Mitochondrial heteroplasmic shifts reveal a positive selection of breast cancer

Background Breast cancer is, despite screening, not always detected early enough and is together with other tumor types known to shed genetic information in circulation. Unlike single-copy nuclear DNA, mitochondrial DNA (mtDNA) copies range from 100s to 10,000s per cell, thus providing a potentially...

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Bibliographic Details
Published in:Journal of Translational Medicine Vol. 21; no. 1; pp. 1 - 14
Main Authors: Li, Yanni, Sundquist, Kristina, Vats, Sakshi, Hong, Mun-Gwan, Wang, Xiao, Chen, Yilun, Hedelius, Anna, Saal, Lao H., Sundquist, Jan, Memon, Ashfaque A.
Format: Journal Article
Language:English
Published: London Springer Science and Business Media LLC 05.10.2023
BioMed Central
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
Analysis
Basic Medicine
Bioinformatics
Biomedical and Life Sciences
Biomedicine
Biopsy
Breast cancer
Breast Neoplasms
Cancer
Cancer and Oncology
Cancer och onkologi
Case-Control Studies
Cellular Metabolism Therapy
Clinical Medicine
ddPCR validation
Development and progression
Diagnosis
DNA, Mitochondrial
Exercise
Female
Gene mutations
Genetic aspects
Genetic testing
Genomes
Germ-Line Mutation
Health aspects
Health surveys
Heteroplasmic mutation
Heteroplasmy
Humans
Klinisk medicin
Mammography
Medical and Health Sciences
Medical diagnosis
Medical Genetics and Genomics (including Gene Therapy)
Medical prognosis
Medicin och hälsovetenskap
Medicine
Medicine/Public Health
Medicinsk genetik och genomik (Här ingår: Genterapi)
Medicinska och farmaceutiska grundvetenskaper
Middle Aged
Mitochondrial DNA
Mortality
mtDNA
Mutation
Natural selection
Oncology, Experimental
Plasma
Positive selection
Prevention
R
Risk factors
Sequencing
Womens health
Sweden
United States > US
Germany
Breast cancer
ddPCR validation
mtDNA
Sequencing
Heteroplasmic mutation
ISSN:1479-5876, 1479-5876
Online Access:Get full text
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Summary:Background Breast cancer is, despite screening, not always detected early enough and is together with other tumor types known to shed genetic information in circulation. Unlike single-copy nuclear DNA, mitochondrial DNA (mtDNA) copies range from 100s to 10,000s per cell, thus providing a potentially alternative to identify potential missing cancer information in circulation at an early stage. Methods To characterize mitochondrial mutation landscapes in breast cancer, whole mtDNA sequencing and bioinformatics analyses were performed on 86 breast cancer biopsies and 50 available matched baseline cancer-free whole blood samples from the same individuals, selected from a cohort of middle-aged women in Sweden. To determine whether the mutations can be detected in blood plasma prior to cancer diagnosis, we further designed a nested case-control study (n = 663) and validated the shortlisted mutations using droplet digital PCR. Results We detected different mutation landscapes between biopsies and matched whole blood samples. Compared to whole blood samples, mtDNA from biopsies had higher heteroplasmic mutations in the D-loop region ( P  = 0.02), RNR2 ( P  = 0.005), COX1 ( P  = 0.037) and CYTB ( P  = 0.006). Furthermore, the germline mtDNA mutations had higher heteroplasmy level than the lost ( P  = 0.002) and de novo mutations ( P  = 0.04). The nonsynonymous to synonymous substitution ratio (dN/dS) was higher for the heteroplasmic mutations ( P  = 7.25 × 10 −12 ) than that for the homoplasmic mutations, but the de novo ( P  = 0.06) and lost mutations ( P  = 0.03) had lower dN/dS than the germline mutations. Interestingly, we found that the critical regions for mitochondrial transcription: MT-HSP1 (odds ratio [OR]: 21.41), MT-TFH (OR: 7.70) and MT-TAS2 (OR: 3.62), had significantly higher heteroplasmic mutations than the rest of the D-loop sub-regions. Finally, we found that the presence of mt.16093T > C mutation increases 67% risk of developing breast cancer. Conclusions Our findings show that mitochondrial genetic landscape changes during cancer pathogenesis and positive selection of mtDNA heteroplasmic mutations in breast cancer. Most importantly, the mitochondrial mutations identified in biopsies can be traced back in matched plasma samples and could potentially be used as early breast cancer diagnostic biomarkers.
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ISSN:1479-5876
1479-5876
DOI:10.1186/s12967-023-04534-4