Microsatellite Instability and 8p Allelic Imbalance in Stage B2 and C Colorectal Cancers

Halling, Kevin C.; French, Amy J.; McDonnell, Shannon K.; Burgart, Lawrence J.; Schaid, Daniel J.; Peterson, Brett J.; Moon-Tasson, Laurie L.; Mahoney, Michelle R.; Sargent, Daniel J.; O’Connell, Michael J.; Witzig, Thomas E.; Farr, Gist H.; Goldberg, Richard M.; Thibodeau, Stephen N.

doi:10.1093/jnci/91.15.1295

Cited by 335 publications

(210 citation statements)

References 61 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: 79%

“…It is well established that tumours exhibiting MSI have a better prognosis in older patient cohorts than tumours that are microsatellite stable. [1][2][3][4]6 However, our findings that MSI is not associated with good prognosis in young patients are novel and are of practical as well as biological importance.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6] However, the age distribution of the cohorts analysed in many of these studies reflects the fact that the majority of patients with colorectal cancer are elderly, with the highest age-specific incidence in the oldest age groups. 7,8 Most tumours exhibiting the MSI phenotype are in older patients, very few of whom carry germline MMR gene mutations.…”

mentioning

confidence: 99%

“…Around 50% of all tumours in patients Ͻ 30 years old exhibit MSI, 9,15 whereas only 7-15% of tumours are MSI in older cohorts. [1][2][3][4][5][6] Hence, there is reason to question the validity of applying survival data from MSI analysis of older patient cohorts to estimation of prognosis for younger patients.…”

mentioning

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: 79%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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“…Consistent with our Genetic profiling of early colorectal cancer F Al-Mulla et al finding, numerous studies established an association between loss of chromosome arm 8p and reduced survival. 4,[18][19][20] Loss of chromosome arm 9p is not an infrequent event in colorectal cancer. 13,21 We identified a significant association between 9p loss and high Bold represents values which are statistically significant.…”

Section: Discussionmentioning

confidence: 99%

Genetic profiling of stage I and II colorectal cancer may predict metastatic relapse

et al. 2006

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A substantial number of patients with early-stage colorectal cancer relapse from metastatic disease. Identification of these patients by genetic profiling of their primary tumours may allow more informed followup and tailored administration of adjuvant therapy. Primary tumours from 70 patients with early-stage and largely microsatellite-stable colorectal cancer were profiled using metaphase-based comparative genomic hybridization (CGH) and the aberrations confirmed independently in a subset of patients using microarraybased CGH. Of the 70 cancers, 61 were amenable to CGH, and follow-up data was available from 56 patients. Genomic aberrations were correlated with patients' survival using univariate, multivariate and Kaplan-Meier survival curves. Metastatic primary tumours exhibited more complex genomic aberrations than non-metastatic primary tumours. Loss of chromosome 4p was an independent prognostic factor in early-stage colorectal cancer using multivariate analysis (Hazard ratio, 9.6; 95% CI, 3.3-28; P ¼ 0.0001). Loss of both chromosome arms 8p and 18q had a statistically significant negative effect on disease-free survival. Moreover, primary tumours with loss of both chromosomes 4 and 14q bestowed poorer prognosis than tumours with loss of any one of the two chromosomes (Po0.0001). Genetic profiling of primary tumours of patients with early-stage colorectal cancer is of significant value in identifying the subset of patients who may relapse with metastatic disease. Accordingly, the molecular genetic features of primary tumours should be considered in the mainstream management of patients with this specific stage of the disease.

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Prognostic Effect ofBRAFandKRASMutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab

et al. 2016

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Microsatellite Instability and 8p Allelic Imbalance in Stage B2 and C Colorectal Cancers

Cited by 335 publications

References 61 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

Genetic profiling of stage I and II colorectal cancer may predict metastatic relapse

Prognostic Effect ofBRAFandKRASMutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab

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