Integrative genomics identified RFC3 as an amplified candidate oncogene in esophageal adenocarcinoma.
OBJECTIVE
Esophageal adenocarcinoma (EAC) is a lethal malignancy that can develop from the premalignant condition, Barrett's esophagus (BE). Currently, there are no validated simple methods to predict which patients will progress to EAC. A better understanding of the genetic mechanisms driving EAC tumorigenesis is needed to identify new therapeutic targets and develop biomarkers capable of identifying high-risk patients that would benefit from aggressive neoadjuvant therapy. We employed an integrative genomics approach to identify novel genes involved in EAC biology that may serve as useful clinical markers.


METHODS
Whole genome tiling-path array comparative genomic hybridization was used to identify significant regions of copy number alteration in 20 EACs and 10 matching BE tissues. Copy number and gene expression data were integrated to identify candidate oncogenes within regions of amplification and multiple additional sample cohorts were assessed to validate candidate genes.


RESULTS
We identified RFC3 as a novel, candidate oncogene activated by amplification in approximately 25% of EAC samples. RFC3 was also amplified in BE from a patient whose EAC harbored amplification and was differentially expressed between nonmalignant and EAC tissues. Copy number gains were detected in other cancer types and RFC3 knockdown inhibited proliferation and anchorage-independent growth of cancer cells with increased copy number but had little effect on those without. Moreover, high RFC3 expression was associated with poor patient outcome in multiple cancer types.


CONCLUSIONS
RFC3 is a candidate oncogene amplified in EAC. RFC3 DNA amplification is also prevalent in other epithelial cancer types and RFC3 expression could serve as a prognostic marker.
Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada. william.lockwood@nih.gov
William W
WW
Lockwood
Kelsie L
KL
Thu
Lin
L
Lin
Larissa A
LA
Pikor
Raj
R
Chari
Wan L
WL
Lam
David G
DG
Beer
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000706:statistics & numerical data; D009857:Oncogenes / Q000235:genetics*; D016016:Proportional Hazards Models; D034622:RNA Interference; D051818:Replication Protein C / Q000235:genetics*
C497562:RFC3 protein, human; D051818:Replication Protein C