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Mitochondrial heteroplasmic shifts reveal a positive selection of breast cancer

Li, Yanni LU ; Sundquist, Kristina LU ; Vats, Sakshi LU ; Hong, Mun-Gwan LU ; Wang, Xiao LU ; Chen, Yilun LU ; Hedelius, Anna LU ; Saal, Lao H LU orcid ; Sundquist, Jan LU and Memon, Ashfaque A LU orcid (2023) In Journal of Translational Medicine 21(1).
Abstract

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... (More)

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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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Middle Aged, Humans, Female, Breast Neoplasms/genetics, Case-Control Studies, Mutation/genetics, DNA, Mitochondrial/genetics, Germ-Line Mutation
in
Journal of Translational Medicine
volume
21
issue
1
article number
696
pages
14 pages
publisher
BioMed Central (BMC)
external identifiers
  • pmid:37798736
  • scopus:85173336130
ISSN
1479-5876
DOI
10.1186/s12967-023-04534-4
project
Circulating DNA as biomarker of early detection and diagnosis of cancer
language
English
LU publication?
yes
additional info
© 2023. BioMed Central Ltd., part of Springer Nature.
id
96759b5e-7794-433b-a528-82bec9f6845a
date added to LUP
2023-10-24 11:12:32
date last changed
2025-04-19 13:52:22
@article{96759b5e-7794-433b-a528-82bec9f6845a,
  abstract     = {{<p>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.</p><p>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.</p><p>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 <br>
 -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 &gt; C mutation increases 67% risk of developing breast cancer.<br>
 </p><p>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.</p>}},
  author       = {{Li, Yanni and Sundquist, Kristina and Vats, Sakshi and Hong, Mun-Gwan and Wang, Xiao and Chen, Yilun and Hedelius, Anna and Saal, Lao H and Sundquist, Jan and Memon, Ashfaque A}},
  issn         = {{1479-5876}},
  keywords     = {{Middle Aged; Humans; Female; Breast Neoplasms/genetics; Case-Control Studies; Mutation/genetics; DNA, Mitochondrial/genetics; Germ-Line Mutation}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Journal of Translational Medicine}},
  title        = {{Mitochondrial heteroplasmic shifts reveal a positive selection of breast cancer}},
  url          = {{http://dx.doi.org/10.1186/s12967-023-04534-4}},
  doi          = {{10.1186/s12967-023-04534-4}},
  volume       = {{21}},
  year         = {{2023}},
}