Dataset Information

Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer.

ABSTRACT:

Background

APC mutations (APC-mt) occur in ∼70% of colorectal cancers (CRCs), but their relationship to prognosis is unclear.

Methods

APC prognostic value was evaluated in 746 stage I-IV CRC patients, stratifying for tumour location and microsatellite instability (MSI). Microarrays were used to identify a gene signature that could classify APC mutation status, and classifier ability to predict prognosis was examined in an independent cohort.

Results

Wild-type APC microsatellite stable (APC-wt/MSS) tumours from the proximal colon showed poorer overall and recurrence-free survival (OS, RFS) than APC-mt/MSS proximal, APC-wt/MSS distal and APC-mt/MSS distal tumours (OS HR⩾1.79, P⩽0.015; RFS HR⩾1.88, P⩽0.026). APC was a stronger prognostic indicator than BRAF, KRAS, PIK3CA, TP53, CpG island methylator phenotype or chromosomal instability status (P⩽0.036). Microarray analysis similarly revealed poorer survival in MSS proximal cancers with an APC-wt-like signature (P=0.019). APC status did not affect outcomes in MSI tumours. In a validation on 206 patients with proximal colon cancer, APC-wt-like signature MSS cases showed poorer survival than APC-mt-like signature MSS or MSI cases (OS HR⩾2.50, P⩽0.010; RFS HR⩾2.14, P⩽0.025). Poor prognosis APC-wt/MSS proximal tumours exhibited features of the sessile serrated neoplasia pathway (P⩽0.016).

Conclusions

APC-wt status is a marker of poor prognosis in MSS proximal colon cancer.

SUBMITTER: Jorissen RN

PROVIDER: S-EPMC4578087 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer.

Jorissen Robert N RN Christie Michael M Mouradov Dmitri D Sakthianandeswaren Anuratha A Li Shan S Love Christopher C Xu Zheng-Zhou ZZ Molloy Peter L PL Jones Ian T IT McLaughlin Stephen S Ward Robyn L RL Hawkins Nicholas J NJ Ruszkiewicz Andrew R AR Moore James J Burgess Antony W AW Busam Dana D Zhao Qi Q Strausberg Robert L RL Lipton Lara L Desai Jayesh J Gibbs Peter P Sieber Oliver M OM

British journal of cancer 20150825 6

<h4>Background</h4>APC mutations (APC-mt) occur in ∼70% of colorectal cancers (CRCs), but their relationship to prognosis is unclear.<h4>Methods</h4>APC prognostic value was evaluated in 746 stage I-IV CRC patients, stratifying for tumour location and microsatellite instability (MSI). Microarrays were used to identify a gene signature that could classify APC mutation status, and classifier ability to predict prognosis was examined in an independent cohort.<h4>Results</h4>Wild-type APC microsatel ...[more]

PMID: 26305864

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Project description:BackgroundThe prognostic implication of wild-type APC (APC-WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined.Materials and methodsAPC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC).ResultsIn comparison with the APC-mutant (APC-MT) population (n = 255), APC-WT patients (n = 86) tended to be younger (59% of age < 40 vs. 26% of age > 50), right-sided (41.7% vs. 27%), BRAFV600E mutated (23.3% vs. 0.8%), and KRAS wild type (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1, were over-represented in the APC-WT versus APC-MT population (7% vs. 0.4% and 4.7% vs. 0.4%, respectively). APC-WT patients had a worse overall survival (OS) than APC-MT patients (22.6 vs. 45.6 months, p < .0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC-WT was predictive of poor survival (APC-MT vs. APC-WT, hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44-0.86, p = .0037). The prognostic implication of APC-WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database (APC-MT vs. APC-WT, HR, 0.63, 95% CI, 0.49-0.81, p < .0001).ConclusionAPC-WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC-MT mCRC tumors, APC-WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1. Our data suggest alternative therapy needs to be investigated in APC-WT patients.Implications for practicePatients with microsatellite stable metastatic colorectal cancer with wild-type APC had a worse overall survival than patients with mutated APC regardless of RAS/RAF status. APC status should be considered as a stratification factor in prospective trials, and novel therapeutic strategies need to be developed for this subgroup of patients.

Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets. Two conditions were compared and each sample has a biological replicate. Samples are hybridized in dye-swap, resulting in 4 hybridizations.

Dataset Information

Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer.

Background

Methods

Results

Conclusions

Publications

Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer.

Similar Datasets

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