Unraveling the gene expression signatures with associated clinical outcomes in papillary renal cell carcinoma.
Authors: Raygoza Garay Juan Antonio , Madala Samragnyi , Kroll Matthew Robert , Grass George Daniel , Gupta Sumati , Graham Laura , Kauffman Eric , King Jennifer , Myint Zin , Viscuse Paul Vincent , Ghodoussipour Saum , Kern Sean , Ayanambakkam Adanma , Salhia Bodour , Churchman Michelle , Singer Eric A. , Zakharia Yousef 
Published: June 2024

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Background: Papillary renal cell carcinoma (pRCC) is the second most common subtype of renal cancer. It is further subdivided into type I and type II, with type II being more aggressive. Previous analysis by the Cancer Genome Atlas (TCGA) Research Network suggested the clustering of pRCC tumors with MET alterations, CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element pathways. Nevertheless, there exists a gap in understanding the impact of altered molecular pathways or gene characteristics on the clinical outcomes of pRCC patients. Our study aims to explore gene expression signatures utilizing the Oncology Research Information Exchange Network (ORIEN) database and their associations with overall survival (OS) patterns in individuals diagnosed with pRCCs. Methods: Through whole RNA sequencing of kidney tumor tissue we examined the genes whose expression was associated with OS. Gene expression data were quantified using salmon and summarized at the gene level. Gene Expression batch correction was performed to remove technical sources of variation, and the vst normalized expression values were used in subsequent analyses. Time to event was defined as the time of the last contact – the time of tissue collection for sequencing. Univariate survival analysis was performed using the Cox-proportional hazards model (R survival package), correcting for Age, Sex, and Race. Results: The cohort consisted of 107 individuals with RNASeq and time-to-event data. 79% of individuals were male. The individuals had a median age of 69 years (IQR 61-72). After p-value adjustment (False Discovery Rate), two genes were significantly associated with OS (fdr≤ 0.05). The first gene was YTHDF2, inversely associated with survival, having a hazard ratio of 0.002 95% CI [0.0289 - 0.0002], p-value= 0.025. Previous studies suggested this gene overexpressed in several cancers relative to adjacent normal tissue, whereas its expression was reduced in pRCC in the TCGA dataset. The second gene, SEC31A, is also negatively associated with OS, with a hazard ratio of 0.02 95% CI [0.0289 - 0.0002], p-value= 0.0001. SEC31A is an outer coat protein complex II (COPII) component associated with pRCC and other papillary-type neoplasms. It is involved in the formation of transport vesicles from the endoplasmic reticulum. Moreover, SEC31A is involved in gene fusions with at least two gene fusion partners. These include PTEN (SEC31A-PTEN) and ALK (SEC31A-ALK). SEC31A-ALK fusion has been reported in a patient with recurrent pRCC and observed in lung metastases and many other pRCC studies. Conclusions: This is the first study to evaluate OS for pRCC tumor in correlation with gene expression profiles. This study highlights the importance of studying the association of molecular profiles with real-world clinical data and its collection, in understanding pRCC.