ReviewA systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis
Introduction
Colorectal cancer (CRC) is one of the most common malignancies in developed countries [1]. In North America, it is the most common cause of cancer-related mortality in non-smoking men and in non-smoking women it is the second common cause of cancer [2]. Although prognosis has improved over the past three decades and a greater proportion of patients now present with potentially curable disease [3], the outlook for most patients still remains relatively poor.
Molecular analyses have shown that the natural history of all CRCs is not the same [4]. Whilst a small proportion of CRCs develop from the microsatellite-instability (MSI) (chromosome-stable) pathway, many develop from the chromosomal-instability (microsatellite-stable) pathway and are characterised by aneuploidy, allelic losses, amplifications and translocations [5]. Although CRC prognosis is stage and grade dependent, cancers with similar clinico-pathological features may show significant differences in outcome. This is likely in part to be due to underlying molecular heterogeneity. Identifying molecular markers of prognosis as an adjunct to traditional staging systems is clearly highly advantageous, and has not surprisingly been an area of active research in recent years [6].
One of the most promising markers studied to date, observed in up to 70% of CRCs, is chromosome 18q loss [7]. This has been evaluated by a number of methods, including loss of heterozygosity (LOH)/allelic imbalance (AI), and DCC gene expression. DCC maps to chromosome 18q21 and is a key gene involved in colorectal carcinogenesis [8] and the primary candidate for the biological effect of chromosome 18q AI 9, 10. Chromosomal loss at this region is thought to result in haploinsufficiency at DCC and therefore reduced protein expression.
A number of studies have investigated the relationship between chromosome 18q AI, DCC expression and prognosis in CRC. Although many have reported a poorer survival with these phenotypes, estimates of the prognostic value have differed considerably between studies, as have the methods used. To gain a better insight into the value of chromosome 18q AI and loss of DCC expression (LOE) as prognostic markers we have undertaken a systematic review of published studies and used standard meta-analysis techniques as per Cochrane [11] and QUOROM [12] guidelines to derive a more precise estimate of the prognostic significance of this phenotype.
Section snippets
Eligibility criteria
Studies were eligible for pooling if survival was assessed in CRC patients stratified by chromosome 18q genotype or DCC expression status. The primary outcomes of interest were overall survival (OS) and disease-free survival (DFS). Only studies providing information on survival were included. Studies assessing the relationship between chromosome 18q markers and stage were not eligible. Care was taken to account for overlapping and duplicated datasets.
Identification of studies
Studies were identified using the PubMed
Eligible studies
Thirty-eight potentially eligible studies were identified and retrieved 10, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 (Fig. 1). Studies by Watanabe and colleagues [24] and Choi and colleagues [14] presented survival data on patients with stage II and III CRC separately, and each of these were treated as separate data sets.
Six of the 38 retrieved studies were not relevant and therefore
Discussion
The molecular profile of CRCs is likely to be a determinant of clinical outcome. This is particularly important in locally advanced disease, where the identification of patients most likely to benefit from adjuvant chemotherapy is of direct clinical relevance. A proportion of patients with stage II and III disease can be cured by surgery alone and do not derive any benefit from adjuvant therapy [56]. The identification of robust molecular prognostic markers to supplement conventional
Conflict of interest statement
The authors have no conflicts of interest to declare.
Acknowledgements
SP is funded by the UK Department of Health. RSH is supported by grants from Cancer Research UK and the Association for International Cancer Research.
References (60)
- et al.
Epidemiology, treatment and chemoprevention in colorectal cancer
Ann Oncol
(2003) - et al.
Genetic pathways in colorectal and other cancers
Eur J Cancer
(1999) - et al.
Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas
Lancet
(1992) - et al.
Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses
Lancet
(1999) - et al.
Survival and acquired genetic alterations in colorectal cancer
Gastroenterology
(1992) - et al.
Allelic loss on chromosome 18q as a prognostic marker in stage II colorectal cancer
Gastroenterology
(1998) - et al.
DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study
Lancet
(2002) - et al.
Meta-analysis in clinical trials
Control Clin Trials
(1986) - et al.
Prognostic significance of allelic lost at chromosome 18q21 for stage II colorectal cancer
Gastroenterology
(1998) - et al.
Microsatellite instability: impact on cancer progression in proximal and distal colorectal cancers
Eur J Cancer
(1999)