The Association of Mitochondrial Copy Number with Sarcopenia in Adult Survivors of Childhood Cancer Open Access

Abstract

Background: Adult childhood cancer survivors (CCS) are at increased risk of frailty, with loss of muscle mass and function (sarcopenia) frequently observed.  While various cancers and treatment-related regimens are known to provoke sarcopenia, the mechanism behind these insults is elusive. Although loss of functioning mitochondria has been implicated in the pathobiology of aging in the general population, their role as agents of pathological change in CCS has yet to be explored.  Using germline (GL) peripheral blood (PBL) mitochondrial copy number (mtCN) as a proxy for functional mitochondria, this cross-sectional study investigates the association of mtCN with sarcopenia among CCS.

Methods: Participants were enrolled in a retrospective St Jude Lifetime Cohort clinical study designed to prospectively assess long-term health outcomes among adult CCS.  mtCN estimates were derived from whole-genome sequencing (WGS) data collected from 1,762 PBL GL samples, and validated by qRT-PCR.  Sarcopenia was the primary outcome, with haplogroup, demographic, clinical and treatment-related factors included as covariates.

Results: The prevalence of sarcopenia among CCS was 27%, with females significantly more afflicted (31.5% vs 22.9%; P <.0001).  Age of diagnosis was significant (P=.04), with 51.7% of CCS with sarcopenia diagnosed between 4 and 13 years of age.  Additionally, 39.0% of CCS with sarcopenia had CNS malignancies.  CCS who received radiation had twice the odds (OR, 1.8; 95% CI 1.4 to 2.2) of having sarcopenia, while glucocorticoids were protective (OR, 0.7; 95% CI 0.5 to 0.8).  WGS mtCN estimates were positively correlated with qRT-PCR (r = 0.589; p <.0001).  Multivariable logistic regression indicated that mtCN decreased with age (β = -0.77; P =.001), and was higher in females (β = 10.38; P =.01) and non-Hispanics (β = 40.66; P =.01). Logistic modeling revealed that the odds of sarcopenia increased 21% (aOR, 0.8; 95% CI 0.7 to 0.9) for every standard deviation decrease in mtCN.

Conclusion: The early appearance of a geriatric syndrome among young survivors suggests a pathobiology irrespective of normal aging.  While a growing body of evidence supports PBL mtCN as a biomarker for adverse health outcomes, this study is the first to find an association between mtCN and sarcopenia among CCS.

Table of Contents

INTRODUCTION...........................................................................1

METHODS......................................................................................2

  Study Population............................................................................2

  Outcome.........................................................................................3

  Mitochondria copy number (mtCN)...............................................4

  Covariates.......................................................................................5

  Statistical Analysis..........................................................................5

RESULTS..........................................................................................6

  Population Characteristics...............................................................6

  Treatment.........................................................................................7

  Factors associated with sarcopenia..................................................7

  Mitochondria copy number (mtCN).................................................8

  Sarcopenia and mitochondria copy number (mtCN)........................9

DISCUSSION.....................................................................................9

REFERENCES..................................................................................18

TABLE 1: Characteristics of 1,762 CCS...........................................23

TABLE 2: Associations between characteristics and sarcopenia......26

FIGURE 1: qPCR validation of WGS mtCN estimates....................29

FIGURE 2: mtCN and age by sex and by ethnic group....................30

FIGURE 3: Final Model Odds Ratios...............................................31

About this Master's Thesis

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Rollins School of Public Health
Department	Executive Masters of Public Health - MPH
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology Biology, Molecular
Keyword	prevalence pathobiology survivor treatment peripheral blood whole genome sequencing cancer survivorship copy number cross-sectional mitochondria germline childhood cohort studies sarcopenia adult
Committee Chair / Thesis Advisor	Mertens, Ann, Emory University
Committee Members	Kundu, Mondira, St. Jude Children's Hospital Ness, Kirsten, St. Jude Children's Hospital
Partnering Agencies	National or regional non-profit organization (e.g., American Cancer Society)

Last modified

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	The Association of Mitochondrial Copy Number with Sarcopenia in Adult Survivors of Childhood Cancer ()	2018-08-08 17:20:16 -0400	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions