TY - JOUR
T1 - Association between Plasma Diacetylspermine and Tumor Spermine Synthase with Outcome in Triple-Negative Breast Cancer
AU - Fahrmann, Johannes F.
AU - Vykoukal, Jody
AU - Fleury, Alia
AU - Tripathi, Satyendra
AU - Dennison, Jennifer B.
AU - Murage, Eunice
AU - Wang, Peng
AU - Yu, Chuan Yih
AU - Capello, Michela
AU - Creighton, Chad J.
AU - Do, Kim Anh
AU - Long, James P.
AU - Irajizad, Ehsan
AU - Peterson, Christine
AU - Katayama, Hiroyuki
AU - Disis, Mary L.
AU - Arun, Banu
AU - Hanash, Samir
N1 - Funding Information:
This work was supported by a faculty fellowship from the University of Texas MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment (JFF) and the National Institutes of Health CA125123 (CJC).
Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press. All rights reserved.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - MYC is an oncogenic driver of development and progression in triple-negative breast cancer (TNBC). Ornithine decarboxylase, the rate-limiting enzyme in polyamine metabolism, is a transcriptional target of MYC. We therefore hypothesized that a plasma polyamine signature may be predictive of TNBC development and progression. Methods: Using liquid chromatography mass spectrometry, polyamine levels were determined in plasma samples from newly diagnosed patients with TNBC (n = 87) and cancer-free controls (n = 115). Findings were validated in plasma samples from an independent prospective cohort of 54 TNBC, 55 estrogen receptor negative (ER-) and progesterone receptor negative (PR-) and HER2 positive (HER2+), and 73 ER+ case patients, and 30 cancer-free control subjects. Gene expression data and clinical data for 921 and 2359 breast cancer tumors were obtained from The Cancer Genome Atlas repository and the Oncomine database, respectively. Relationships between plasma diacetylspermine (DAS) and tumor spermine synthase (SMS) mRNA expression with metastasis-free survival and overall survival were determined using Cox proportional hazard models; Fisher exact tests were used to assess risk of distant metastasis in relation to tumor SMS mRNA expression. Results: An increase in plasma DAS, a catabolic product of spermine mediated through SMS, was observed in the TNBC subtype of breast cancer. Plasma levels of DAS in TNBC associated with increased risk of metastasis (plasma DAS value = 1.16, hazard ratio = 3.06, 95% confidence interval [CI] = 1.15 to 8.13, two-sided P =. 03). SMS mRNA expression in TNBC tumor tissue was also found to be predictive of poor overall survival (top 25th percentile hazard ratio = 2.06, 95% CI = 1.04 to 4.08, one-sided P =. 04) and increased risk of distant metastasis in TNBC (comparison of lowest SMS quartile [reference] to highest SMS quartile relative risk = 1.90, 95% CI = 0.97 to 4.06, one-sided Fisher exact test P=.03). Conclusions: Metabolomic profiling identified plasma DAS as a predictive marker for TNBC progression and metastasis.
AB - MYC is an oncogenic driver of development and progression in triple-negative breast cancer (TNBC). Ornithine decarboxylase, the rate-limiting enzyme in polyamine metabolism, is a transcriptional target of MYC. We therefore hypothesized that a plasma polyamine signature may be predictive of TNBC development and progression. Methods: Using liquid chromatography mass spectrometry, polyamine levels were determined in plasma samples from newly diagnosed patients with TNBC (n = 87) and cancer-free controls (n = 115). Findings were validated in plasma samples from an independent prospective cohort of 54 TNBC, 55 estrogen receptor negative (ER-) and progesterone receptor negative (PR-) and HER2 positive (HER2+), and 73 ER+ case patients, and 30 cancer-free control subjects. Gene expression data and clinical data for 921 and 2359 breast cancer tumors were obtained from The Cancer Genome Atlas repository and the Oncomine database, respectively. Relationships between plasma diacetylspermine (DAS) and tumor spermine synthase (SMS) mRNA expression with metastasis-free survival and overall survival were determined using Cox proportional hazard models; Fisher exact tests were used to assess risk of distant metastasis in relation to tumor SMS mRNA expression. Results: An increase in plasma DAS, a catabolic product of spermine mediated through SMS, was observed in the TNBC subtype of breast cancer. Plasma levels of DAS in TNBC associated with increased risk of metastasis (plasma DAS value = 1.16, hazard ratio = 3.06, 95% confidence interval [CI] = 1.15 to 8.13, two-sided P =. 03). SMS mRNA expression in TNBC tumor tissue was also found to be predictive of poor overall survival (top 25th percentile hazard ratio = 2.06, 95% CI = 1.04 to 4.08, one-sided P =. 04) and increased risk of distant metastasis in TNBC (comparison of lowest SMS quartile [reference] to highest SMS quartile relative risk = 1.90, 95% CI = 0.97 to 4.06, one-sided Fisher exact test P=.03). Conclusions: Metabolomic profiling identified plasma DAS as a predictive marker for TNBC progression and metastasis.
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U2 - 10.1093/jnci/djz182
DO - 10.1093/jnci/djz182
M3 - Article
C2 - 31503278
AN - SCOPUS:85086749697
SN - 0027-8874
VL - 112
SP - 607
EP - 616
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 6
M1 - djz182
ER -