Top

Published in:

Open Access 01-12-2016 | Research article

PTEN mRNA expression is less pronounced in left- than right-sided colon cancer: a retrospective observational study

Authors: Hidekazu Kuramochi, Ayako Nakamura, Go Nakajima, Yuka Kaneko, Tatsuo Araida, Masakazu Yamamoto, Kazuhiko Hayashi

Published in: BMC Cancer | Issue 1/2016

Abstract

Background

Several recent studies have reported that patients with metastatic colorectal cancer (CRC) whose primary tumor is located in left side of the colon have more favorable responses to anti-epidermal growth factor receptor (EGFR) antibody therapy than those with right-sided tumors. However, the mechanism for this phenomenon is unknown.

Methods

Fifty-two cases of primary CRC with liver metastases were analyzed in this retrospective study. The mRNA levels of 19 signal transduction genes in both primary tumor and liver metastases were measured by real-time reverse transcription polymerase chain reaction. The purposes of this study were (1) to determine the correspondence between signal transduction gene expressions in primary tumors and corresponding liver metastases, and (2) to determine whether expression levels of these genes differ by primary tumor location.

Results

mRNA expression levels of 14 of 19 signal transduction genes, including PTEN, ERBB2, MET, HGF, AREG, and EREG, showed significant correlations between the primary tumor and corresponding liver metastases. When the mRNA levels of the primary tumors were compared by tumor location, only PTEN mRNA expression differed significantly between left and right-sided CRC (median PTEN expression: left 1.00 vs. right 1.68; p = 0.017). When rectal cancers were separated from left-sided colon cancers, PTEN mRNA levels increased progressively from rectum to right-sided colon (median; rectum 0.84, left colon 1.23, right colon 1.68, p = 0.013). PTEN mRNA expression in liver metastases also differed significantly according to primary tumor location (median; left 0.92 vs. right 1.27, p = 0.048). There was no difference in overall survival between patients with high versus low levels of PTEN mRNA (p = 0.59).

Conclusions

Our data suggest that the PIK3/AKT/mTOR pathway is more active in left- than right-sided CRC, which provides a possible explanation for the fact that efficacy of anti-EGFR therapy differs by location of primary tumor.

Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–45. doi:10.1056/NEJMoa033025.CrossRefPubMed

Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658–64. doi:10.1200/JCO.2006.08.1620.CrossRefPubMed

Brule SY, Jonker DJ, Karapetis CS, O’Callaghan CJ, Moore MJ, Wong R, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51(11):1405–14. doi:10.1016/j.ejca.2015.03.015.CrossRefPubMed

von Einem JC, Heinemann V, von Weikersthal LF, Vehling-Kaiser U, Stauch M, Hass HG, et al. Left-sided primary tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer treated with cetuximab plus chemotherapy: an analysis of the AIO KRK-0104 trial. J Cancer Res Clin Oncol. 2014;140(9):1607–14. doi:10.1007/s00432-014-1678-3.CrossRef

Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med. 1990;113(10):779–88.CrossRefPubMed

Kaneko Y, Kuramochi H, Nakajima G, Inoue Y, Yamamoto M. Degraded DNA may induce discordance of KRAS status between primary colorectal cancer and corresponding liver metastases. Int J Clin Oncol. 2014;19(1):113–20. doi:10.1007/s10147-012-0507-4.CrossRefPubMed

Heinemann V, Modest DP, von Weikersthal LF, Decker T, Kiani A. Gender and tumor location as predictors for efficacy: Influence on endpoints in first-line treatment with FOLFIRI in combination with cetuximab or bevacizumab in the AIO KRK 0306 (FIRE3) trial. J Clin Oncol. 2014;32:5s. Abst. 3600.CrossRef

Loupakis F, Yang D, Yau L, Feng S, Cremolini C, Zhang W, et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst. 2015;107(3). doi:10.1093/jnci/dju427.

Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem/FEBS. 1999;263(3):605–11.CrossRef

10.

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

11.

Johnson SM, Gulhati P, Rampy BA, Han Y, Rychahou PG, Doan HQ, et al. Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J Am Coll Surg. 2010;210(5):767–76. doi:10.1016/j.jamcollsurg.2009.12.008. 76–8.CrossRefPubMedPubMedCentral

12.

Day FL, Jorissen RN, Lipton L, Mouradov D, Sakthianandeswaren A, Christie M, et al. PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in colorectal cancer. Clin Cancer Res. 2013;19(12):3285–96. doi:10.1158/1078-0432.CCR-12-3614.CrossRefPubMed

13.

Lan YT, Jen-Kou L, Lin CH, Yang SH, Lin CC, Wang HS, et al. Mutations in the RAS and PI3K pathways are associated with metastatic location in colorectal cancers. J Surg Oncol. 2015;111(7):905–10. doi:10.1002/jso.23895.CrossRefPubMed

14.

Sood A, McClain D, Maitra R, Basu-Mallick A, Seetharam R, Kaubisch A, et al. PTEN gene expression and mutations in the PIK3CA gene as predictors of clinical benefit to anti-epidermal growth factor receptor antibody therapy in patients with KRAS wild-type metastatic colorectal cancer. Clin Colorectal Cancer. 2012;11(2):143–50. doi:10.1016/j.clcc.2011.12.001.CrossRefPubMedPubMedCentral

15.

Frayling IM, Bodmer WF, Tomlinson IP. Allele loss in colorectal cancer at the Cowden disease/juvenile polyposis locus on 10q. Cancer Genet Cytogenet. 1997;97(1):64–9.CrossRefPubMed

16.

Razis E, Pentheroudakis G, Rigakos G, Bobos M, Kouvatseas G, Tzaida O, et al. EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab. J Cancer Res Clin Oncol. 2014;140(5):737–48. doi:10.1007/s00432-014-1626-2.CrossRefPubMed

17.

Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol. 2009;27(16):2622–9. doi:10.1200/JCO.2008.20.2796.CrossRefPubMed

18.

Karapetis CS, Jonker D, Daneshmand M, Hanson JE, O’Callaghan CJ, Marginean C, et al. PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer--results from NCIC CTG/AGITG CO.17. Clin Cancer Res. 2014;20(3):744–53. doi:10.1158/1078-0432.CCR-13-0606.CrossRefPubMed

19.

Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res. 2009;15(9):3184–8. doi:10.1158/1078-0432.CCR-08-2961.CrossRefPubMed

20.

Mao C, Wu XY, Yang ZY, Threapleton DE, Yuan JQ, Yu YY, et al. Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases. Sci Rep. 2015;5:8065. doi:10.1038/srep08065.CrossRefPubMedPubMedCentral

21.

Hocking C, Hardingham JE, Broadbridge V, Wrin J, Townsend AR, Tebbutt N, et al. Can we accurately report PTEN status in advanced colorectal cancer? BMC Cancer. 2014;14:128. doi:10.1186/1471-2407-14-128.CrossRefPubMedPubMedCentral

22.

Siena S, Sartore-Bianchi A, Lonardi S, Trusolino L, Martino C, Bencardino K, et al. Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients (mCRC): The HERACLES trial. J Clin Oncol. 2015;33(suppl;abstr 3508).

23.

Cunningham D, Tebbutt N, Davidenko I, Murad A, Al-Batran S, Ilson D, et al. Phase III, randomized, double-blind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as first-line therapy in patients (pts) with advanced MET-positive (pos) gastric or gastroesophageal junction (G/GEJ) cancer: RILOMET-1 study. J Clin Oncol. 2015;33(suppl;abstr 4000).

24.

Shah M, Bang Y, Lordick F, Tabernero J, Chen M, Hack S. METGastric: A phase III study of onartuzumab plus mFOLFOX6 in patients with metastatic HER2-negative (HER2-) and MET-positive (MET+) adenocarcinoma of the stomach or gastroesophageal junction (GEC). J Clin Oncol. 2015;33(suppl:abstr 4012).

25.

Spigel D, Edelman M, O’Byme K, Paz-Ares L, Shames D, Yu W. Onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIb or IV NSCLC: Results from the pivotal phase III randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial. J Clin Oncol. 2014;52(s):Suppl;abstr 8000.

26.

Van Cutsem E, Eng C, Nowara E, Swieboda-Sadlej A, Tebbutt NC, Mitchell E, et al. Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer. Clin Cancer Res. 2014;20(16):4240–50. doi:10.1158/1078-0432.CCR-13-2752.CrossRefPubMedPubMedCentral

27.

Koeppen H, Yu W, Zha J, Pandita A, Penuel E, Rangell L, et al. Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib+/−onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin Cancer Res. 2014;20(17):4488–98. doi:10.1158/1078-0432.CCR-13-1836.CrossRefPubMedPubMedCentral

28.

Maus MK, Hanna DL, Stephens CL, Astrow SH, Yang D, Grimminger PP, et al. Distinct gene expression profiles of proximal and distal colorectal cancer: implications for cytotoxic and targeted therapy. Pharmacogenomics J. 2015;15(4):354–62. doi:10.1038/tpj.2014.73.CrossRefPubMed

29.

Rosty C, Young JP, Walsh MD, Clendenning M, Walters RJ, Pearson S, et al. Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features. Mod Pathol. 2013;26(6):825–34. doi:10.1038/modpathol.2012.240.CrossRefPubMed

30.

Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut. 2012;61(6):847–54. doi:10.1136/gutjnl-2011-300865.CrossRefPubMedPubMedCentral

31.

Samowitz WS, Curtin K, Schaffer D, Robertson M, Leppert M, Slattery ML. Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival: a population-based study. Cancer Epidemiol Biomarkers Prev. 2000;9(11):1193–7.PubMed

32.

Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6. doi:10.1038/nm.3967.CrossRefPubMedPubMedCentral

33.

Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20. doi:10.1056/NEJMoa1500596.CrossRefPubMedPubMedCentral

Title: PTEN mRNA expression is less pronounced in left- than right-sided colon cancer: a retrospective observational study
Authors: Hidekazu Kuramochi
Ayako Nakamura
Go Nakajima
Yuka Kaneko
Tatsuo Araida
Masakazu Yamamoto
Kazuhiko Hayashi
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-016-2400-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

Interleukin 12 shows a better curative effect on lung cancer than paclitaxel and cisplatin doublet chemotherapy

Improving gastric cancer preclinical studies using diverse in vitro and in vivo model systems

A phase I/II clinical trial for the hybrid of intracavitary and interstitial brachytherapy for locally advanced cervical cancer

Risks of developing breast and colorectal cancer in association with incomes and geographic locations in Texas: a retrospective cohort study

Long-lasting reduction in clonogenic potential of colorectal cancer cells by sequential treatments with 5-azanucleosides and topoisomerase inhibitors

Accelerated hypofractionated three-dimensional conformal radiation therapy (3 Gy/fraction) combined with concurrent chemotherapy for patients with unresectable stage III non-small cell lung cancer: preliminary results of an early terminated phase II trial

Keynote webinar | Spotlight on antibody–drug conjugates in cancer