Genetic mutations associated with metastatic clear cell renal cell carcinoma.

Zhongjun Li,Xuelian Chen,Yibu Chen,Meng Li,Kaijin Wu,Fengjie Li,Ping Hao,Jiang F Zhong,Qingjian Wu,Jiangjian Zhong,Cunye Qu,Jiang Zhao,Andres Stucky,Longkun Li

doi:10.18632/oncotarget.7473

Zhongjun Li, Xuelian Chen + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.7473

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Abstract

Metastasis is the major cause of death among cancer patients, yet early detection and intervention of metastasis could significantly improve their clinical outcomes. We have sequenced and analyzed RNA (Expression) and DNA (Mutations) from the primary tumor (PT), tumor extension (TE) and lymphatic metastatic (LM) sites of patients with clear cell renal cell carcinoma (CCRCC) before treatment. Here, we report a three-nucleotide deletion near the C-region of Plk5 that is specifically associated with the lymphatic metastasis. This mutation is un-detectable in the PT, becomes detectable in the TE and dominates the LM tissue. So while only a few primary cancer cells carry this mutation, the majority of metastatic cells have this mutation. The increasing frequency of this mutation in metastatic tissue suggests that this Plk5 deletion could be used as an early indicator of CCRCC metastasis, and be identified by low cost PCR assay. A large scale clinical trial could reveal whether a simple PCR assay for this mutation at the time of nephrectomy could identify and stratify high-risk CCRCC patients for treatments.

Highlights

Renal cell carcinoma (RCC) accounts for about 2-3% of all cancers and worldwide more than 250,000 new cases each year [1]
To identify the mutations that are unique to the metastatic RCC cells, we harvested both DNA and RNA from tissue slides of primary tumor (PT), tumor extension (TE) and lymph node metastasis (LM) from the same patient for next generation sequencing (NGS) on HiSeq 2000 (Illumina, USA)
Biomarkers associated with lymphatic metastasis could be a valuable and powerful tool for detection and intervention of metastasis, the major cause of cancer death

Summary

Introduction

Renal cell carcinoma (RCC) accounts for about 2-3% of all cancers and worldwide more than 250,000 new cases each year [1]. The most common type of RCC is clear cell renal cell carcinoma (CCRCC), which originates from the epithelial lining of the proximal convoluted tubules and is responsible for 60% to 80% of RCC among adults [2]. At the time of diagnosis approximately 25-30% patient already present metastasis with a median overall survival of less than 2 years [3]. More than 40% of RCC patients develop metastases after radical nephrectomy with poor survival rate [4]. Patients with metastatic RCC still have poor prognosis with an average survival of only 6 to 12 months from the time of diagnosis [5]. Biomarkers associated with metastatic CCRCC are important for early detection and selection of appropriate therapeutic strategies

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