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

Jones, Angela; Douglas, Eleanor J.; Halford, Sarah; Fiegler, Heike; Gorman, Patricia; Roylance, Rebecca; Carter, Nigel P.; Tomlinson, Ian

doi:10.1038/sj.onc.1208194

Cited by 85 publications

(70 citation statements)

References 19 publications

(20 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most published articles, but not all, indicate that diploid tumors have a better outcome than aneuploid tumors. [5][6][7]42 The disparity of prognosis in patients with diploid tumors might be due to the fact that a small proportion of the MSS-diploid tumors have a p53 mutation.…”

Section: Discussionmentioning

confidence: 99%

Relationship between genetic alterations and prognosis in sporadic colorectal cancer

Chang

Lin

Yang

et al. 2005

Intl Journal of Cancer

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 99%

Relationship between genetic alterations and prognosis in sporadic colorectal cancer

Chang

Lin

Yang

et al. 2005

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…It is intriguing that TTK, a CIN-related gene, is mutated in MSI. There is evidence that MSI and CIN may not be mutually exclusive, and that both 'CIN-negative and MSInegative' and 'CIN-positive and MSI-positive' cancers may exist (23,24). Frequent somatic mutations of other CIN-related genes in MSI-H cancers and the TTK mutations identified in the present study might possibly explain the overlapping of MSI and CIN in the cancers.…”

Section: Discussionmentioning

confidence: 65%

Mutational Analysis of TTK Gene in Gastric and Colorectal Cancers with Microsatellite Instability

Ahn

Kim

et al. 2009

Cancer Res Treat

View full text Add to dashboard Cite

PurposeThe TTK gene plays a crucial role in regulation of the mitotic checkpoint. The TTK gene has an A9 mononucleotide repeat in the coding sequences, which harbors mutations in gastric (GC) and colorectal cancers (CRC) with microsatellite instability (MSI). However, there are three more repeats (the A7s) in the coding sequences that have not been analyzed. The aim of this study was to explore whether the three A7s as well as the A9 are altered in GC and CRC, and to find any association of TTK mutation with clinocopathologic characteristics of GC and CRC. Materials and MethodsWe analyzed exon 5 (A7 and A7) and exon 22 (A9 and A7) which have repeat sequences in 30 GC with high MSI (MSI-H), 15 GC with low MSI (MSI-L), 35 CRC with MSI-H, and 15 CRC with MSI-L, by single-strand conformation polymorphism (SSCP) and DNA sequencing assays. ResultsOverall, we detected 23 frameshift mutations in the repeat sequences of TTK in the GC with MSI-H (11/30; 36.7%) and the CRC with MSI-H (12/35; 34.3%), but not in the cancers with MSI-L. The mutations were observed in both A9 and A7 of exon 22, but in neither of the two A7s of exon 5. The mutations consisted of c.2560delA, c.2560dupA, c.2571delA and c.[2560delA (+)2571delA]. All of the mutations were frameshift mutations and would result in premature stops of TTK protein synthesis. There was no significant difference in clinopathologic parameters of the cancers with the mutations. ConclusionOur data indicate that frameshift mutations of TTK are common in both GC and CRC with MSI-H, and that the mutations occur not only in the A9 repeat but also in the A7 repeat. The data suggest that frameshift mutations of TTK might alter cell cycle control in the affected cells and contribute to pathogenesis of cancers with MSI-H.

show abstract

“…For example, most methods of overall instability assessment are based on the initial identification of altered segments through the use of author-selected thresholds (Itzhar et al, 2011;Tap et al, 2011;Rousseau et al, 2010;Tsuji et al, 2010;Liu et al, 2009;Hsu et al, 2008;O'Regan et al, 2006;Jones et al, 2005). Alternatively, Fridlyand et al (2006) used the MergeLevels segment combination procedure as a foundation for genetic instability assessment.…”

Section: Limitations Of Current Methodsmentioning

confidence: 99%

“…In some recent studies, differences (across cancer subtypes) in the average number of alterations per hybridization were merely reported and statistical significance was not assessed (see, e.g., Itzhar et al, 2011;Tap et al, 2011;Rousseau et al, 2010; Liu et al, 2009;Carvalho et al, 2007;Bernardini et al, 2005). Other authors have made comparisons based upon the total number of altered clones per tumor were made utilizing tests of statistical significance (see, e.g., Buffart et al, 2011;Tsuji et al, 2010;Hsu et al, 2008;Natrajan et al, 2007;O'Regan et al, 2006;Wilting et al, 2006;Jones et al, 2005).…”

Section: Current Measures Of Acgh-based Instabilitymentioning

confidence: 99%

Comparison of Clinical Subgroup aCGH Profiles through Pseudolikelihood Ratio Tests

Engler¹,

Shen

Gusella

et al. 2011

Statistical Applications in Genetics and Molecular Biology

View full text Add to dashboard Cite

Array-based Comparative Genomic Hybridization (aCGH) is a microarray-based technology that assists in identification of DNA sequence copy number changes across the genome. Examination of differences in instability phenotype, or pattern of copy number alterations, between cancer subtypes can aid in classification of cancers and lead to better understanding of the underlying cytogenic mechanism. Instability phenotypes are composed of a variety of copy number alteration features including height or magnitude of copy number alteration level, frequency of transition between copy number states such as gain and loss, and total number of altered clones or probes. That is, instability phenotype is multivariate in nature. Current methods of instability phenotype assessment, however, are limited to univariate measures and are therefore limited in both sensitivity and interpretability. In this paper, a novel method of instability assessment is presented that is based on the Engler et al. (2006) pseudolikelhood approach for aCGH data analysis. Through use of a pseudolikelihood ratio test (PLRT), more sensitive assessment of instability phenotype differences between cancer subtypes is possible. Evaluation of the PLRT method is conducted through analysis of a meningioma data set and through simulation studies. Results are shown to be more accurate and more easily interpretable than current measures of instability assessment.

show abstract

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

Cited by 85 publications

References 19 publications

Relationship between genetic alterations and prognosis in sporadic colorectal cancer

Relationship between genetic alterations and prognosis in sporadic colorectal cancer

Mutational Analysis of TTK Gene in Gastric and Colorectal Cancers with Microsatellite Instability

Comparison of Clinical Subgroup aCGH Profiles through Pseudolikelihood Ratio Tests

Contact Info

Product

Resources

About