Microsatellite instability as a marker of prognosis and response to therapy: A meta-analysis of colorectal cancer survival data
Introduction
Colorectal cancer (CRC) is one of the most common malignancies in western countries, representing the third most common cancer in both women and men. Despite advances in early detection and improvements in dosing and scheduling of therapies in both adjuvant and advanced settings, CRC is still responsible for a substantial mortality and represents the second leading cause of cancer-related death in the United States, with a relative 5-year survival rate of about 67%.1
CRC shows a significant heterogeneity even within the same pathologic stage in both prognosis and response to therapy.2 The clinical heterogeneity may be a sign of underlying molecular heterogeneity in the pathogenesis of CRC. Current knowledge on molecular mechanisms involved in colorectal carcinogenesis indicates that CRC is a multi-pathway disease and two major genomic instability pathways are involved in its pathogenesis: microsatellite instability (MSI) and chromosome instability (CIN). Approximately 15% of sporadic CRC are characterised by MSI, showing insertions and deletions at DNA microsatellite sequences, whereas the remaining 85% of CRC develop through the CIN pathway and are characterised by gross chromosomal alterations, either qualitative or quantitative. Although the MSI and CIN phenotypes can be distinguished from one another, there is evidence suggesting some degree of overlap.3 In CRC MSI is mainly caused by mutations in the DNA mismatch repair (MMR) genes hMLH1 and hMSH2 and, less frequently, hMSH6, hPMS1and hPMS2. Genetic and epigenetic inactivation of MMR genes leads to mutations in cancer-related genes and to cancer development and progression.4
MSI is typically assessed by analysing five microsatellite markers: three dinucleotide (D2S123, D5S346, D17S250) and two mononucleotide (BAT25 and BAT 26) repeats referred to as the National Cancer Institute (NCI) consensus panel.5 Three levels of MSI can be identified: high-level MSI (MSI-H), generally defined as MSI in more than 30% of the standard markers; low-level MSI (MSI-L), when changes are exhibited in less than 30% of the markers and microsatellite stable (MSS) in the absence of microsatellite alterations. Mononucleotide repeat markers have been shown to be highly sensitive in detecting MSI-H tumours, indeed the use of BAT 26 alone has been found highly correlated with the NCI panel and has been shown to identify nearly all MSI-H CRC cancers.6 MMR deficiency leading to MSI can be also detected by lack of expression of one or more of the MMR proteins by immunohistochemistry (IHC). Recently a scoring system (MsPath), based on easily assessable clinicopathological features, was developed to predict MSI-H status in CRC and proposed to triage tumours for MSI or IHC testing.7
MSI-H identifies a well-defined subset of CRC that tends to show diploid state, to be more proximal, poorly differentiated, mucinous and to have marked lymphocyte infiltration.8 Thus, MSI genotyping may allow the identification of discrete molecular CRC subtypes and MSI seems to represent one of the most promising molecular markers with both prognostic and predictive value for chemosensitivity.9 Indeed, a pooled analysis of survival data support the notion that patients with tumours showing MSI-H phenotype have a better prognosis than those with MSS tumours.10 MSI testing could also result in more patients being assigned to proper treatment based on their disease profile. An intact MMR system is a determinant of sensitivity to a variety of chemotherapeutic agents, it is therefore reasonable to consider MSI-H tumours as a separate entity when determining response to chemotherapy. Indeed non-responsiveness to 5-fluoruracil (5-FU) chemotherapy was shown in two clinical trials although its significance was limited by the small number of treated MSI-H patients.10 Other studies including prospective studies have addressed this issue.11 To gain better insight into the clinical value of MSI status we have undertaken a systematic review of published studies and used meta-analysis techniques to derive a more precise and updated estimate of the prognostic and predictive significance of this CRC phenotype.
Section snippets
Eligibility criteria
Studies were eligible for pooling if survival was assessed in CRC patients stratified by MSI status. The primary outcomes of interest were overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS). Only studies providing information on survival were included. Studies assessing MSI by analysing DNA molecular markers and/or IHC were included. Studies only quoting the p value of the logrank statistics were not eligible. Care was taken to account for overlapping and
Eligible studies
Fifty-five potentially eligible studies were identified and retrieved. Seven studies22, 23, 24, 25, 26, 27, 28 were excluded as survival data were not stratified by MSI status, three29, 30, 31 as survival data cannot be extrapolated separately for MSI and MSS patients, two32, 33 as they only quoted the median survival time, five34, 35, 36, 37, 38 as they reported only the p-value of the logrank statistics. Datasets were duplicated in seven studies6, 39, 40, 41, 42, 43, 44 and in order to reduce
Discussion
We have shown that the published data support the view that MSI-H is associated with a better prognosis in CRC, and it appears that this molecular marker can stratify CRC patients further after standard pathological staging. There is a great variability in clinical outcome of CRC patients with the same staging, underlining the need for robust prognostic and predictive molecular markers. Patients with stages I–IV MSI-H CRC appear to have a better survival and we determined that MSI-H in stages
Conflict of interest statement
None declared.
Acknowledgements
The work was supported by Ricerca Oncologica – Project of integrated program Ministero della Salute 2008-2011 within the sub project of Identification of population risk profiles as an approach to cancer prevention.
References (85)
- et al.
The genetics of HNPCC: application to diagnosis and screening
Crit Rev Oncol Hematol
(2006) - et al.
Colon cancer family registry. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study
Gastroenterology
(2007) - et al.
The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status
Eur J Cancer
(2009) - et al.
Mucinous carcinoma of the colon: correlation of loss of mismatch repair enzymes with clinicopathologic features and survival
Mod Pathol
(2004) - 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
Controlled Clin Trials
(1986) - et al.
P53 is an independent pre-treatment markers for long-term survival in stage II and III colorectal cancers: an analysis of interaction between genetic markers and fluorouracil-based adjuvant therapy
Cancer Lett
(2004) - et al.
Significance of mutations in TGFBR2 and BAX in neoplastic progression and patient outcome in sporadic colorectal tumours with high-frequency microsatellite instability
Cancer Genet Cytogenet
(2005) - et al.
Prognostic role of CD8+ tumour-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability
Hum Pathol
(2004) - et al.
Prevalence and prognostic role of microsatellite instability in patients with rectal carcinoma
Ann Oncol
(2002)
Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy
Gastroenterology
Microsatellite instability is a predictive marker for survival benefit from adjuvant chemotherapy in a population-based series of stage III colorectal carcinoma
Clin Colorectal Cancer
Use of 5-Fluorouracil and survival in patients with microsatellite-unstable colorectal cancer
Gastroenterology
Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients
Gastroenterology
Molecular classification and correlates in colorectal cancer
J Mol Diagn
Prediction of the response of colorectal cancer to systemic therapy
Lancet Oncol
A review on the use of molecular markers of cytotoxic therapy for colorectal cancer, what have we learned?
Eur J Cancer
5-Fluorouracil is efficiently removed from DNA by the base excision and mismatch repair systems
Gastroenterology
Genome-wide expression profile of sporadic gastric cancers with microsatellite instability
Eur J Cancer
Colon cancer survival rates with the new American joint committee on cancer sixth edition staging
J Natl Cancer Inst
Molecular heterogeneity of colorectal cancer: implications for cancer control
Surg Oncol
Genomic instability and colorectal cancer
Curr Opin Gastroenterol
A national cancer institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer
Cancer Res
Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level
Cancer Epidemiol Biomarkers Prev
Microsatellite instability in colorectal cancer
Br J Surg
AIO Colorectal Study Group Predictive and prognostic value of microsatellite instability in patients with advanced colorectal cancer treated with a fluoropyrimidine and oxaliplatin containing first-line chemotherapy. A report of the AIO Colorectal Study Group
Int J Colorectal Dis
Systematic review of microsatellite instability and colorectal cancer prognosis
J Clin Oncol
Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation
Pathol Int
Prognostic and predictive relevance of microsatellite instability in colorectal cancer
Oncol Rep
Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer
Br J Surg
Microsatellite instability and colorectal cancer prognosis
Clin Cancer Res
The combination of estimates from different experiments
Biometrics
Measuring inconsistency in meta-analyses
BMJ
Clinical value of mitochondrial mutations in colorectal cancer
J Clin Oncol
The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumour stage
Cell Oncol
Ethnicity and risk for colorectal cancers showing somatic BRAF V600E mutation or CpG island methylator phenotype
Cancer Epidemiol Biomarkers Prev
Association of family history with cancer recurrence and survival among patients with stage III colon cancer
JAMA
Colorectal cancer expression of PPARG (peroxisome proliferator-activated receptor-γ) is associated with good prognosis
Gastroenterology
Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases
Cancer Res
Deficient mismatch repair system in patients with sporadic advanced colorectal cancer
Br J Cancer
Differential prognosis of replication error phenotype and loss of heterozygosity in sporadic colorectal cancer
Eur J Cancer
Cited by (314)
The prognostic significance of microsatellite instability in colorectal cancer: a Swedish multi-center study
2023, International Journal of Colorectal DiseasePrognostic value of primary tumor location in colorectal cancer: an updated meta-analysis
2023, Clinical and Experimental Medicine