Molecular and cellular pathways associated with chromosome 1p deletions during colon carcinogenesis

Payne, Claire M.; Crowley-Skillicorn, Cheray; Bernstein, Carol; Holubec, Hana; Bernstein, Harris

doi:10.2147/ceg.s17114

Cited by 11 publications

(13 citation statements)

References 621 publications

(555 reference statements)

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“…Previous studies based on lower resolution cytogenetic analyses of primary tumors from patients with metastatic sCRC demonstrated frequent alterations of different regions at chromosomes 1p, 7, 13q, 17p, and 18q . Herein, we identified 58 different regions in these same chromosomes that were altered preferentially in primary metastatic tumors versus primary nonmetastatic tumors.…”

Section: Discussionmentioning

confidence: 76%

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Identification of a characteristic copy number alteration profile by high‐resolution single nucleotide polymorphism arrays associated with metastatic sporadic colorectal cancer

González‐González

Fontanillo

Abad³

et al. 2014

Cancer

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BACKGROUND: Metastatic dissemination is the most frequent cause of death in patients with sporadic colorectal cancer (sCRC). It is believed that the metastatic process is related at least in part to a specific background of genetic alterations accumulated in cells from primary tumors, and the ability to detect such alterations is critical for the identification of patients with sCRC who are at risk of developing metastases. METHODS: The authors used high-resolution, 500-K single nucleotide polymorphism arrays to identify copy number alteration profiles present at diagnosis in primary tumors from patients with metastatic (n 5 23) versus nonmetastatic (n 5 26) sCRC. RESULTS: The results revealed a characteristic pattern of copy number alterations in metastatic sCRC tumors that involved losses of 23 regions at chromosomes 1p, 17p, and 18q, together with gains of 35 regions at chromosomes 7 and 13q. CONCLUSIONS: In line with expectations, the copy number profile investigated involved multiple genes that were associated previously with sCRC (ie, SMAD2) and=or the metastatic process (ie, podocalyxin-like [PODXL]), and it also was associated with a poorer outcome. Cancer 2014;120:1948-59. V C 2014 American Cancer Society.KEYWORDS: liver metastases, colorectal carcinoma, copy number change, single nucleotide polymorphism array. INTRODUCTIONSporadic colorectal cancer (sCRC) is the second leading cause of death from cancer in the Western world. 1 Up to 50% of all patients with sCRC eventually will develop metastases, and their 5-year overall survival rate is approximately 50% to 60%. 2 Once metastases (ie, mostly liver metastasis) have occurred, a complete cure is unlikely, 2 and up to two-thirds of patients with sCRC who die have evidence of liver metastasis. 3 Accumulating evidence indicates that sCRC metastasis may emerge in the context of a specific genetic tumor background associated or not with other genetic alterations, further affecting cellular control of growth and proliferation. 4 The discovery of those specific genetic alterations that would contribute toward identifying patients who are at risk of harboring or developing metastases could contribute significantly to the development of new strategies for the diagnosis and management of the diseases.In recent years, multiple recurrent chromosomal abnormalities identified in primary tumors have been associated with metastatic CRC. 4,5 Among others, these include numerical gains of the long arm of chromosome 8 (8q), 13q, and 20q and losses of the short arm of chromosome 1 (1p), 8p, 17p, 18q, and 22q. In a recent study, we used interphase fluorescence in situ hybridization (iFISH) to further establish that 17p deletion (del[17p]) involving the 17p11.2 breakpoint region and del(22q) were highly prevalent cytogenetic alterations among patients with primary sCRC who had synchronous liver metastasis. 6 However, the identification of specific genes targeted by such chromosomal alterations has proven difficult, partially because of technical issues. In recent years, the ...

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Section: Discussionmentioning

confidence: 76%

“…Loss of chromosome 1p is well documented in sCRC . Allelic losses of chromosome 1p have been associated with increased tumor aggressiveness and reduced patient survival .…”

Section: Discussionmentioning

confidence: 99%

Identification of a characteristic copy number alteration profile by high‐resolution single nucleotide polymorphism arrays associated with metastatic sporadic colorectal cancer

González‐González

Fontanillo

Abad³

et al. 2014

Cancer

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“…Rad54l and Mad2l2 ), the tumor suppressor gene Trp73 , numerous apoptotic genes ( Bcl10 , Casp9 , etc), as well as multiple micro-RNAs (e.g. Mir200a , Mir200b , and Mir34-a ) (Payne et al, 2011). The same reasoning may also apply to mouse chromosome 9, which is always lost in our cell lines and that contains segments homologous to portions of human chromosome arm 3p (3p21.2–3).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous transformation of murine epithelial cells requires the early acquisition of specific chromosomal aneuploidies and genomic imbalances

Padilla‐Nash¹,

Hathcock²,

McNeil³

et al. 2011

Genes Chromosomes & Cancer

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Human carcinomas are defined by recurrent chromosomal aneuploidies, which result in tissue-specific distribution of genomic imbalances. In order to develop models for these genome mutations and determine their role in tumorigenesis, we generated 45 spontaneously transformed murine cell lines from normal epithelial cells derived from bladder, cervix, colon, kidney, lung, and mammary gland. Phenotypic changes, chromosomal aberrations, centrosome number, and telomerase activity were assayed in control uncultured cells and in three subsequent stages of transformation. Supernumerary centrosomes, bi-nucleate cells, and tetraploidy were observed as early as 48 hr after explantation. In addition, telomerase activity increased throughout progression. Live-cell imaging revealed that failure of cytokinesis, not cell fusion, promoted genome duplication. Spectral karyotyping demonstrated that aneuploidy preceded immortalization, consisting predominantly of whole chromosome losses (4, 9, 12, 13, 16, and Y) and gains (1, 10, 15, and 19). After transformation, focal amplifications of the oncogenes Myc and Mdm2 were frequently detected. Fifty percent of the transformed lines resulted in tumors upon injection into immuno-compromised mice. The phenotypic and genomic alterations observed in spontaneously transformed murine epithelial cells recapitulated the aberration pattern observed during human carcinogenesis. The dominant aberration of these cell lines was the presence of specific chromosomal aneuploidies. We propose that our newly derived cancer models will be useful tools to dissect the sequential steps of genome mutations during malignant transformation, and also to identify cancer-specific genes, signaling pathways, and the role of chromosomal instability in this process.

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“…The chromosomal instability group includes cancers with polypoid or aneuploid karyotypes, and cancers which have numerous insertions or losses of chromosomal arms. Chromosomal instability results from speciic molecular alterations, gene silencing, and also result from structural defects occurred during cell cycle [21]. In some of the colorectal adenomas it was observed that the tumor progression starts with chromosome 7 ampliication.…”

Section: Genomic Instabilitymentioning

confidence: 99%

Microsatellite Instability in Colorectal Cancer

Parine¹,

Varsha²,

SaudAlanazi³

2016

Microsatellite Markers

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Cancer is a genetic disease. Cancer cells contain various mutations, which includes SNPs to chromosomal aberrations. Together, these changes are referred to as genome instability. Genetic instability is one of the common characteristics of colorectal cancer. In colorectal cancer three major types of genetic instability have been reported. They are chromosomal translocations, microsatellite instability (MSI), and chromosome instability (CIN). Microsatellite instability occurs due to variations in DNA mismatch repair genes, while chromosomal instability is distinguished by major chromosomal alterations occurring at cell division and usually involves -catenin and Adenomatous polyposis coli protein (APC) mutations. This chapter summarizes the major molecular mechanisms leading to genomic and microsatellite instability and tumorigenesis.

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Molecular and cellular pathways associated with chromosome 1p deletions during colon carcinogenesis

Cited by 11 publications

References 621 publications

Identification of a characteristic copy number alteration profile by high‐resolution single nucleotide polymorphism arrays associated with metastatic sporadic colorectal cancer

Identification of a characteristic copy number alteration profile by high‐resolution single nucleotide polymorphism arrays associated with metastatic sporadic colorectal cancer

Spontaneous transformation of murine epithelial cells requires the early acquisition of specific chromosomal aneuploidies and genomic imbalances

Microsatellite Instability in Colorectal Cancer

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