Comprehensive molecular characterization of human colon and rectal cancer
To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome seq...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2014
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| Online Access: | http://hdl.handle.net/1721.1/84660 |
| _version_ | 1826204728166449152 |
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| author | Lander, Eric Steven |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Lander, Eric Steven |
| author_sort | Lander, Eric Steven |
| collection | MIT |
| description | To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression. |
| first_indexed | 2024-09-23T13:00:27Z |
| format | Article |
| id | mit-1721.1/84660 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:00:27Z |
| publishDate | 2014 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/846602022-10-01T12:24:23Z Comprehensive molecular characterization of human colon and rectal cancer Lander, Eric Steven Massachusetts Institute of Technology. Department of Biology Lander, Eric S. To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression. National Institutes of Health (U.S.) (Grant U24CA143799) National Institutes of Health (U.S.) (Grant U24CA143835) National Institutes of Health (U.S.) (Grant U24CA143840) National Institutes of Health (U.S.) (Grant U24CA143843) National Institutes of Health (U.S.) (Grant U24CA143845) National Institutes of Health (U.S.) (Grant U24CA143848) National Institutes of Health (U.S.) (Grant U24CA143858) National Institutes of Health (U.S.) (Grant U24CA143866) National Institutes of Health (U.S.) (Grant U24CA143867) National Institutes of Health (U.S.) (Grant U24CA143882) National Institutes of Health (U.S.) (Grant U24CA143883) National Institutes of Health (U.S.) (Grant U24CA144025) National Institutes of Health (U.S.) (Grant U54HG003067) National Institutes of Health (U.S.) (Grant U54HG003079) National Institutes of Health (U.S.) (Grant U54HG003273) 2014-02-03T20:39:43Z 2014-02-03T20:39:43Z 2012-07 2011-11 Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/84660 Muzny, Donna M., Matthew N. Bainbridge, Kyle Chang, Huyen H. Dinh, Jennifer A. Drummond, Gerald Fowler, Christie L. Kovar, et al. “Comprehensive molecular characterization of human colon and rectal cancer.” Nature 487, no. 7407 (July 18, 2012): 330-337. en_US http://dx.doi.org/10.1038/nature11252 Nature Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Nature Publishing Group Nature |
| spellingShingle | Lander, Eric Steven Comprehensive molecular characterization of human colon and rectal cancer |
| title | Comprehensive molecular characterization of human colon and rectal cancer |
| title_full | Comprehensive molecular characterization of human colon and rectal cancer |
| title_fullStr | Comprehensive molecular characterization of human colon and rectal cancer |
| title_full_unstemmed | Comprehensive molecular characterization of human colon and rectal cancer |
| title_short | Comprehensive molecular characterization of human colon and rectal cancer |
| title_sort | comprehensive molecular characterization of human colon and rectal cancer |
| url | http://hdl.handle.net/1721.1/84660 |
| work_keys_str_mv | AT landerericsteven comprehensivemolecularcharacterizationofhumancolonandrectalcancer |