Microsatellite-stable diploid carcinoma: a biologically distinct and aggressive subset of sporadic colorectal cancer

Hawkins, Nicholas J.; Tomlinson, Ian; Meagher, Alan P.; Ward, Robyn L.

doi:10.1054/bjoc.2000.1554

Cited by 66 publications

(50 citation statements)

References 25 publications

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“…The frequency of tumors with chromosome and microsatellite stability (MSS-diploid, 26.3%) is also comparable with that published in a previous report. 19 As compared to aneuploid CRCs, relatively more poor differentiation and mucin production were found in MSS-diploid tumors and our result agrees well with the report of Tang et al 35 The molecular profile of MSSdiploid tumors included a relatively low p53 mutation rate (17.9%), low frequency of allelic loss and very low frequency of BRAF mutation. An array CGH analysis showed that MSSdiploid tumors had fewer gains and losses at chromosomal level than those of MSS-aneuploid tumors, but more than those of MSI-H tumors.…”

Section: Discussionsupporting

confidence: 92%

“…Although the carcinogenesis pathway of microsatellite stable (MSS) diploid tumors has not been elucidated, MSS diploid tumors seem to have an aggressive behavior. 19 However, it is interesting that some published reports demonstrated that patients with diploid tumors had relatively good outcome. 6,7,20 In the present study, we classified colorectal cancers into 3 major groups: MSI-H, MSS diploid and MSS aneuploid based on microsatellite analysis and DNA flow cytometry.…”

Section: 3mentioning

confidence: 99%

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Relationship between genetic alterations and prognosis in sporadic colorectal cancer

Chang

Lin

Yang

et al. 2005

Intl Journal of Cancer

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Because chromosomal chromosomal instability (CIN) and microsatellite instability (MSI) are important genetic alterations in colorectal cancers, we classified the sporadic colorectal cancers (CRC) on the status of the CIN and MSI and explored their molecular profiles. A total of 213 colorectal tumors were collected for analysis of DNA ploidy, MSI, loss of heterozygosity (LOH), mutation of p53 (exons 5 to 9), Ki-ras (exons 1 and 2) and BRAF (V599E). Relationships between clinicopathological variables and molecular analyses were analyzed with the v 2 test (Yates' correction). Kaplan-Meier survival curves were compared using logrank test. Variables with p < 0.1 were entered into the Cox regression hazard model for multivariate analysis. High microsatellite instability (MSI-H) existed in 19 tumors (8.9%), which were more likely to be right-sided (31.6%) with poor differentiation (26.3%). Seventy-one (33.3%) tumors were diploid and 142 (66.7%) were aneuploid. Mutations in p53, Ki-ras and BRAF were found in 45.1%, 41.8% and 4.2% of tumors, respectively. Based on MSI, and CIN, 3 classes were defined: (i) High microsatellite instability MSI-H tumors: young age, high carcinoembryonic antigen (CEA) level, right colon, poorly differentiated, mucin production, high BRAF mutation, lower allelic loss and relatively good prognosis; (ii) Microsatellite stability (MSS) diploid tumors: right colon, poorly differentiated, less infiltrative tumor, mucin production, lower allelic loss and low p53, BRAF mutation; (iii) MSS aneuploid tumors: more infiltrative invasion, greater allelic loss and high p53 mutation. According to multivariate analysis, tumor stage and p53 mutation were significantly associated with disease progression. The MSS diploid and MSS aneuploid CRCs could be subtyped with p53 mutation and had different prognostic outcome and molecular profiles. The 4-year disease-free survival (DFS) of patients with MSS-diploid, wild-type p53 tumors was 67% and significantly higher than those of patients with MSS-diploid, mutant p53 CRC (30%, p 5 0.003). The same trend was found in patients with MSS-aneuploid CRC(wild p53 vs. mutant p53, 64% vs. 41%, p 5 0.009). We concluded that CIN, MSI and p53 mutation status might be used as a multiple parameter profile for the prognosis of sporadic colorectal cancer. ' 2005 Wiley-Liss, Inc.Key words: p53; aneuploidy; microsatellite instability; colorectal cancer; prognosis Colorectal cancer is the third most common cancer followed behind cervix cancer and breast cancer in women and lung cancer and hepatoma in men, in Taiwan. 1 The development of most colorectal carcinomas is associated with allelic losses of tumor suppressor genes 17p (p53 gene), 5q (adenomatous polyposis coli, APC) and 18q (deleted in colorectal cancer, DCC), as well as a mutation-based dysregulation of the Ki-ras proto-oncogene. 2,3

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Section: Discussionsupporting

confidence: 92%

Section: 3mentioning

confidence: 99%

Relationship between genetic alterations and prognosis in sporadic colorectal cancer

Chang

Lin

Yang

et al. 2005

Intl Journal of Cancer

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“…This finding is similar to the situation in colorectal cancer, where MACS is identified in 15-30% of tumors. 17,[41][42][43] The pathogenesis of MACS tumors is not understood. It is noteworthy, however, that we have previously identified 44 largescale N-terminal deletion mutations of b-catenin in three small bowel adenocarcinomas characterized as MACS in the present study, indicating that inactivation of DNA repair mechanisms other than those implicated in mismatch or chromosomal repair could be involved in MACS tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

et al. 2011

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Characterization of tumor genetics and epigenetics allows to stratify a tumor entity according to molecular pathways and may shed light on the interactions of different types of DNA alterations during tumorigenesis. Small intestinal adenocarcinoma is rare, and to date the interrelation of genomic instability and epigenetics has not been investigated in this tumor type. We therefore analyzed 37 primary small bowel carcinomas with known microsatellite instability and KRAS status for chromosomal instability using comparative genomic hybridization, for the presence of aberrant methylation (CpG island methylation phenotype) by methylation-specific polymerase chain reaction, and for BRAF mutations. Chromosomal instability was detected in 22 of 37 (59%) tumors (3 of 9 microsatellite instable, and 19 of 28 microsatellite stable carcinomas). Nine carcinomas (24%) were microsatellite and chromosomally stable. High-level DNA methylation was found in 16% of chromosomal instable tumors and in 44% of both microsatellite instable and microsatellite and chromosomally stable carcinomas. KRAS was mutated in 55, 0, and 10% of chromosomal instable, microsatellite instable, and microsatellite and chromosomally stable tumors, respectively whereas the frequencies of BRAF mutations were 6% for chromosomal instable and 22% for both microsatellite instable and microsatellite and chromosomally stable carcinomas. In conclusion, in this study we show that chromosomal instable carcinomas of the small intestine are distinguished from microsatellite instable and microsatellite and chromosomally stable tumors by a high frequency of KRAS mutations, low frequencies of CpG island methylation phenotype, and BRAF mutations. In microsatellite instable and microsatellite and chromosomally stable cancers, CpG island methylation phenotype and BRAF/KRAS mutations are similarly distributed, indicating common mechanisms of tumor initiation or progression in their molecular pathogenesis.

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“…This phenotype, also known as MACS (microsatellite and chromosome stable), was originally reported by Georgiades et al (1999) in four colorectal carcinomas. Subsequent studies have confirmed that MSIÀ, neardiploid colorectal cancers do exist, and have variously suggested that they account for up to a third of all bowel cancers, have aggressive behaviour and occur more often than expected in a familial context (Hawkins et al, 2001;Giaretti et al, 2003). Conventional comparative genomic hybridization (CGH) has shown that MSIÀCINÀ cancers have fewer large-scale genetic aberrations than CIN þ carcinomas and may have fewer p53 mutations, although no specific MSIÀCINÀ molecular pathway has consistently been shown.…”

Section: Introductionmentioning

confidence: 99%

Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma

et al. 2004

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Microsatellite-stable, near-diploid (MSIÀCINÀ) colorectal carcinomas have been reported, but it is not clear as to whether these tumours form a discrete group or represent one end of the distribution of MSIÀCIN þ cancers. In order to address this question, we screened 23 MSIÀCINÀ colorectal cancers for gains and losses using array-based comparative genomic hybridization (aCGH) based on large-insert clones at about 1 Mb density. We compared our findings with those from a small set of MSI þ CIN þ cancers, and with our reported data from MSIÀCIN þ and MSI þ CINÀ cancers. We found no evidence of any form of genomic instability in MSIÀCINÀ cancers. At the level of the chromosome arm, the MSIÀCINÀ cancers had significantly fewer gains and losses than MSIÀCIN þ tumours, but more than the MSI þ CINÀ and MSI þ CIN þ lesions. The chromosomal-scale changes found in MSIÀCINÀ cancers generally involved the same sites as those in MSIÀCIN þ tumours, and in both cancer groups, the best predictor of a specific change was the total number of such changes in that tumour. A few chromosomal-scale changes did, however, differ between the MSIÀCINÀ and MSIÀCIN þ pathways. MSIÀCINÀ cancers showed: low frequencies of gain of 9p and 19p; infrequent loss of 5q and a high frequency of 20p gain. Overall, our data suggested that the MSIÀCINÀ group is heterogeneous, one type of MSIÀCINÀ cancer having few (p6) chromosomal-scale changes and the other with more (X10) changes resembling MSIÀCIN þ cancers. At the level of individual clones, frequent and/or discrete gains or losses were generally located within regions of chromosomal-scale changes in both MSIÀCINÀ and MSIÀCIN þ cancers, and fewer losses and gains were present in MSIÀCINÀ than MSIÀCIN þ tumours. No changes by clone, which were specific to the MSIÀCINÀ cancers, were found. In addition to indicating differences among the cancer groups, our results also detected over 50 sites (amplifications, potential homozygous deletion and gains or losses which extended over only a few megabases) which might harbour uncharacterized oncogenes or tumour suppressor loci. In conclusion, our data support the suggestion that some MSIÀCINÀ carcinomas form a qualitatively different group from the other cancer types, and also suggest that the MSIÀCINÀ group is itself heterogeneous.

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Microsatellite-stable diploid carcinoma: a biologically distinct and aggressive subset of sporadic colorectal cancer

Cited by 66 publications

References 25 publications

Relationship between genetic alterations and prognosis in sporadic colorectal cancer

Relationship between genetic alterations and prognosis in sporadic colorectal cancer

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma

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