Integrative Genomics Identified RFC3 As an Amplified Candidate Oncogene in Esophageal Adenocarcinoma

Abstract

Purpose 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. Experimental Design Whole genome tiling-path array CGH was used to identify significant regions of copy number (CN) alteration in 20 EACs and 10 matching BE tissues. CN 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 ~25% of EAC samples. RFC3 was also amplified in BE from a patient whose EAC harbored amplification, and was differentially expressed between non-malignant and EAC tissues. CN gains were detected in other cancer types and RFC3 knockdown inhibited proliferation and anchorage-independent growth of cancer cells with increased CN, 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.

Sine oculis homeobox homolog 1 promotes DNA replication and cell proliferation in cervical cancer

“…DNA polymerases and RFC are important not only for DNA replication, but also for cell cycle control (26). RFC3 and RFC4 were reported to promote tumor cell proliferation (28,29). High RFC3 expression was associated with poor prognosis in a variety of cancers (28).…”

“…RFC3 and RFC4 were reported to promote tumor cell proliferation (28,29). High RFC3 expression was associated with poor prognosis in a variety of cancers (28). Importantly, SIX1 not only increased the expression of DNA polymerase δ3 (POLD3) and polymerase ε2 (POLE2), but also upregulated the expression of RFC (RFC3, RFC4, RFC5).…”

Residual Esophageal Cancer after Neoadjuvant Chemoradiotherapy Frequently Involves the Mucosa and Submucosa

“…27 This heterogeneity could be caused by microsatellite instability, 28 loss of heterozygosity, 29,30 and copy number variations. 31,32 Extrinsic factors include differences in oxygenation levels and cancer cell-stroma interactions. It has long been recognized that low tissue oxygenation levels are negatively correlated with cancer cell sensitivity to radiotherapy 33,34 and chemotherapy.…”

Identification of a subset of patients with acute myeloid leukemia characterized by long-termin vitroproliferation and altered cell cycle regulation of the leukemic cells

“…Increased protein and/or mRNA expression of these genes (HMMR, NUSAP1, TOP2A, BUB1, AURKB) is found in AML [33][34][35][36][37][38][39][40], and an association between high levels and adverse prognosis has been described for HMMR, TOP2A and AURKB [37,38,40,41]. Several of the identified genes also show high expression in other human malignancies [27,28,[42][43][44][45]]. In addition, some of the differentially expressed genes appear to have coordinated expression and direct functional links [46]; NUSAP, DLGAP5, AURKB and BUB1 seem to be regulated by the Ran-GTPase [26,29,47,48], and there is also a complex interaction between BUB1 and aurora kinase B; several reports suggest that BUB1 is an upstream activator of AURKB and thereby can be involved in cellular transformation, whereas other observations suggest that BUB1 is found downstream or involved in a parallel pathway [43].…”