Tumor Microsatellite Instability and Clinical Outcome in Young Patients with Colorectal Cancer

Gryfe, Robert; Kim, Hyeja; Hsieh, Eugene; Aronson, Melyssa; Holowaty, Eric J.; Bull, Shelley B.; Redston, Mark; Gallinger, Steven

doi:10.1056/nejm200001133420201

Cited by 1,231 publications

(836 citation statements)

References 33 publications

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“…Thus, the proportion of germline MMR mutation carriers in each cohort probably explains differences in tumour distribution and survival reported previously. [1][2][3][4][5][6]33,34 Patients presenting before age 30 years tended to have more advanced malignancy (Dukes' stage C or D, 64% vs. 51%) and a greater proportion of mucinous-type tumours (37% vs. 23%), which is consistent with previous smaller studies. [35][36][37][38][39][40] Although there is evidence that mucinous tumours are more likely to recur locally, there is no convincing evidence for an effect on ultimate survival.…”

Section: Discussionsupporting

confidence: 77%

“…These findings indicate that our understanding of the process of MSI is incomplete and we caution against using MSI alone as a predictor of survival or as a pragmatic tool. 2,34 However, the poor prognosis also underscores the rationale for surveillance of MMR gene carriers in order to detect MSI tumours at an early stage. Thus, these data support surveillance of asymptomatic DNA MMR gene carriers, identified either as part of HNPCC families or by systematic population-based genetic screening approaches.…”

Section: Discussionmentioning

confidence: 99%

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Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

Farrington

McKinley

Carothers

et al. 2002

Intl Journal of Cancer

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It is well established that microsatellite instability (MSI), the hallmark of defective DNA mismatch repair (MMR), is associated with prolonged survival in colorectal cancer compared with tumours that are microsatellite stable (MSS). MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1. However, there are no prospective population-based studies of survival in patients with germline MMR gene mutations who develop cancer. Although MSI is almost universal in tumours from HNPCC family members, there is a potential confounding effect of ascertainment and other biases that could explain the apparent survival benefit in HNPCC families. Resolving whether germline MMR gene mutations impact on survival is important because it potentially undermines the rationale for surveillance of mutation carriers. Here, we report an investigation of the influence of MSI on survival in cohorts of cancer patients (aged < 30 years at diagnosis, n ‫؍‬ 118; non-age-selected, n ‫؍‬ 181) in the context of clinicopathologic variables. There was a substantial age-related influence of tumour MSI status on survival. In young patients with tumour MSI, 65% of patients with MSI tumours had germline MSH2 or MLH1 mutations. Clinicopathologic variables and tumour MSI of the cohort were studied with respect to survival and compared with control groups. Young patients had excess MSI tumours (p < 0.000001), mucinous tumours (p < 0.01), advanced disease (p ϳ 0.001) and poorer 5-year survival compared with older cases. Cox proportional hazard analysis identified Dukes' stage, age at diagnosis and calendar year of treatment as independent predictors of survival. There was no detectable association between tumour MSI and survival in young patients, although we confirmed previous observations that MSI is associated with better prognosis in later onset cohorts. These findings underscore the rationale for surveillance and early identification of tumours in MMR gene carriers as well as refining understanding of the influence of MSI on cancer progression.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

Farrington

McKinley

Carothers

et al. 2002

Intl Journal of Cancer

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“…[4][5][6][7][8][9] Colon cancer with MSI-H has a better prognosis than other colon cancers; the difference is partly dependent on stage (microsatellite instability-high tumors tend not to produce metastatic disease), but has been found to be independent of stage in some studies. [10][11][12][13][14][15][16] Signet ring cell carcinoma is a rare subtype of colorectal cancer, accounting for 0.1-2.4% of all colorectal malignancy. [17][18][19][20] By definition, more than 50% of tumor cells must have signet ring cell morphology.…”

mentioning

confidence: 99%

Signet ring cell carcinoma of the colorectum: correlations between microsatellite instability, clinicopathologic features and survival

Kakar

Smyrk

2005

Modern Pathology

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Colorectal cancer with microsatellite instability has a characteristic clinicopathologic profile, featuring rightsided, lymphocyte-rich tumors with a better prognosis than microsatellite stable (MSS) carcinoma. Mucinous and signet ring cell carcinomas are both over-represented among microsatellite instability-high cancers. The clinicopathologic features of mucinous microsatellite instability-high cancer parallel those of the overall microsatellite instability-high set, but it is not known whether the same is true for signet ring cell carcinoma, particularly given the fact that signet ring histology is a well-documented adverse prognostic factor. We recorded age, sex, tumor size, site, grade, stage, histologic pattern, growth pattern, Crohn-like reaction, vascular invasion and tumor-infiltrating lymphocytes in 72 resected signet ring cell carcinomas of the colorectum. Microsatellite instability was determined by a combination of polymerase chain reaction and immunohistochemical stains for hMLH1, hMSH2 and hMSH6. Tumors with instability at 430% of informative markers and/or loss of hMLH1 or hMSH2 expression were designated microsatellite instability-high; all others were classified as MSS. A total of 22 (31%) signet ring cell carcinomas were microsatellite instability-high. Compared to MSS signet ring cell carcinoma, they were more likely to be right-sided (81 vs 45%, P ¼ 0.005) and to affect older patients (68 vs 26%, P ¼ 0.0007) of female sex (59 vs 28%, P ¼ 0.03). Crohn-like reaction (45 vs 16%, P ¼ 0.02) and high tumor infiltrating lymphocyte counts (32 vs 8%, P ¼ 0.03) were more common in the microsatellite instability-high setting. There was no significant difference in 5-year survival in microsatellite instability-high vs MSS patients (41 vs 34%, P ¼ 0.3). In conclusion, approximately one-third of signet ring carcinomas of the colorectum are microsatellite instability-high. Microsatellite instability-high signet ring carcinomas share clinicopathologic features with other microsatellite instability-high cancers: older age group, female preponderance, right-sided location, Crohn-like reaction and numerous tumor-infiltrating lymphocytes. Microsatellite instability status does not appear to be a significant predictor of survival in signet ring cell carcinoma of the colorectum.

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“…Numerous studies have shown a survival advantage and a less aggressive clinical course for patients with high frequency MSI. 23,24 Furthermore, MSIhigh tumours have been reported to metastasise less often than microsatellite stable tumours. 24 The MSI phenotype also appears to be associated with excellent survival in patients who receive adjuvant 5FU-based chemotherapy.…”

Section: Microsatellite Instability (Msi)mentioning

confidence: 99%

“…23,24 Furthermore, MSIhigh tumours have been reported to metastasise less often than microsatellite stable tumours. 24 The MSI phenotype also appears to be associated with excellent survival in patients who receive adjuvant 5FU-based chemotherapy. 25 A recent study found that 61% of stage III CRC patients with MSI-high tumours had a mutation in the gene for the type II receptor for TGF␤-1.…”

Section: Microsatellite Instability (Msi)mentioning

confidence: 99%

Clinical significance of prognostic and predictive markers in colorectal cancer

2002

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Tumor Microsatellite Instability and Clinical Outcome in Young Patients with Colorectal Cancer

Abstract: High-frequency microsatellite instability in colorectal cancer is independently predictive of a relatively favorable outcome and, in addition, reduces the likelihood of metastases.

Cited by 1,231 publications

References 33 publications

Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

Signet ring cell carcinoma of the colorectum: correlations between microsatellite instability, clinicopathologic features and survival

Clinical significance of prognostic and predictive markers in colorectal cancer

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