10.1111/j.1365-2559.2009.03468.x.CrossRefPubMed Jang KS, Song YS, Jang SH, Min KW, Na W, Jang SM, et al. Clinicopathological significance of nuclear PTEN expression in colorectal adenocarcinoma. Histopathology. 2010;56(2):229–39. doi:10.1111/j.1365-2559.2009.03468.x.CrossRefPubMed
30.
go back to reference Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH, et al. The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res. 2001;61(20):7426–9.PubMed Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH, et al. The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res. 2001;61(20):7426–9.PubMed
31.
go back to reference Roy HK, Olusola BF, Clemens DL, Karolski WJ, Ratashak A, Lynch HT, et al. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis. 2002;23(1):201–5.CrossRefPubMed Roy HK, Olusola BF, Clemens DL, Karolski WJ, Ratashak A, Lynch HT, et al. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis. 2002;23(1):201–5.CrossRefPubMed
32.
go back to reference Yu M, Trobridge P, Wang Y, Kanngurn S, Morris SM, Knoblaugh S, et al. Inactivation of TGF-beta signaling and loss of PTEN cooperate to induce colon cancer in vivo. Oncogene. 2014;33(12):1538–47. doi:10.1038/onc.2013.102.CrossRefPubMedCentralPubMed Yu M, Trobridge P, Wang Y, Kanngurn S, Morris SM, Knoblaugh S, et al. Inactivation of TGF-beta signaling and loss of PTEN cooperate to induce colon cancer in vivo. Oncogene. 2014;33(12):1538–47. doi:10.1038/onc.2013.102.CrossRefPubMedCentralPubMed
Metadata
Title
A comprehensive analysis of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) loss in colorectal cancer
Authors
Pei-Ching Lin
Jen-Kou Lin
Hung-Hsin Lin
Yuan-Tzu Lan
Chun-Chi Lin
Shung-Haur Yang
Wei-Shone Chen
Wen-Yi Liang
Jeng-Kai Jiang
Shih-Ching Chang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
World Journal of Surgical Oncology / Issue 1/2015
Electronic ISSN: 1477-7819
DOI
https://doi.org/10.1186/s12957-015-0601-y

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