Molecular Predictors of Survival after Adjuvant Chemotherapy for Colon Cancer

Watanabe, Toshiaki; Wu, Tsung Teh; Catalano, Paul J.; Ueki, Takashi; Satriano, Robert; Haller, Daniel G.; Benson, Al B.; Hamilton, Stanley R.

doi:10.1056/nejm200104193441603

Cited by 787 publications

(538 citation statements)

References 62 publications

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“…To date, many reports suggest that this deletion is a molecular predictor that affects survival (Fearon et al, 1990;Jen et al, 1994;Chung, 1998;Lanza et al, 1998;Ogunbiyi et al, 1998;Jernvall et al, 1999;McLeod and Murray, 1999;Sarli et al, 2004). We too reported that the allelic deletion of chromosome 18q was associated with poorer prognosis in stage III colon cancer after adjuvant chemotherapy (Watanabe et al, 2001. These reports suggest that there might be tumour suppressor genes located at chromosome 18q, which has a strong influence on survival.…”

mentioning

confidence: 62%

Chromosome 18q deletion and Smad4 protein inactivation correlate with liver metastasis: a study matched for T- and N- classification

et al. 2006

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Smad4 protein, whose gene is coded at chromosome 18q21.1, is an important tumour suppressor that mediates transforming growth factor-beta. It has been reported that inactivation of the Smad4 gene and allelic loss of chromosome 18q correlate with liver metastasis and poorer prognosis in colorectal cancers. Utilising a recently developed method of immunohistochemical staining for Smad4 protein, we focused on the specific impact of Smad4 protein expression on liver metastasis in colorectal cancer. We also evaluated the association between chromosome18q deletion and liver metastasis. We selected 20 colorectal cancers with liver metastasis for the experimental group, and 20 cases without liver metastasis for the control. In order to exclude the influence of lymph node metastasis, all cases were lymph node negative. In addition, the two groups were matched for tumour depth, tumour differentiation and tumour location. We compared the expression level of Smad4 protein immunohistochemically in these 20 matched pairs. We also compared the loss of heterozygosity status at chromosome 18q in these 20 matched pairs. Immunohistochemical staining revealed a significant difference (P ¼ 0.024) in the level of Smad4 protein between the two groups. We also observed a significantly different (P ¼ 0.0054) ratio of allelic deletion at chromosome 18q21. Smad4 protein expression level and allelic loss at 18q21 are associated with the process of liver metastasis in colorectal cancers evaluated when excluding clinical and pathological features except for liver metastasis. (Vogelstein et al, 1988(Vogelstein et al, , 1989Benhattar et al, 1993;Kinzler and Vogelstein, 1996;Span et al, 1996;Kambara et al, 2004;Nassif et al, 2004). Loss of heterozygosity (LOH) is one of the major types of genetic inactivation, and the long arm of chromosome 18 is the most frequently deleted region in colorectal cancers. To date, many reports suggest that this deletion is a molecular predictor that affects survival (Fearon et al, 1990;Jen et al, 1994;Chung, 1998;Lanza et al, 1998;Ogunbiyi et al, 1998;Jernvall et al, 1999;McLeod and Murray, 1999;Sarli et al, 2004). We too reported that the allelic deletion of chromosome 18q was associated with poorer prognosis in stage III colon cancer after adjuvant chemotherapy (Watanabe et al, 2001. These reports suggest that there might be tumour suppressor genes located at chromosome 18q, which has a strong influence on survival. Smad4 gene, which mediates the intracellular signalling pathway of transforming growth factor (TGF)-beta receptor, has been detected as one of the target genes at 18q21 (Wang et al, 1995;Eppert et al, 1996;Hahn et al, 1996;Thiagalingam et al, 1996;Carethers et al, 1998;Markowitz, 2000;Fink et al, 2003;Alazzouzi et al, 2005;Li et al, 2005). Recently, an immunohistochemical method for evaluating Smad4 protein has been developed and several studies found higher frequency of Smad4 protein inactivation in the cases with liver metastasis and in the cases presenting unfavourable survival (Maitra et al, 20...

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confidence: 62%

Chromosome 18q deletion and Smad4 protein inactivation correlate with liver metastasis: a study matched for T- and N- classification

et al. 2006

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“…This is an important issue taking into account the possibility to introduce immunohistochemical analysis of MMR protein expression as a routine diagnostic test and would provide valuable management information in addition to the histopathological assessment of tumour stage and grade. This is all the more important since the predictive value of the MSI status in the good response to chemotherapy has recently been stressed (Elsaleh et al, 2000;Hemminki et al, 2000;Watanabe et al, 2001).…”

Section: Molecular and Cellular Pathologymentioning

confidence: 99%

Microsatellite instability and intratumoural heterogeneity in 100 right-sided sporadic colon carcinomas

et al. 2002

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Microsatellite instability has been proposed as an alternative pathway of colorectal carcinogenesis. The aim of this study was to evaluate the interest of immunohistochemistry as a new tool for highlighting mismatch repair deficiency and to compare the results with a PCR-based microsatellite assay. A total of 100 sporadic proximal colon adenocarcinomas were analysed. The expression of hMLH1, hMSH2 and hMSH6 proteins evaluated by immunohistochemistry was altered in 39% of the cancers, whereas microsatellite instability assessed by PCR was detected in 43%. There was discordance between the two methods in eight cases. After further analyses performed on other tumoural areas for these eight cases, total concordance between the two techniques was observed (Kappa=100%). Our results demonstrate that immunohistochemistry may be as efficient as microsatellite amplification in the detection of unstable phenotype provided that at least two samples of each carcinoma are screened, because of intratumoural heterogeneity.

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“…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. 17 Furthermore, these patients had a 74% 5-year survival following adjuvant 5FU-based chemotherapy compared to 46% in patients with MSI-high tumours that lacked the mutation. Thus, mutation of the gene for the type II receptor for TGF␤-1 may predict the response of MSI-high tumours to 5FU-based chemotherapy.…”

Section: Microsatellite Instability (Msi)mentioning

confidence: 95%

“…5,6 This association has not been a consistent observation as some studies have found the opposite, 7 or no correlation. 8,9 However, the majority of DNA sequencing studies have shown a significantly shorter survival time in patients with mutant p53. 10 Data from studies in cell line models have suggested that p53 status influences 5FU chemosensitivity.…”

Section: Colorectal Cancer Biologymentioning

confidence: 99%