Replication error phenotype, clinicopathological variables, and patient outcome in Dukes' B stage II (T3,N0,M0) colorectal cancer

Abstract

Aims-To examine the relation between the replication error (RER) phenotype and other genetic events, clinical features, and long term survival in patients with Dukes' B stage II (T3,N0,M0) colorectal cancer. Methods-RER phenotype was investigated in 159 patients by PCR amplification of microsatellite marker loci on chromosomes 5q, 17p, 17q, and 18q from tumour DNA extracted from archival tissue. Data on activating c-Ki-ras mutations were available from a previous study. Immunohistochemical detection of p53 and c-erbB-2 expression was performed on paraYn wax embedded tissue. Results-Of 159 colorectal cancers studied, 22 (14%) were RER+ while 137 (86%) were RER− for two or more loci. RER+ tumours were more commonly located in the right colon, tended to be larger than RER− tumours, and were more often poorly diVerentiated than RER− cancers. No significant associations were seen between RER status and the presence of a mutant c-Ki-ras gene, or between RER status and p53, c-erbB-2, or c-myc gene expression. Univariate survival analysis showed that outcome was similar in RER+ and RER− cases. Multivariate survival analysis showed that the relative risk of death for patients with RER+ cancers was 0.95 that of patients with RER− cancers. Conclusions-The results suggest that, while the RER phenotype may be associated with some diVerences in tumour pathology (site, size, diVerentiation), it is not associated with the genetic alterations studied or with significant diVerences in long term survival.

Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy

“…Most published studies suggest that MSI ϩ CRC generally has a more favorable outcome, 4,7,10,12,[31][32][33][34][35] although not all reports agree. 37,38 To our knowledge, our study is the first analysis based on a prospective series, and the analysis restricted to stage C only, eliminating the confounding effect of the unequal stage distribution between MSI ϩ and MSI Ϫ populations. 4,9 -12 Furthermore, unlike in earlier studies, we restricted the analysis to patients treated with 5-FU-based adjuvant chemotherapy, because adjuvant therapy has a substantial effect on outcome and needs to be taken into account when assessing prognosis.…”

“…However, adjuvant therapy had not been randomized and the stage distribution of MSI ϩ cases was more favorable. Curran et al 38 studied 159 stage B CRC patients, and found no association between survival and MSI status. In a retrospective series of 213 patients with stage C CRC who had not received adjuvant chemotherapy, MSI ϩ cases were found to have a more favorable prognosis.…”

Frequency of loss of hMLH1 expression in colorectal carcinoma increases with advancing age

“…Several studies have found no correlation between MSI and age in patients with colon carcinoma. 17,[27][28][29][30] However, most of those studies had a small sample sizes and may have lacked the power to detect statistically significant associations. hMLH1 expression loss spread over different age groups was not examined systematically in any of those studies.…”

Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis

“…Furthermore, patients with MSI-H tumours and a high content of activated cytotoxic lymphocytes showed improved overall survival (Guidoboni et al, 2001). Some studies have reported improved survival among colorectal cancer patients with microsatellite unstable tumours (Lothe et al, 1993;Thibodeau et al, 1993;Bubb et al, 1996;Lukish et al, 1998;Halling et al, 1999;Johannsdottir et al, 1999;Massa et al, 1999;Elsaleh et al, 2000;Gryfe et al, 2000;Hemminki et al, 2000;Wright et al, 2000;Ward et al, 2001;Watanabe et al, 2001), while others have not (Messerini et al, 1997;Senba et al, 1998;Feeley et al, 1999;Salahshor et al, 1999;Curran et al, 2000).…”