Whole mitochondrial genome sequencing highlights mitochondrial impact in gastric cancer

Giovanna Chaves Cavalcante,Samia Demachki,Ândrea Ribeiro-Dos-Santos,Gilderlanio S De Araújo,Amanda Ferreira Vidal,Anderson N R Marinho,André Ribeiro-Dos-Santos,Ana Karyssa Anaissi,Tatiana Vinasco-Sandoval

doi:10.1038/s41598-019-51951-x

Giovanna Chaves Cavalcante, Samia Demachki + Show 7 more

Open Access

https://doi.org/10.1038/s41598-019-51951-x

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Journal: Scientific Reports	Publication Date: Oct 31, 2019
Citations: 19	License type: open-access

Affiliation: Universidade Federal do Pará

Abstract

Mitochondria are organelles that perform major roles in cellular operation. Thus, alterations in mitochondrial genome (mtGenome) may lead to mitochondrial dysfunction and cellular deregulation, influencing carcinogenesis. Gastric cancer (GC) is one of the most incident and mortal types of cancer in Brazil, particularly in the Amazon region. Here, we sequenced and compared the whole mtGenome extracted from FFPE tissue samples of GC patients (tumor and internal control – IC) and cancer-free individuals (external control – EC) from this region. We found 3-fold more variants and up to 9-fold more heteroplasmic regions in tumor when compared to paired IC samples. Moreover, tumor presented more heteroplasmic variants when compared to EC, while IC and EC showed no significant difference when compared to each other. Tumor also presented substantially more variants in the following regions: MT-RNR1, MT-ND5, MT-ND4, MT-ND2, MT-DLOOP1 and MT-CO1. In addition, our haplogroup results indicate an association of Native American ancestry (particularly haplogroup C) to gastric cancer development. To the best of our knowledge, this is the first study to sequence the whole mtGenome from FFPE samples and to apply mtGenome analysis in association to GC in Brazil.

Highlights

Mitochondria are organelles that perform major roles in cellular operation
There are many copies of mitochondria in each cell and such copies may present different alleles for the same variant, a state called heteroplasmy. It is well-known that mitochondrial DNA is more susceptible to alterations in comparison to nuclear DNA5–7. These alterations may lead to mitochondrial dysfunction, which in turn may account for cellular deregulation due to DNA repair defects, leading to the development of different diseases, such as cancer[8]
It is notable that hallmarks of cancer include energy deregulation and evasion of cell death, both directly related to mitochondrial function[9]

Summary

Introduction

Mitochondria are organelles that perform major roles in cellular operation. alterations in mitochondrial genome (mtGenome) may lead to mitochondrial dysfunction and cellular deregulation, influencing carcinogenesis. Mitochondria are cytoplasmic organelles that perform major roles in cell operation, including energy generation through oxidative phosphorylation (OXPHOS), cell death, calcium levels control, lipid homeostasis and metabolic cell signaling[1] These organelles have their own genome (mtGenome), with 16,569 bp of length and 37 genes, of which 13 are protein-coding genes involved in OXPHOS, 22 are transfer RNA (tRNA) genes and two are ribosomal RNA (rRNA) genes[2,3]. There are many copies of mitochondria in each cell and such copies may present different alleles for the same variant, a state called heteroplasmy It is well-known that mitochondrial DNA (mtDNA) is more susceptible to alterations in comparison to nuclear DNA5–7. These provide information about women migration and have been associated to development and outcome of different diseases, including GC18–21

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