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1.
Oncotarget ; 6(31): 30500-15, 2015 Oct 13.
Article in English | MEDLINE | ID: mdl-26437221

ABSTRACT

Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target.


Subject(s)
Biomarkers, Tumor/genetics , Colonic Neoplasms/mortality , Colonic Neoplasms/pathology , Proteins/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/genetics , Colon/cytology , Colon/metabolism , Female , Gene Expression Regulation, Neoplastic , Gene Knockout Techniques , HeLa Cells , Humans , Hyaluronic Acid/metabolism , Hyaluronoglucosaminidase , Intestinal Mucosa/cytology , Intestinal Mucosa/metabolism , Kaplan-Meier Estimate , Mice , Mice, Nude , Molecular Sequence Data , Neoplasm Staging , Neoplasm Transplantation , Oligonucleotide Array Sequence Analysis , Prognosis , Proteins/genetics , RNA, Messenger/biosynthesis , Transplantation, Heterologous
2.
Genome Med ; 7: 69, 2015.
Article in English | MEDLINE | ID: mdl-26269717

ABSTRACT

Reliable detection of somatic copy-number alterations (sCNAs) in tumors using whole-exome sequencing (WES) remains challenging owing to technical (inherent noise) and sample-associated variability in WES data. We present a novel computational framework, ENVE, which models inherent noise in any WES dataset, enabling robust detection of sCNAs across WES platforms. ENVE achieved high concordance with orthogonal sCNA assessments across two colorectal cancer (CRC) WES datasets, and consistently outperformed a best-in-class algorithm, Control-FREEC. We subsequently used ENVE to characterize global sCNA landscapes in African American CRCs, identifying genomic aberrations potentially associated with CRC pathogenesis in this population. ENVE is downloadable at https://github.com/ENVE-Tools/ENVE.


Subject(s)
Black or African American/genetics , Colorectal Neoplasms/genetics , DNA Copy Number Variations , Software , Exome , Genomics , Humans , Mutation , Polymorphism, Single Nucleotide
4.
Proc Natl Acad Sci U S A ; 112(4): 1149-54, 2015 Jan 27.
Article in English | MEDLINE | ID: mdl-25583493

ABSTRACT

We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors.


Subject(s)
Black or African American/genetics , Colonic Neoplasms/ethnology , Colonic Neoplasms/genetics , Mutation , Proto-Oncogene Proteins/genetics , Receptor, EphA6/genetics , Tumor Suppressor Proteins/genetics , Exome , Female , Genome-Wide Association Study , Humans , Male , White People/genetics
5.
Oncogene ; 24(4): 724-31, 2005 Jan 20.
Article in English | MEDLINE | ID: mdl-15580307

ABSTRACT

Cancers of the colon and rectum are the second leading cause of cancer death among adult Americans. When detected at early stages, colon cancer is highly curable. Colonoscopy, an effective but invasive screening test, has been limited in its public acceptance. The goal of this study was to identify novel serum markers of colon cancers and precancerous colon adenomas as potential candidates for noninvasive detection of early colon neoplasms. Employing expression microarrays, we identified colon cancer secreted protein-2 (CCSP-2) as a novel transcript whose expression is generally absent in normal colon and other normal body tissues, but that is induced an average of 78-fold in Stage II, III, and IV colon cancers, as well as in colon adenomas and colon cancer cell lines. These findings were validated by real-time PCR analysis in an independent panel of colon cancer cases. Moreover, CCSP-2 was shown to encode a secreted protein that circulates stably and is detectable in the blood of mice bearing human cancer xenografts transfected with epitope-tagged CCSP-2. As a novel secreted protein that is markedly induced in colon adenomas and cancers, CCSP-2 is a novel candidate for development as a diagnostic serum marker of early stage colon cancer.


Subject(s)
Biomarkers, Tumor/blood , Colonic Neoplasms/blood , Colonic Neoplasms/pathology , Transcription Factors/blood , Amino Acid Sequence , Animals , Base Sequence , Biomarkers, Tumor/chemistry , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Calcium-Binding Proteins , Cell Line, Tumor , Colonic Neoplasms/genetics , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Humans , Mice , Molecular Sequence Data , Neoplasm Transplantation , Oligonucleotide Array Sequence Analysis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transcription Factors/chemistry , Transcription Factors/genetics , Transcription Factors/metabolism , Transplantation, Heterologous
6.
Cancer Res ; 63(7): 1568-75, 2003 Apr 01.
Article in English | MEDLINE | ID: mdl-12670906

ABSTRACT

To identify potential effectors of transforming growth factor (TGF)-beta-mediated suppression of colon cancer, we used GeneChip expression microarrays to identify TGF-beta-induced genes in VACO 330, a nontransformed TGF-beta-sensitive cell line derived from a human adenomatous colon polyp. PMEPA1 was identified as a gene highly up-regulated by TGF-beta treatment of VACO 330. Northern blot analysis confirmed TGF-beta induction of PMEPA1 in VACO 330, as well as a panel of three other TGF-beta-sensitive colon cell lines. PMEPA1 induction could be detected as early as 2 h after TGF-beta treatment and was not inhibited by pretreatment of cells with cycloheximide, suggesting that PMEPA1 is a direct target of TGF-beta signaling. Wild-type PMEPA1 and an alternative splice variant lacking the putative transmembrane domain were encoded by the PMEPA1 locus and were shown by epitope tagging to encode proteins with differing subcellular localization. Both variants were found to be expressed in normal colonic epithelium, and both were shown to be induced by TGF-beta. Consistent with TGF-beta playing a role in terminal differentiation of colonocytes, in situ hybridization of normal colonic epithelium localized PMEPA1 expression to nonproliferating, terminally differentiated epithelium located at the top of colonic crypts. Intriguingly, in situ hybridization and Northern blot analysis showed that the expression of PMEPA1 was well maintained both in colon cancer primary tumors and in colon cancer liver metastases. PMEPA1 is thus a novel TGF-beta-induced marker of a differentiated crypt cell population. Moreover, as PMEPA1 expression is maintained, presumptively in a TGF-beta-independent manner after malignant transformation and metastasis, it demonstrates that even late colon cancers retain a strong capacity to execute many steps of the normal colonic differentiation program.


Subject(s)
Colonic Neoplasms/metabolism , Membrane Proteins/biosynthesis , Transforming Growth Factor beta/physiology , Alternative Splicing , Amino Acid Sequence , Base Sequence , Cell Differentiation/genetics , Cell Division/physiology , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Colon/cytology , Colon/metabolism , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/secondary , Membrane Proteins/genetics , Membrane Proteins/metabolism , Molecular Sequence Data , Protein Isoforms , Signal Transduction/physiology , Subcellular Fractions/metabolism , Transfection , Transforming Growth Factor beta/pharmacology , Up-Regulation
7.
Cancer Res ; 62(4): 1134-8, 2002 Feb 15.
Article in English | MEDLINE | ID: mdl-11861394

ABSTRACT

Oncogene activation by gene amplification is a major pathogenetic mechanism in human cancer. Using comparative genomic hybridization, we determined that metastatic human colon cancers commonly acquire numerous extra copies of chromosome arms 7p, 8q, 13q, and 20q. We then examined the consequence of these amplifications on gene expression using DNA microarrays. Of 55,000 transcripts profiled, 2,146 were determined to map to one of the four common colon cancer amplicons and to also be expressed in normal or malignant colon tissues. Of these, only 81 transcripts (3.8%) demonstrated a 2-fold increase over normal expression among cancers bearing the corresponding chromosomal amplification. Chromosomal amplifications are common in colon cancer metastasis, but increased expression of genes within these amplicons is rare.


Subject(s)
Colonic Neoplasms/genetics , Gene Amplification , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Neoplasm Metastasis , Nucleic Acid Hybridization , Oligonucleotide Array Sequence Analysis , Up-Regulation
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