D-loop Mutations in Renal Cell Carcinoma Improve Predictive Accuracy for Cancer-Related Death by Integrating with Mutations in the NADH Dehydrogenase Subunit 1 Gene

Hakushi Kim,Naoya Nakamura,Masanori Hasegawa,Sunao Shoji,Yasushi Orihashi,Akira Miyajima,Hiroyuki Kobayashi,Chie Inomoto,Yoshiaki Kawamura,Masahiro Nitta,Hiroshi Kajiwara,Tomoyoshi Komiyama

doi:10.3390/genes10120998

Abstract

Renal cell carcinoma (RCC) is associated with various genetic alterations. Although whole-genome/exome sequencing analysis has revealed that nuclear genome alterations are associated with clinical outcomes, the association between nucleotide alterations in the mitochondrial genome and RCC clinical outcomes remains unclear. In this study, we analyzed somatic mutations in the mitochondrial D-loop region, using RCC samples from 61 consecutive patients with localized RCC. Moreover, we analyzed the relationship between D-loop mutations and NADH dehydrogenase subunit 1 (MT-ND1) mutations, which we previously found to be associated with clinical outcomes in localized RCC. Among the 61 localized RCCs, 34 patients (55.7%) had at least one mitochondrial D-loop mutation. The number of D-loop mutations was associated with larger tumor diameter (>32 mm) and higher nuclear grade (≥ISUP grade 3). Moreover, patients with D-loop mutations showed no differences in cancer-specific survival when compared with patients without D-loop mutations. However, the co-occurrence of D-loop and MT-ND1 mutations improved the predictive accuracy of cancer-related deaths among our cohort, increasing the concordance index (C-index) from 0.757 to 0.810. Thus, we found that D-loop mutations are associated with adverse pathological features in localized RCC and may improve predictive accuracy for cancer-specific deaths when combined with MT-ND1 mutations.

Highlights

In renal cell carcinoma (RCC), representative gene mutations and chromosomal hyperploidy have been shown to depend on the histological subtype of the RCC, e.g., clear cell, papillary, chromophobe, or other subtypes [1]
We found that displacement loop (D-loop) mutations are associated with adverse pathological features in localized RCC, which may improve the prediction of cancer-specific deaths when used in combination with mutations and NADH dehydrogenase subunit 1 (MT-ND1) mutations
We evaluated the association of cancer-specific survival (CSS) with D-loop mutations with or without MT-ND1 mutations identified in our previous study

Summary

Introduction

In renal cell carcinoma (RCC), representative gene mutations and chromosomal hyperploidy have been shown to depend on the histological subtype of the RCC, e.g., clear cell, papillary, chromophobe, or other subtypes [1]. Mutations in the von Hippel–Lindau gene have been extensively studied in clear cell RCC (ccRCC) and have been shown to play a critical role in the initiation and progression. Papillary RCC is the second most common histological subtype of RCC and is characterized genetically by trisomy and tetrasomy of chromosome 7, trisomy of chromosome 17, and loss of the Y chromosome [3]. Recent large-scale whole-exome and targeted sequencing studies have revealed frequent recurrent mutations in ccRCC [6,7] and have reported that specific gene mutations, such as BAP1 or SETD2 mutations, are associated with shorter overall survival and higher relapse rates [8]. A comprehensive genome analysis of RCC is currently underway to assess nuclear DNA (nDNA) mutations in RCC; the mutational profiles of mitochondrial DNA (mtDNA) in patients with RCC have not been sufficiently elucidated, and the associations of mtDNA mutations with clinicopathological features and prognoses among patients with localized RCC are poorly understood

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Discussion

Conclusion