Dataset Information

Copy number abnormalities in sporadic canine colorectal cancers.

ABSTRACT: Human colorectal cancer (CRC) is one of the better-understood systems for studying the genetics of cancer initiation and progression. To develop a cross-species comparison strategy for identifying CRC causative gene or genomic alterations, we performed array comparative genomic hybridization (aCGH) to investigate copy number abnormalities (CNAs), one of the most prominent lesion types reported for human CRCs, in 10 spontaneously occurring canine CRCs. The results revealed for the first time a strong degree of genetic homology between sporadic canine and human CRCs. First, we saw that between 5% and 22% of the canine genome was amplified/deleted in these tumors, and that, reminiscent of human CRCs, the total altered sequences directly correlated to the tumor's progression stage, origin, and likely microsatellite instability status. Second, when mapping the identified CNAs onto syntenic regions of the human genome, we noted that the canine orthologs of genes participating in known human CRC pathways were recurrently disrupted, indicating that these pathways might be altered in the canine CRCs as well. Last, we observed a significant overlapping of CNAs between human and canine tumors, and tumors from the two species were clustered according to the tumor subtypes but not the species. Significantly, compared with the shared CNAs, we found that species-specific (especially human-specific) CNAs localize to evolutionarily unstable regions that harbor more segmental duplications and interspecies genomic rearrangement breakpoints. These findings indicate that CNAs recurrent between human and dog CRCs may have a higher probability of being cancer-causative, compared with CNAs found in one species only.

SUBMITTER: Tang J

PROVIDER: S-EPMC2840980 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Copy number abnormalities in sporadic canine colorectal cancers.

Tang Jie J Le Shoshona S Sun Liang L Yan Xiuzhen X Zhang Mucheng M Macleod Jennifer J Leroy Bruce B Northrup Nicole N Ellis Angela A Yeatman Timothy J TJ Liang Yanchun Y Zwick Michael E ME Zhao Shaying S

Genome research 20100119 3

Human colorectal cancer (CRC) is one of the better-understood systems for studying the genetics of cancer initiation and progression. To develop a cross-species comparison strategy for identifying CRC causative gene or genomic alterations, we performed array comparative genomic hybridization (aCGH) to investigate copy number abnormalities (CNAs), one of the most prominent lesion types reported for human CRCs, in 10 spontaneously occurring canine CRCs. The results revealed for the first time a st ...[more]

PMID: 20086242

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Project description:Colorectal cancer (CRC) is a major health concern worldwide, and recently becomes the most common cancer in Asia. The case collection of this study is one of the largest sets of CRC in Asia, and serves as representative data for investigating genomic differences between ethnic populations. We took comprehensive and high-resolution approaches to compare the clinicopathologic and genomic profiles of microsatellite instability (MSI) vs. microsatellite stability (MSS) in Taiwanese sporadic CRCs.1,173 CRC tumors were collected from the Taiwan population, and sequencing-based microsatellite typing assay was used to determine MSI and MSS. Genome-wide SNP array was used to detect CN alterations in 16 MSI-H and 13 MSS CRCs and CN variations in 424 general controls. Gene expression array was used to evaluate the effects of CN alterations, and quantitative PCR methods were used to replicate the findings in independent clinical samples.These 1,173 CRC tumors can be classified into 75 high-frequency MSI (MSI-H) (6.4%), 96 low-frequency MSI (8.2%) and 1,002 MSS (85.4%). Of the 75 MSI-H tumors, 22 had a BRAF mutation and 51 showed MLH1 promoter hypermethylation. There were distinctive differences in the extent of CN alterations between CRC MSS and MSI-H subtypes (300 Mb vs. 42 Mb per genome, p-value < 0.001). Also, chr7, 8q, 13 and 20 gains, and 8p and 18 losses were frequently found in MSS but not in MSI-H. Nearly a quarter of CN alterations were smaller than 100 kb, which might have been missed in previous studies due to low-resolution technology. 514 expressed genes showed CN differences between subtypes, and 271 of them (52%) were differentially expressed.Sporadic CRCs with MSI-H displayed distinguishable clinicopathologic features, which differ from those of MSS. Genomic profiling of the two types of sporadic CRCs revealed significant differences in the extent and distribution of CN alterations in the cancer genome. More than half of expressed genes showing CN differences can directly contribute to their expressional diversities, and the biological functions of the genes associated with CN changes in sporadic CRCs warrant further investigation to establish their possible clinical implications.

Project description:BackgroundThe cyclin-dependent-kinase inhibitors (CDKN)/retinoblastoma (RB1) pathway has been implicated as having a role in medullary thyroid carcinoma (MTC) tumorigenesis. CDKN2C loss has been associated with RET-mediated MTC in humans but with minimal phenotypic correlation provided. The objective of this study was to evaluate the association between tumor RET mutation status, CDKN2C loss, and aggressiveness of MTC in a cohort of patients with sporadic disease.MethodsTumors from patients with sporadic MTC treated at a single institution were evaluated for somatic RETM918T mutation and CDKN2C copy number loss. These variables were compared to patient demographics, pathology detail, clinical course, and disease-specific and overall survival.ResultsSixty-two MTC cases with an initial surgery date ranging from 1983 to 2009 met the inclusion criteria, of whom 36 (58%) were male. The median age at initial surgery was 53 years (range 22-81 years). The median tumor size was 30 mm (range 6-145 mm) with 29 (57%) possessing extrathyroidal extension. Nodal and/or distant metastasis at presentation was found in 47/60 (78%) and 12/61 (20%) patients, respectively. Median follow-up time was 10.5 years (range 1.1-27.8 years) for the censored observations. The presence of CDKN2C loss was associated with worse M stage and overall AJCC stage. Median overall survival of patients with versus without CDKN2C loss was 4.14 [confidence interval (CI) 1.93-NA] versus 18.27 [CI 17.24-NA] years (p < 0.0001). Median overall survival of patients with a combined somatic RETM918T mutation and CDKN2C loss versus no somatic RETM918T mutation and CDKN2C loss versus somatic RETM918T mutation and CDKN2C 2N versus no somatic RETM918T mutation and CDKN2C 2N was 2.38 [CI 1.67-NA] years versus 10.81 [CI 2.46-NA] versus 17.24 [CI 9.82-NA] versus not reached [CI 13.46-NA] years (p < 0.0001).ConclusionsThe detection of somatic CDKN2C loss is associated with the presence of distant metastasis at presentation as well decreased overall survival, a relationship enhanced by concomitant RETM918T mutation. Further defining the genes involved in the progression of metastatic MTC will be an important step toward identifying pathways of disease progression and new therapeutic targets.

Dataset Information

Copy number abnormalities in sporadic canine colorectal cancers.

Publications

Copy number abnormalities in sporadic canine colorectal cancers.

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