Prognostic Impact of Microsatellite Instability and DNA Ploidy in Human Colon Carcinoma Patients

Sinicrope, Frank A.; Rego, Rafaela L.; Halling, Kevin C.; Foster, Nathan R.; Sargent, Daniel J.; Plant, Betsy La; French, Amy J.; Laurie, John A.; Goldberg, Richard M.; Thibodeau, Stephen N.; Witzig, Thomas E.

doi:10.1053/j.gastro.2006.06.005

Cited by 195 publications

(164 citation statements)

References 35 publications

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“…Our finding of improved survival associated with MSI in colorectal carcinomas of any histologic subtype is consistent with previous reports [11][12][13]. This supports the recent WHO recommendation to grade mucinous carcinoma according to their MSI status [3].…”

Section: Discussionsupporting

confidence: 92%

“…Up to 15% of all colorectal carcinomas demonstrate MSI, more frequently secondary to acquired methylation of MLH1 (sporadic cases) than caused by a germline mutation in an MMR gene (Lynch syndrome). MSI has been reported to be a strong positive prognostic factor by multiple independent studies [11][12][13]. Some histologic subtypes of colorectal carcinomas are more commonly observed in MSI tumors, including medullary carcinomas, mucinous adenocarcinomas and signet ring cell carcinomas [14].…”

Section: Introductionmentioning

confidence: 99%

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Should the grading of colorectal adenocarcinoma include microsatellite instability status?

et al. 2014

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Adenocarcinomas of the colon and rectum are graded using a two-tiered system into histologic low-grade and high-grade tumors based on the proportion of gland formation. The current grading system does not apply to subtypes of carcinomas associated with a high frequency of microsatellite instability (MSI), such as mucinous and medullary carcinomas.We investigated the combined effect of histologic grade and MSI status on survival for 738 patients with colorectal carcinoma (48% female; mean age at diagnosis 68.2 years). The proportion of high-grade adenocarcinoma was 18%. MSI was observed in 59 adenocarcinomas (9%), with higher frequency in high-grade tumors compared with lowgrade tumors (20% vs. 6%; P<0.001). Using Cox regression models, adjusting for sex, age at diagnosis and stratifying by the American Joint Committee on Cancer (AJCC) stage, microsatellite stable (MSS) high-grade tumors were associated with increased hazard of allcause and colorectal cancer-specific mortality: hazard ratio (HR) 2.09 (95% confidence interval (CI), 1.58-2.77) and 2.54 (95% CI, 1.86-3.47), respectively, both P<0.001. A new grading system separating adenocarcinoma into low-grade (all histologic low-grade and MSI high-grade) and high-grade (MSS histologic high-grade) gave a lower Akaike information criterion value when compared with the current grading system and, thus, represented a better model fit to stratify patients according to survival. We found that patients with a high-grade adenocarcinoma had significantly shorter survival than patients with low-grade adenocarcinoma only if the tumor was MSS, suggesting that the grading of colorectal adenocarcinoma with high-grade histologic features should be made according to the MSI status of the tumor.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Should the grading of colorectal adenocarcinoma include microsatellite instability status?

et al. 2014

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“…15 The reason for aggressive behavior of signet ring cell carcinoma including tumors with high-level microsatellite instability is not clear. High-level microsatellite-unstable tumors tend to be diploid 38 and chromosomal instability is a relatively infrequent phenomenon; LOH is observed in 16-21% of cancers with high-level microsatellite instability, compared with 56-83% of microsatellite-stable tumors. [38][39][40] Hence, it has been argued that chromosomal instability is not a major mechanism for carcinogenesis in high-level microsatellite-unstable tumors.…”

Section: Discussionmentioning

confidence: 99%

“…High-level microsatellite-unstable tumors tend to be diploid 38 and chromosomal instability is a relatively infrequent phenomenon; LOH is observed in 16-21% of cancers with high-level microsatellite instability, compared with 56-83% of microsatellite-stable tumors. [38][39][40] Hence, it has been argued that chromosomal instability is not a major mechanism for carcinogenesis in high-level microsatellite-unstable tumors. 41 Several studies have shown that chromosomal instability is an adverse prognostic factor in colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

et al. 2012

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The relationship of molecular abnormalities with clinicopathologic features and survival in colorectal signet ring cell carcinoma, and its comparison with mucinous and conventional adenocarcinomas, has not been well studied. High-level microsatellite instability, loss of heterozygosity (LOH) at four loci, CpG island methylation phenotype based on seven loci, BRAF V600E mutation and KRAS mutation in signet ring cell carcinoma were compared with mucinous and conventional adenocarcinomas. The relationship of these molecular features in signet ring cell carcinoma with clinicopathologic features and survival was examined. LOH was observed in 93% of signet ring cell carcinomas compared with 62 and 70% of mucinous and conventional adenocarcinomas. Also, 80% of signet ring cell carcinomas with high-level microsatellite instability showed LOH compared with 14% each of mucinous and conventional adenocarcinomas. High-level microsatellite instability, CpG island methylation phenotype-positive status and BRAF V600E mutation were more often seen in signet ring cell carcinoma and mucinous adenocarcinoma compared with conventional adenocarcinoma. BRAF V600E mutation was significantly associated with CpG island methylation phenotype-positive status. Stage and BRAF V600E mutation in microsatellite-stable cases were the only variables with an affect on survival. In conclusion, chromosomal instability manifested by LOH is nearly a universal finding in signet ring cell carcinoma, including cases with highlevel microsatellite instability. This may explain the aggressive behavior of signet ring cell carcinoma irrespective of high-level microsatellite-instability status. BRAF V600E mutation and CpG island methylation phenotypepositive status are similar in signet ring cell carcinoma and mucinous adenocarcinoma but more frequent when compared with conventional adenocarcinoma. In signet ring cell carcinoma, BRAF V600E mutation adversely affects survival in microsatellite-stable tumors, but not in high-level microsatellite-unstable tumors. The high frequency of methylation and BRAF V600E mutation suggests that many signet ring cell carcinomas may be related to the serrated pathway of carcinogenesis.

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“…11,12 Most previous studies on MSI status in patients with CRC have focused on survival and response to chemotherapy, for which recent data continue to produce equivocal results. [14][15][16][17][18][19] Conversely, few, if any, studies have investigated the effect of MSI status in CRC on recurrence patterns and survival among patients who were included in a strict surveillance program. Thus, in this study, we investigated the role of MSI and CIN on the influence on recurrence (locoregional or distant) and disease-specific survival (DSS) in a defined patient cohort that underwent systematic surveillance after curative resection of CRC.…”

mentioning

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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Prognostic Impact of Microsatellite Instability and DNA Ploidy in Human Colon Carcinoma Patients

Cited by 195 publications

References 35 publications

Should the grading of colorectal adenocarcinoma include microsatellite instability status?

Should the grading of colorectal adenocarcinoma include microsatellite instability status?

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

Microsatellite instability and DNA ploidy in colorectal cancer

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