Abstract
Abstract Background: Telomeres (T) consist of thousands of copies of TTAGGG tandem repeats capping the ends of the chromosome. Studies have linked short T length (TL) with premalignant and malignant stages of colorectal cancer (CRC) carcinogenesis. However, the relation of TL to response to drugs used in treatment of CRC has not been conclusively determined. In this study, we used a panel of CRC cell lines and analyzed each TL, and determined relationship to drug sensitivity. We validated our in vitro findings in a pool of samples collected from patients with metastatic CRC (mCRC) undergone anti-EGFR therapy at our institution. Methods: DNA was isolated from CRC cell lines grown in culture, and from formalin fixed paraffin embedded specimens. Cells were cultured and treated with varying concentrations of cetuximab, oxaliplatin, 5-FU, camptothecin, aspirin, sulindac, trichostatin, curcumin, and butyrate. TL was measured using a qRT-PCR method that provided the relative T copy number, compared to reference single copy number of the housekeeping gene, β-Globin (S), which resulted in a T/S ratio. One T/S ratio unit is equivalent to a mean TL of 4,270 base pairs. Results: In a panel of 22 CRC cell lines, TL was independently predicative of cetuximab sensitivity. When split at the median, thee cell lines with a shorter TL had a mean cetuximab sensitivity of 18.6% (growth inhibition at 20 ug/ml at 72 hours by MTT assay), as compared to 39.7% in those cells with longer TL; p=0.02. Response to all of the other drugs did not bear any relationship to TL. To further validate our in vitro finding, we analyzed the TL in patients with mCRC who had been treated with cetuximab or panitumumab. In this sample of 75 patients, 118 tissue samples were identified (66 primary, 52 metastases, 29 matched pairs). Forty five patients had received greater than 4 weeks of therapy and were considered for clinical correlates. Patients with K-Ras WT tumors had a superior progression free survival (PFS) and overall survival than those with K-Ras mutated tumors (p<0.05). Importantly, among the patients with K-Ras WT tumors, those with a longer TL had a superior outcome with median PFS of 28.1 weeks as compared to those with shorter TL, median14.7 weeks, p=0.019. Conclusion: TL is a potential biomarker predictive of sensitivity to cetuximab, in vitro, and of outcome for patients treated with cetuximab/panitumumab, as measured by PFS. These findings will be validated in a larger dataset, and the mechanistic basis for this finding is currently under investigation. Citation Format: Titto A. Augustine, Mahadi A. Baig, John M. Mariadason, Radhashree Maitra, Sanjay Goel. Telomere length: A novel biomarker for anti-EGFR therapy in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2835. doi:10.1158/1538-7445.AM2014-2835
Published Version
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