Mechanisms of Microsatellite Instability in Colorectal Cancer Patients in Different Age Groups

Yiu, Raymond Y. C.; Qiu, Hongming; Lee, Kil Yeon; Garcia‐Aguilar, Julio

doi:10.1007/s10350-005-0171-0

Cited by 29 publications

(20 citation statements)

References 46 publications

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“…The age of patients testing positive for microsatellite instability in the study group was high, with a median of 69 years (range = 41-90), data consistent with reports by Yiu et.al and Yearsley et al (11). This presence of MSI-H at an advanced age is due most likely to sporadic/spontaneous rather than inherited genetic changes.…”

Section: Msi Testingsupporting

confidence: 79%

Does sex of the patient play a role in survival for MSI colorectal cancer?

Tulin¹,

Slavu²,

Tulin³

et al. 2018

JMMS

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Microsatellite instability (MSI) is a feature of colorectal tumors that develops as a result of inactivation of the DNA mismatch repair system. It is found in about 15% of all colorectal cancers and is an important prognostic molecular marker when assessing patients with colorectal cancer. It can influence prognosis and treatment decisions in both the advanced and early stages. Although in early stages this marker suggests a favorable prognosis and presents an important argument against adjuvant treatment in stage II disease, in metastatic stages it no longer associated with such an optimistic outcome. The present trial is a prospective, single-center study which included 122 colorectal cancer patients who were tested for MSI using immunohistochemistry. The trial included patients with stage II to IV colorectal cancer, treated in the Prof. Dr. Agrippa Ionescu Emergency Hospital, Bucharest, Romania. Follow-up data were collected during a 24-month period. The study attempted to determine whether differences exist in overall survival for MSI (microsatellite instability) vs. MSS (microsatellite stable) colorectal cancer and to ascertain whether sex of the patient influences prognosis in MSI patients, irrespective of stage or treatment. Results demonstrated no significant differences in survival for MSI vs MSS colorectal patients, and patients' gender proved not to influence the outcome in MSI patients.

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Section: Msi Testingsupporting

confidence: 79%

Does sex of the patient play a role in survival for MSI colorectal cancer?

Tulin¹,

Slavu²,

Tulin³

et al. 2018

JMMS

View full text Add to dashboard Cite

show abstract

“…16,31 Also, the discrepancies in the reported survival results also reflect the heterogeneity of the populations studied; eg, unselected or institutional series of sporadic CRC, 14,32 hereditary cancer (hereditary nonpolyposis CRC) screening, 19 analysis of adjuvant chemotherapy trials, 15,17 site-and/or stage-specific analyses (ie, only colonic cancers, only stage II and/or III cancers), as well as in age-related, geographic, and ethnical differences. 20,33 It is also is worth noting that, in the current study, the majority of older patients (aged >75 years) were excluded from the systematic surveillance program and, as such, were not included in the current survival analysis. Table 4 for TNM stages (A).…”

Section: Discussionmentioning

confidence: 99%

“…It also is worth noting that MSI is an age-related phenomenon: It has a bimodal MSI distribution at the extremes of age, and up to 33% of all CRC in the elderly is positive for MSI. 33 MSI also has demonstrated prognostic value in very young CRC patient populations 34 and, in several heterogeneous (stage-dependent) analyses, included patients of all ages derived from trials on adjuvant chemotherapy or selected cohorts of patients. 14,15,17,18,28,32,35,36 In the current population-based study on surveillance after surgery, the exclusion of elderly patients may have masked an overall survival benefit with regard to MSI.…”

Section: Discussionmentioning

confidence: 99%

Microsatellite instability and DNA ploidy in colorectal cancer

Søreide

Slewa

Stokkeland

et al. 2009

Cancer

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BACKGROUND:Appropriate stratification tools for targeted surveillance after resection for colorectal cancer (CRC) are lacking. The objective of the current study was to investigate the effect of microsatellite instability (MSI) and DNA ploidy on surveillance after surgery.METHODS:The authors evaluated 186 consecutive, population‐based patients with stage I through III CRC who underwent surgery with curative intent and who entered a systematic surveillance program. MSI was analyzed with polymerase chain reaction for 5 known quasimonomorphic markers (BAT‐26, BAT‐25, NR‐21, NR‐24, and NR‐27), and DNA ploidy was analyzed with automated cytometry. Recurrence, recurrence‐free survival (RFS), and disease‐specific survival (DSS) were evaluated by univariate and multivariate statistical tests.RESULTS:Patients with MSI (20%) were significantly younger than patients without MSI (median age, 61 years vs 67 years; P = .016). Proximal location (adjusted odds ratio [AOR], 5.4; 95% confidence interval [95% CI], 2.1‐14.1 [P = .001]), large tumor size (≥5 cm: AOR, 3.5; 95% CI, 1.3–9.6 [P = .015]), and poor tumor differentiation (AOR, 6.6; 95% CI, 2–21.8 [P = .002]) were associated with MSI. MSI conveyed an increased risk for locoregional recurrence (OR, 2.9; 95% CI, 1.2–7 [P = .016]), with a trend toward a shorter time to recurrence (P = .060). Neither MSI status nor DNA ploidy predicted distant metastasis, RFS, or DSS. Lymph node status was the best predictor of distant spread (AOR, 3.9; 95% CI, 2–7.9 [P < .001]) and DSS (hazard ratio, 4.9; 95% CI, 2.6–9 [P < .001]).CONCLUSIONS:Patients who had microsatellite instable tumors were at increased risk for locoregional recurrence, whereas lymph node status was the best predictor of distant metastasis. Clinical surveillance and choice of modality (ie, endoscopy vs radiologic imaging) may be improved when patients are stratified according to these cancer features. Cancer 2009. © 2009 American Cancer Society.

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“…9 As is the case for endometrial cancers, MSI with MLH1 methylation is associated with older age at diagnosis in colorectal cancers. 6,10 MSI1 colorectal cancers tend to be right-sided tumors. 11 To date, there have been no genetic factors associated with the risk for epigenetic silencing of MLH1 in tumors.…”

mentioning

confidence: 99%

Evidence for heritable predisposition to epigenetic silencing of MLH1

Chen

Taylor

Sotamaa

et al. 2007

Intl Journal of Cancer

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Epigenetic silencing of MLH1 is the most common cause of defective DNA mismatch repair in endometrial and colorectal cancers. We hypothesized that variation in the MLH1 gene might contribute to the risk for MLH1 methylation and epigenetic silencing. We undertook a case-control study to test for the association between MLH1 variants and abnormal MLH1 methylation. Eight MLH1 SNPs were typed in the normal DNA from women with endometrial carcinoma. For these studies, the cases were women whose cancers exhibited MLH1 methylation (N 5 98) and the controls were women whose cancers had no MLH1 methylation (N 5 219). One MLH1 SNP, rs1800734, located in the MLH1 CpG island at 293 from the translation start site, was significantly associated with MLH1 methylation as were age at diagnosis and patient body mass index. In validation experiments, a similar-sized cohort of colorectal carcinoma patients (N 5 387) showed a similar degree of association with the 293 SNP; a smaller cohort of endometrial carcinomas (N 5 181) showed no association. Combining all 3 cohorts showed an odds ratio of 1.61 (95% CI: 1.20-2.16) for the AA or AG vs. GG genotype at the 293 SNP. Identification of risk alleles for MLH1 methylation could shed light on mechanisms of epigenetic silencing and may ultimately lead to new approaches to the prevention or treatment of malignancies associated with MLH1 inactivation. Epigenetic silencing of MLH1 is the most common cause of defective DNA mismatch repair. [2][3][4][5][6][7][8] In our large series of endometrial carcinomas, >20% have MLH1 promoter methylation.1 We previously showed that MLH1 methylation is associated with increased age at diagnosis.1 Furthermore, MSI1 endometrial cancers appear to be associated with lower body mass index (BMI).9 As is the case for endometrial cancers, MSI with MLH1 methylation is associated with older age at diagnosis in colorectal cancers. 6,10 MSI1 colorectal cancers tend to be right-sided tumors.11 To date, there have been no genetic factors associated with the risk for epigenetic silencing of MLH1 in tumors.Murrell et al. reported an association between polymorphisms in the IGF2 gene and Beckwith-Wiedemann syndrome, an overgrowth syndrome in which loss of imprinting of IGF2 and KCNQ1 is frequently observed.12 Variants in the IGF2 differentially methylated region were found to be significantly associated with sporadic Beckwith-Wiedemann syndrome in which loss of maternal allele-specific methylation of the differentially methylated region KvDMR1 in the KCNQ1 gene was observed.12 This was the first evidence that sequence variation within a gene may be causally associated with abnormalities in methylation (loss of methylation).Unlike the loss of methylation in Beckwith-Wiedemann syndrome, the MLH1 methylation defect in endometrial cancer is a gain of methylation in sequences that are normally unmethylated. We hypothesized that germline variation in the MLH1 locus might contribute to the risk for MLH1 methylation. We undertook a case-control association study to test for MLH1...

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Mechanisms of Microsatellite Instability in Colorectal Cancer Patients in Different Age Groups

Abstract: The age-related proximal shift of colorectal cancers is associated with the microsatellite instability phenotype, MLH1 inactivation, and MLH1 promoter hypermethylation.

Cited by 29 publications

References 46 publications

Does sex of the patient play a role in survival for MSI colorectal cancer?

Does sex of the patient play a role in survival for MSI colorectal cancer?

Microsatellite instability and DNA ploidy in colorectal cancer

Evidence for heritable predisposition to epigenetic silencing of MLH1

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