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Mutations in Mitochondrial DNA From Pancreatic Ductal Adenocarcinomas Associate With Survival Times of Patients

Julia F Hopkins1, Robert E Denroche2, Jennifer A Aguiar1

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Mitochondrial somatic mutations (mtSNVs) are common in early pancreatic cancer, with some linked to shorter survival. Tumors accumulate these mutations during progression, suggesting a role in cancer development.

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Area of Science:

  • Genetics
  • Oncology
  • Mitochondrial Biology

Background:

  • Somatic mutations in mitochondrial DNA are observed in various cancers.
  • Their precise role in tumorigenesis and cancer progression remains unclear.

Purpose of the Study:

  • To investigate the presence and impact of mitochondrial somatic mutations (mtSNVs) in early-stage pancreatic ductal adenocarcinoma.
  • To explore the association between mtSNVs and patient survival, as well as their interaction with nuclear mutations.

Main Methods:

  • Analysis of mitochondrial genomes from 268 pancreatic tumors and paired non-tumor tissues.
  • Definition of mtSNVs based on heteroplasmy fraction difference (≥0.2).
  • Investigation of mutation patterns, affected genes, and co-occurrence with nuclear mutations.

Main Results:

  • 61% of tumors harbored at least one mtSNV, with 304 identified in total.
  • The noncoding control region was frequently affected, alongside genes like ND5, RNR2, CO1, and tRNA genes.
  • mtSNVs in ND4 and ND6 were associated with shorter overall survival, dependent on heteroplasmy levels.
  • Evidence of non-random co-occurrence between mtSNVs and nuclear mutations was found.
  • Mitochondrial mutations accumulated with tumor progression in primary tumors and metastases.

Conclusions:

  • Mitochondrial somatic mutations are prevalent in early pancreatic cancer and can impact patient survival.
  • Interactions between mitochondrial and nuclear mutations suggest complex oncogenic mechanisms.
  • Mitochondrial mutational burden increases during tumor progression.