Popat S, Hubner R, Houlston RSSystematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23: 609-618

MRCP, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG, UK.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2005; 23(3):609-18. DOI: 10.1200/JCO.2005.01.086
Source: PubMed

ABSTRACT A number of studies have investigated the relationship between microsatellite instability (MSI) and colorectal cancer (CRC) prognosis. Although many have reported a better survival with MSI, estimates of the hazard ratio (HR) among studies differ. To derive a more precise estimate of the prognostic significance of MSI, we have reviewed and pooled data from published studies.
Studies stratifying survival in CRC patients by MSI status were eligible for analysis. The principal outcome measure was the HR. Data from eligible studies were pooled using standard techniques.
Thirty-two eligible studies reported survival in a total of 7,642 cases, including 1,277 with MSI. There was no evidence of publication bias. The combined HR estimate for overall survival associated with MSI was 0.65 (95% CI, 0.59 to 0.71; heterogeneity P = .16; I(2) = 20%). This benefit was maintained restricting analyses to clinical trial patients (HR = 0.69; 95% CI, 0.56 to 0.85) and patients with locally advanced CRC (HR = 0.67; 95% CI, 0.58 to 0.78). In patients treated with adjuvant fluorouracil (FU) CRCs with MSI had a better prognosis (HR = 0.72; 95% CI, 0.61 to 0.84). However, while data are limited, tumors with MSI derived no benefit from adjuvant FU (HR = 1.24; 95% CI, 0.72 to 2.14).
CRCs with MSI have a significantly better prognosis compared to those with intact mismatch repair. Additional studies are needed to further define the benefit of adjuvant chemotherapy in locally advanced tumors with MSI.

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    • "And the advantages of a single register include the sufficient number of suffers which can be collected data based on a truly unselected study population and without biases or confounding factor (Yang et al., 2013). Meta analysis showed that colorectal cancer with high microsatellite instable have a significantly better prognosis compared to those with intact mismatch repair (Popat et al., 2005), which is consist with our outcomes that the patients with tumor exhibiting high microsatellite-instable had a better DFS than those with tumor exhibiting low microsatellite-instable or microsatellite-stable (p=0.001). Besides that, it was found that among 201 patients who did not receive adjuvant chemotherapy, those cancers with high microsatellite-instable have a better 5-year rate of DFS than tumors with microsatellite-stable or low microsatellite-instable (p=0.010) . "
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    ABSTRACT: Rectal cancers with high microsatellite-instable have clinical and pathological features that differentiate them from microsatellite-stable or low- frequency carcinomas, which was studied rarely in stage II rectal cancer, promoting the present investigation of the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II rectal cancer. Data of 460 patients who underwent primary anterior resection with a double stapling technique for rectal carcinoma at a single institution from 2008 to 2012 were retrospectively collected. All patients experienced a total mesorectal excision (TME) operation. Survival analysis were analyzed using the Cox regression method. Five-year rate of disease-free survival (DFS) was noted in 390 (84.8%) of 460 patients with stage II rectal cancer. Of 460 tissue specimens, 97 (21.1%) exhibited high-frequency microsatellite instability. Median age of the patients was 65 (50-71) and 185 (40.2%) were male. After univariate and multivariate analysis, microsatellite instability (p= 0.001), female sex (p< 0.05) and fluorouracil-based adjuvant chemotherapy (p< 0.001), the 3 factors were attributed to a favorable survival status independently. Among 201 patients who did not receive adjuvant chemotherapy, those cancers displaying high-frequency microsatellite instability had a better 5-year rate of DFS than tumors exhibiting microsatellite stability or low-frequency instability (HR, 13.61 [95% CI, 1.88 to 99.28]; p= 0.010), while in 259 patients who received adjuvant chemotherapy, there was no DFS difference between the two groups (p= 0.145). Furthermore, patients exhibiting microsatellite stability or low-frequency instability who received adjuvant chemotherapy had a better 5-year rate of DFS than patients did not (HR, 5.16 [95% CI, 2.90 to 9.18]; p< 0.001), while patients exhibiting high-frequency microsatellite instability were not connected with increased DFS (p= 0.696). It was implied that female patients had better survival than male. Survival status after anterior resection of rectal carcinoma is related to the microsatellite instability status, adjuvant chemotherapy and gender. Fluorouracil-based adjuvant chemotherapy benefits patients of stage II rectal cancer with microsatellite-stable or low microsatellite-instable, but not those with high microsatellite- instable. Additionally, free of adjuvant chemotherapy, carcinomas with high microsatellite-instable have a better 5-year rate of DFS than those with microsatellite-stable or low microsatellite-instable, and female patients have a better survival as well.
    Asian Pacific journal of cancer prevention: APJCP 03/2015; 16(4):1545-51. DOI:10.7314/APJCP.2015.16.4.1545 · 2.51 Impact Factor
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    • "Genetic profiling of patients for KRAS mutation, BRAF genes, Microsatellite instability (MSI) and CpG island methylator phenotypes (CIMP) is now being increasingly carried out for colorectal cancer patients in the developed world and this has contributed significantly to treatment planning. Patients that exhibit MSI have been found to possess better overall survival than those with chromosomal instability and are less affected by p53 mutations [40], whilst CRC with p53 +, MSI + profiles are usually more aggressive than those with p53-, MSI + profiles. [41] Biomarkers such as telomerase and survivin have been used to assess the long term risk of CRC development [42] whilst morphologic biomarkers in patients include neoplastic colorectal polyposis and the presence of aberrant cryptic foci (AFC); the presence of adenomas with Intraepithelial Neoplasm in the colorectal region can also be used in surveillance as surrogate endpoint biomarkers. "
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    ABSTRACT: Themes 1. Brief history and evolution of –omics based molecular approach. 2. Diagnostic inaccuracies in colorectal cancer. I. Reliability of Histopathology reports. II. Tumour classification and staging. III. Role of surgical pathology. IV. Patient evaluation and therapeutic loop-holes. 3. Omics based techniques relevant to colorectal cancer management. I. Genomics and Epigemomics II. Transcriptomics III. Proteomics IV. Lipidomics V. Metabolomics VI. Molecular imaging in cancer VII. Pharmacogenomics VIII. Cancer nanothechnology 4. Prospects of –omics based approaches in a developing country: Cape Town case example. 5. Recommendations and conclusion. 1. Brief history and evolution of –omics based molecular approach The fields of genomics, proteomics and lipidomics have classically been concerned with documentation of the identity, abundance and localization of DNA, RNA, protein and lipid biomolecules in a given cell, tissue or organism. These high throughput technologies have found considerable utility in many areas of human biology, particularly following the completion of the human genome sequence in 2003. More recently, clinical ‘omics approaches have become concerned with determination of disease-associated changes in the human genome, transcriptome, proteome, lipidome and metabolome with the aim of identifying disease-associated biomarkers for use in diagnostic tests, as well as with identifying underlying molecular mechanisms of disease. This review will focus on the potential for ‘omics technologies to impact on the diagnosis and treatment of colorectal cancer. 2. Diagnostic inaccuracies in colorectal cancer The intricacies imbued in colorectal cancer are partly due to its multiple implicated aetiologies, and the heterogeneous nature of the tumour. This sometimes makes disease assessment complex and presents a diagnostic dilemma. I. Reliability of Histopathology reports: Basic descriptive and morphologic histopathology has hitherto been of immense benefit for the diagnosis of colorectal cancer and continues to be so. However, newer molecular information suggests that these reports can be plagued with inaccuracies and that they therefore need to be supported with novel molecular and -omics based staging. II. Tumour classification and staging: Newer and often more reliable molecular based assessment of tumour staging and prognosis have emerged and needs to be incorporated into routine diagnostic practice. III. Role of Surgical Pathology: Early detection and prompt intervention is key in the effective management of colorectal cancer, including aiding in determining the type of adjuvant therapy a patient may benefit from. Surgical pathology is the interphase between surgery and pathologic specimen processing where the pathologist determines which area of the whole specimen to take samples from. Given recent molecular evidence on tumour heterogeneity, such sampling techniques are a potential minefield for diagnostic errors, even with the best mastery. IV. Patient evaluation and therapeutic loop holes: The orthodox approach of prescribing a common therapeutic cancer regimen to all colorectal cancer patients treated at a given clinic has recently been a subject of debate in terms of its effectiveness and long term benefit to individual patients. Therapeutic focus is shifting towards personalized or individualized treatments based on individual genetic variability. For example, oncologists can now predict prognosis based on microsatellite instability (MSI) status, BRAF gene, and KRAS mutations, etc. 3. Omics based techniques relevant to colorectal cancer management Omics based techniques in most instances are non- or minimally invasive and can assist in disease diagnosis, surveillance, treatment and prevention. A number of techniques relevant to colorectal cancer management will be highlighted as follows: I. Genomics and Epigenomics II. Transcriptomics III. Proteomics IV. Lipidomics V. Metabolomics VI. Molecular imaging in cancer VII. Pharmacogenomics VIII. Cancer nanotechnology 4. Prospects of –omics based approaches in a developing country: Cape Town case example. Diagnosis and management of colorectal cancer in a developing country are characterized by problems typical to such economies, such as lack of routine health checks resulting in late presentation and advanced cancer stages. Other relevant factors include: cultural and religious beliefs; poverty; political unrest; educational level; infrastructure; maintenance culture; disease; nutrition; genetic variability; patient compliance; expertise; personnel; and many more. South Africa, being the largest economy in Africa, occupies a strategic location for treatment, research and enlightenment outreaches to the rest of Africa. Cape Town has relatively good access to modern molecular facilities and expertise and has the potential to be a major regional molecular and ‘omics centre in the near future. 5. Recommendations and Conclusion We will recommend in this review that surgeons and clinicians should consider a more profound participation in basic medical researches to improve understanding and effectiveness of molecular approaches to cancer management. Education and health enlightenments are key to early diagnosis and management of colorectal cancer in the developing nations. The emergence of –omics based approaches may therefore be the much awaited future of cancer diagnosis and treatment.
    Colorectal Cancer - Surgery, Diagnostics and Treatment, 1st edited by Jim S Khan, 03/2014: chapter 15: pages 1-40; INTECH., ISBN: 978-953-51-1231-0
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    • "The majority of MSI in colorectal and endometrial cancers is caused by defects in DNA mismatch repair genes, mainly MLH1, MSH2, MSH6 and PMS2 [12]. Although MSI is an independent prognostic marker of a favorable outcome in colorectal cancer [13] [14] [15], it is feasible that MSI may also influence endometrial cancer survival. Evidence of MSI association with prognosis in endometrial cancer is controversial. "
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    ABSTRACT: Background and objective Endometrial cancer (EC) is the most commonly diagnosed gynecologic malignancy among women worldwide and may be classified on the basis of different molecular, pathologic and genetic alterations, including microsatellite instability (MSI). Although MSI is associated with a more favorable outcome in colorectal cancer, its relationship with prognosis in EC cancer is not yet clear. The aim of our study is to identify whether MSI correlates with survival of patients in EC. Materials and methods We examined MSI status and survival of 109 women. MSI was detected by employing the Promega MSI Analysis System, which used 5 mononucleotides markers (BAT-25, BAT-26, NR-21, NR-24, and MONO-27) to identify MSI in a tumor and normal tissue DNA and 2 pentanucleotide markers (Penta C and Penta D) for specimen identification. Median follow-up of patients was 40.4 months (range 5.2–47.9). Survival was estimated by the Kaplan–Meier method and Cox regression analysis was used to assess the effects of different variables on patient survival. Results MSI-high was detected in 15.6% EC cases, all of which were associated with endometrioid type histology. Kaplan–Meier survival analysis showed no statistically significant differences between patients with MSI-high and MSI stable tumors (P = 0.4) and multivariate analysis concluded that MSI status remained insignificant after stage, histology and tumor grade adjustment (P = 0.5). Conclusions Our study showed no statistically significant relationship between MSI-high and survival of endometrial cancer patients.
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