Characterization of sporadic colon cancer by patterns of genomic instability

Ajay Goel, Christian N. Arnold, Donna Niedzwiecki, Dong K. Chang, Luigi Ricciardiello, John M. Carethers, Jeannette M. Dowell, Linda Wasserman, Carolyn Compton, Robert J. Mayer, Monica M. Bertagnolli, C. Richard Boland

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Abstract

Colorectal cancer (CRC) can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). We hypothesized that these two pathways are not always independent and that some tumorstherefore show a significant degree of overlap between these two mechanisms. We classified 209 high-risk stage II and stage III sporadic CRCs based on their MSI status, using a National Cancer Institute-recommended panel of microsatellite markers, and also identified MSI-associated mutations of CRC target genes such as TGFβRII. Evidence for CIN was gathered by identifying loss of heterozygosity (LOH) events on chromosomal arms 1p, 2p, 3p, 5q, 17p, and 18q, which are regions harboring mismatch-repair and tumor-suppressor genes that are significant in CRC development. Results of all molecular markers tested were correlated with clinicopathological variables of the cohort, including treatment outcome. Of the 209 cases, 65% cancers were microsatellite stable, 21% were MSI-low, and 14% were MSI-high (MSI-H). Overall, 51% of the tumors had at least one LOH event, with most frequent chromosomal losses observed on 18q (72.5%), followed by 5q (22%), 17p (21%), and 3p (14%). Interestingly, we observed a significant degree of overlap between MSI and CIN pathways. Of 107 cancers with LOH events, 7 (6.5%) were also MSI-H, and of 30 cancers that were MSI-H, 7 (23.3%) also had one or more LOH events. We also found that 37.8% of microsatellite-stable cancers had no LOH events identified, thus comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. Our data suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways.

Original languageEnglish (US)
Pages (from-to)1608-1614
Number of pages7
JournalCancer Research
Volume63
Issue number7
StatePublished - Apr 1 2003
Externally publishedYes

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Microsatellite Instability
Genomic Instability
Colonic Neoplasms
Loss of Heterozygosity
Microsatellite Repeats
Colorectal Neoplasms
Neoplasms
Chromosomal Instability
DNA Mismatch Repair
National Cancer Institute (U.S.)
Neoplasm Genes
Tumor Suppressor Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Goel, A., Arnold, C. N., Niedzwiecki, D., Chang, D. K., Ricciardiello, L., Carethers, J. M., ... Boland, C. R. (2003). Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Research, 63(7), 1608-1614.

Characterization of sporadic colon cancer by patterns of genomic instability. / Goel, Ajay; Arnold, Christian N.; Niedzwiecki, Donna; Chang, Dong K.; Ricciardiello, Luigi; Carethers, John M.; Dowell, Jeannette M.; Wasserman, Linda; Compton, Carolyn; Mayer, Robert J.; Bertagnolli, Monica M.; Boland, C. Richard.

In: Cancer Research, Vol. 63, No. 7, 01.04.2003, p. 1608-1614.

Research output: Contribution to journalArticle

Goel, A, Arnold, CN, Niedzwiecki, D, Chang, DK, Ricciardiello, L, Carethers, JM, Dowell, JM, Wasserman, L, Compton, C, Mayer, RJ, Bertagnolli, MM & Boland, CR 2003, 'Characterization of sporadic colon cancer by patterns of genomic instability', Cancer Research, vol. 63, no. 7, pp. 1608-1614.
Goel A, Arnold CN, Niedzwiecki D, Chang DK, Ricciardiello L, Carethers JM et al. Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Research. 2003 Apr 1;63(7):1608-1614.
Goel, Ajay ; Arnold, Christian N. ; Niedzwiecki, Donna ; Chang, Dong K. ; Ricciardiello, Luigi ; Carethers, John M. ; Dowell, Jeannette M. ; Wasserman, Linda ; Compton, Carolyn ; Mayer, Robert J. ; Bertagnolli, Monica M. ; Boland, C. Richard. / Characterization of sporadic colon cancer by patterns of genomic instability. In: Cancer Research. 2003 ; Vol. 63, No. 7. pp. 1608-1614.
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abstract = "Colorectal cancer (CRC) can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). We hypothesized that these two pathways are not always independent and that some tumorstherefore show a significant degree of overlap between these two mechanisms. We classified 209 high-risk stage II and stage III sporadic CRCs based on their MSI status, using a National Cancer Institute-recommended panel of microsatellite markers, and also identified MSI-associated mutations of CRC target genes such as TGFβRII. Evidence for CIN was gathered by identifying loss of heterozygosity (LOH) events on chromosomal arms 1p, 2p, 3p, 5q, 17p, and 18q, which are regions harboring mismatch-repair and tumor-suppressor genes that are significant in CRC development. Results of all molecular markers tested were correlated with clinicopathological variables of the cohort, including treatment outcome. Of the 209 cases, 65{\%} cancers were microsatellite stable, 21{\%} were MSI-low, and 14{\%} were MSI-high (MSI-H). Overall, 51{\%} of the tumors had at least one LOH event, with most frequent chromosomal losses observed on 18q (72.5{\%}), followed by 5q (22{\%}), 17p (21{\%}), and 3p (14{\%}). Interestingly, we observed a significant degree of overlap between MSI and CIN pathways. Of 107 cancers with LOH events, 7 (6.5{\%}) were also MSI-H, and of 30 cancers that were MSI-H, 7 (23.3{\%}) also had one or more LOH events. We also found that 37.8{\%} of microsatellite-stable cancers had no LOH events identified, thus comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. Our data suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways.",
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AU - Goel, Ajay

AU - Arnold, Christian N.

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AU - Ricciardiello, Luigi

AU - Carethers, John M.

AU - Dowell, Jeannette M.

AU - Wasserman, Linda

AU - Compton, Carolyn

AU - Mayer, Robert J.

AU - Bertagnolli, Monica M.

AU - Boland, C. Richard

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N2 - Colorectal cancer (CRC) can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). We hypothesized that these two pathways are not always independent and that some tumorstherefore show a significant degree of overlap between these two mechanisms. We classified 209 high-risk stage II and stage III sporadic CRCs based on their MSI status, using a National Cancer Institute-recommended panel of microsatellite markers, and also identified MSI-associated mutations of CRC target genes such as TGFβRII. Evidence for CIN was gathered by identifying loss of heterozygosity (LOH) events on chromosomal arms 1p, 2p, 3p, 5q, 17p, and 18q, which are regions harboring mismatch-repair and tumor-suppressor genes that are significant in CRC development. Results of all molecular markers tested were correlated with clinicopathological variables of the cohort, including treatment outcome. Of the 209 cases, 65% cancers were microsatellite stable, 21% were MSI-low, and 14% were MSI-high (MSI-H). Overall, 51% of the tumors had at least one LOH event, with most frequent chromosomal losses observed on 18q (72.5%), followed by 5q (22%), 17p (21%), and 3p (14%). Interestingly, we observed a significant degree of overlap between MSI and CIN pathways. Of 107 cancers with LOH events, 7 (6.5%) were also MSI-H, and of 30 cancers that were MSI-H, 7 (23.3%) also had one or more LOH events. We also found that 37.8% of microsatellite-stable cancers had no LOH events identified, thus comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. Our data suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways.

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