Low Expression of Chloride Channel Accessory 1 Predicts a Poor Prognosis in Colorectal Cancer

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Abstract

BACKGROUND

Chloride channel accessory 1 (CLCA1) is a CLCA protein that plays a functional role in regulating the differentiation and proliferation of colorectal cancer (CRC) cells. Here we investigated the relationship between the level of CLCA1 and the prognosis of CRC.

METHODS

First, the level of CLCA1 was detected quantitatively in normal and cancerous colonic epithelial tissues with immunohistochemistry. Next, the correlations between CLCA1 expression, pathological tumor features, and the overall survival rate of patients was analyzed. Finally, 3 publicly available data sets from the Gene Expression Omnibus were examined: normal CRC versus early CRC (GSE4107), primary CRC versus metastatic lesions (GSE28702), and low chromosomal instability versus high chromosomal instability (GSE30540).

RESULTS

The expression of CLCA1 was decreased markedly in tumor specimens. CLCA1 expression was correlated significantly with the histological grade ( P < .01) and lymph node metastasis ( P < .01). A significantly poorer overall survival rate was found in patients with low levels of CLCA1 expression versus those with high expression levels ( P < .05). The results confirmed that the low expression of CLCA1 in CRC was highly associated with tumorigenesis, metastasis, and high chromosomal instability. In addition, the loss of CLCA1 disrupted the differentiation of human colon adenocarcinoma cells (Caco-2) in vitro.

CONCLUSIONS

These findings suggest that CLCA1 levels may be a potential predictor of prognosis in primary human CRC. Low expression of CLCA1 predicts disease recurrence and lower survival, and this has implications for the selection of patients most likely to need and benefit from adjuvant chemotherapy. Cancer 2015;121:1570–1580 . © 2015 American Cancer Society.

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Most cited references 37

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Understanding survival analysis: Kaplan-Meier estimate

Manish Kumar Goel, Pardeep Khanna, Jugal Kishore (2010)

Kaplan-Meier estimate is one of the best options to be used to measure the fraction of subjects living for a certain amount of time after treatment. In clinical trials or community trials, the effect of an intervention is assessed by measuring the number of subjects survived or saved after that intervention over a period of time. The time starting from a defined point to the occurrence of a given event, for example death is called as survival time and the analysis of group data as survival analysis. This can be affected by subjects under study that are uncooperative and refused to be remained in the study or when some of the subjects may not experience the event or death before the end of the study, although they would have experienced or died if observation continued, or we lose touch with them midway in the study. We label these situations as censored observations. The Kaplan-Meier estimate is the simplest way of computing the survival over time in spite of all these difficulties associated with subjects or situations. The survival curve can be created assuming various situations. It involves computing of probabilities of occurrence of event at a certain point of time and multiplying these successive probabilities by any earlier computed probabilities to get the final estimate. This can be calculated for two groups of subjects and also their statistical difference in the survivals. This can be used in Ayurveda research when they are comparing two drugs and looking for survival of subjects.

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PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients

M Frattini, P Saletti, E Romagnani … (2007)

To evaluate whether the epidermal growth factor receptor (EGFR), K-Ras and PTEN, all members of the EGFR signalling pathway, may affect the clinical response in cetuximab-treated metastatic colorectal cancer (mCRC) patients. Twenty-seven cetuximab-treated mCRC patients were evaluated for drug response and investigated for EGFR protein expression and gene status, K-Ras mutational status and PTEN protein expression. Ten patients achieved a partial response (PR) to cetuximab-based therapy. All 27 patients showed EGFR protein overexpression. Epidermal growth factor receptor gene amplification was observed in eight out of 27 (30%) and chromosome 7 marked polysomy in 16 (59%) patients. Partial response was observed in six out of eight patients with EGFR gene amplification, four out of 16 with marked polysomy and none out of three with eusomy (P<0.05). The K-Ras wild-type sequence was observed in 17 patients, and nine of them experienced a PR. Conversely, K-Ras was mutated in 10 cases, of which one patient experienced a PR (P<0.05). The PTEN protein was normally expressed in 16 patients, and 10 of them achieved a PR. In contrast, no benefit was documented in 11 patients with loss of PTEN activity (P<0.001). Patients with EGFR gene amplification or chromosome 7 marked polysomy respond to cetuximab. In addition to K-Ras mutations, we demonstrate for the first time that the loss of PTEN protein expression is associated with nonresponsiveness to cetuximab.

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The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment.

Antonio Russo, Viviana Bazan, Barry Iacopetta … (2005)

The aims of the TP53 Colorectal Cancer (CRC) International Collaborative Study were to evaluate the possible associations between specific TP53 mutations and tumor site, and to evaluate the prognostic and predictive significance of these mutations in different site, stage, and treatment subgroups. A total of 3,583 CRC patients from 25 different research groups in 17 countries were recruited to the study. Patients were divided into three groups according to site of the primary tumor. TP53 mutational analyses spanned exons 4 to 8. TP53 mutations were found in 34% of the proximal colon tumors and in 45% of the distal colon and rectal tumors. They were associated with lymphatic invasion in proximal tumors. In distal colon tumors, deletions causing loss of amino acids were associated with worse survival. In proximal colon tumors, mutations in exon 5 showed a trend toward statistical significance (P < .05) when overall survival was considered. Dukes' C tumors with wild-type TP53 and those with mutated TP53 (proximal tumors) showed significantly better prognosis when treated with adjuvant chemotherapy. Analysis of TP53 mutations from a large cohort of CRC patients has identified tumor site, type of mutation, and adjuvant treatment as important factors in determining the prognostic significance of this genetic alteration.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer

Journal ID (iso-abbrev): Cancer

Journal ID (publisher-id): cncr

Title: Cancer

Publisher: Blackwell Publishing Ltd (Oxford, UK )

ISSN (Print): 0008-543X

ISSN (Electronic): 1097-0142

Publication date (Print): 15 May 2015

Publication date (Electronic): 20 January 2015

Volume: 121

Issue: 10

Pages: 1570-1580

Affiliations

[1 ]Department of General Surgery, 309th Hospital of the People's Liberation Army Beijing, China

[2 ]School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen Aberdeen, United Kingdom

[3 ]Hebei Northern University Hebei, China

[4 ]Department of Pathology, 309th Hospital of the People's Liberation Army Beijing, China

[5 ]Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen Aberdeen, United Kingdom

Author notes

Corresponding author: Jin Pu, MD, PhD, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, IMS Building, Foresterhill, Aberdeen AB25 2ZD, United Kingdom; Fax: (011) 44(0)1224 437465; jin.pu@ 123456abdn.ac.uk or Colin D. McCaig, PhD, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, IMS Building, Foresterhill, Aberdeen AB25 2ZD, United Kingdom; Fax: 44(0)1224 437465; c.mccaig@ 123456abdn.ac.uk

Jin Pu and Lin Cao conceived and designed the experiments. Jin Pu, Lin Cao, Colin D. McCaig, and Steven D. Heys wrote the article. Bo Yang and Jiaen Liu prepared the patient samples. Bo Yang, Lin Cao, Jiaen Liu, Gillian Milne, Wanhei Chan, and Yanjie Xu performed the experiments. Lin Cao, Jin Pu, Bo Yang, and Jiaen Liu analyzed the data.

The first 2 authors contributed equally to this article.

Article

DOI: 10.1002/cncr.29235

PMC ID: 4654332

PubMed ID: 25603912

SO-VID: c8000fb3-4a42-4894-88fd-d58d7fd49e75

License:

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 09 October 2014

Date revision received : 02 December 2014

Date accepted : 03 December 2014

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Low Expression of Chloride Channel Accessory 1 Predicts a Poor Prognosis in Colorectal Cancer

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Abstract

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

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Karger: Oncology

Most cited references 37

Understanding survival analysis: Kaplan-Meier estimate

PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients

The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment.

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Cited by 30

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