Germline variability and tumor expression level of ribosomal protein gene RPL28 are associated with survival of metastatic colorectal cancer patients

Adrien Labriet,Lyne Villeneuve,Chantal Guillemette,Eric P Allain,Derek Jonker,Angela Buonadonna,Félix Couture,David Simonyan,Éric Lévesque,Mario D’Andrea,Michèle Rouleau,Giuseppe Toffoli,Erika Cecchin,Elena De Mattia

doi:10.1038/s41598-019-49477-3

Abstract

This study investigated the potential of single nucleotide polymorphisms as predictors of survival in two cohorts comprising 417 metastatic colorectal cancer (mCRC) patients treated with the FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) regimen. The rs4806668G > T of the ribosomal protein gene RPL28 was associated with shorter progression-free survival and overall survival by 5 and 9 months (P = 0.002), with hazard ratios of 3.36 (P < 0.001) and 3.07 (P = 0.002), respectively. The rs4806668T allele was associated with an increased RPL28 expression in transverse normal colon tissues (n = 246, P = 0.007). RPL28 expression was higher in colorectal tumors compared to paired normal tissues by up to 124% (P < 0.001) in three independent datasets. Metastatic cases with highest RPL28 tumor expression had a reduced survival in two datasets (n = 88, P = 0.009 and n = 56, P = 0.009). High RPL28 was further associated with changes in immunoglobulin and extracellular matrix pathways. Repression of RPL28 reduced proliferation by 1.4-fold to 5.6-fold (P < 0.05) in colon cancer HCT116 and HT-29 cells. Our findings suggest that the ribosomal RPL28 protein may influence mCRC outcome.

Highlights

IntroductionThis study investigated the potential of single nucleotide polymorphisms as predictors of survival in two cohorts comprising 417 metastatic colorectal cancer (mCRC) patients treated with the FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) regimen
This study investigated the potential of single nucleotide polymorphisms as predictors of survival in two cohorts comprising 417 metastatic colorectal cancer patients treated with the FOLFIRI regimen
We report that the germline variant rs4806668G > T in RPL28 and tumor expression of this gene are associated with survival of metastatic colorectal cancer (mCRC) patients

Summary

Introduction

This study investigated the potential of single nucleotide polymorphisms as predictors of survival in two cohorts comprising 417 metastatic colorectal cancer (mCRC) patients treated with the FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) regimen. The FOLFIRI regimen is composed of irinotecan (CPT-11) used in combination with 5-fluorouracil (5-FU) and folinic acid alone or with targeted therapies[2] Both irinotecan and 5-FU are potent on actively replicating cancer cells. Several genes were found to be associated with response to irinotecan and 5-FU in vitro, but their potential value as markers of treatment response has not been addressed in patients These genes are related to several pathways such as detoxification of reactive oxygen species, cellular responses to stress, DNA damage recognition or DNA repair. We tested the hypothesis that genetic variability in these genes may be associated with survival of mCRC patients treated with FOLFIRI-based regimen

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Results

Conclusion