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
by
Hakushi Kim 1,*,†, Tomoyoshi Komiyama 2,†, Masahiro Nitta 1, Yoshiaki Kawamura 1, Masanori Hasegawa 1, Sunao Shoji 1, Yasushi Orihashi 2, Chie Inomoto 3, Hiroshi Kajiwara 3, Naoya Nakamura 3, Hiroyuki Kobayashi 2 and Akira Miyajima 1
Hakushi Kim 1,*,†, Tomoyoshi Komiyama 2,†, Masahiro Nitta 1, Yoshiaki Kawamura 1, Masanori Hasegawa 1, Sunao Shoji 1, Yasushi Orihashi 2, Chie Inomoto 3, Hiroshi Kajiwara 3, Naoya Nakamura 3, Hiroyuki Kobayashi 2 and Akira Miyajima 1
1
Department of Urology, Tokai University School of Medicine, Kanagawa, Isehara 259-1193, Japan
2
Department of Clinical Pharmacology, Tokai University School of Medicine, Kanagawa, Isehara 259-1193, Japan
3
Department of Pathology, Tokai University School of Medicine, Kanagawa, 259-1193 Isehara, Japan
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Genes 2019, 10(12), 998; https://doi.org/10.3390/genes10120998
Received: 5 November 2019 / Revised: 28 November 2019 / Accepted: 29 November 2019 / Published: 2 December 2019
(This article belongs to the Special Issue Mitochondrial DNA Mutations in Human Diseases)
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.
Keywords:
mitochondrial DNA; D-loop mutations; NADH dehydrogenase subunit 1; renal cell carcinoma; cancer-specific survival; prognostic factor
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Kim, H.; Komiyama, T.; Nitta, M.; Kawamura, Y.; Hasegawa, M.; Shoji, S.; Orihashi, Y.; Inomoto, C.; Kajiwara, H.; Nakamura, N.; Kobayashi, H.; Miyajima, A. 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. Genes 2019, 10, 998.
Show more citation formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.
