Metabolomic Markers of Altered Nucleotide Metabolism in Early Stage Adenocarcinoma

Wikoff, William R.; Grapov, Dmitry; Fahrmann, Johannes F.; DeFelice, Brian C.; Rom, William N.; Pass, Harvey I.; Kim, Kyoungmi; Nguyen, Uyen Thao; Taylor, Sandra L.; Gandara, David R.; Kelly, Karen; Fiehn, Oliver; Miyamoto, Suzanne

doi:10.1158/1940-6207.capr-14-0329

Cited by 87 publications

(117 citation statements)

References 54 publications

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“…A few such studies showed promising results for gliomas (10, 11) and prostate cancers (12, 13). For lung cancer, previous metabolic profiling studies on cancer cell lines or tumors did not report new cancer-specific metabolites, presumably due to their focus on characterizing cancer-selective metabolic fluxes and pathways of common metabolites (14-22). …”

Section: Introductionmentioning

confidence: 99%

Cancer-Specific Production of N-Acetylaspartate via NAT8L Overexpression in Non–Small Cell Lung Cancer and Its Potential as a Circulating Biomarker

Lou

Sethuraman

Dospoy

et al. 2016

Cancer Prevention Research

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In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non-small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA) in cancer cells — undetectable in normal lung epithelium. NAA’s cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA’s cancer-specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N=577), with minimal expression in all non-malignant lung tissues (N=74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA’s clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in 46% of NSCLC patients (N=13) in comparison with age-matched healthy controls (N=21) among individuals aged 55 years or younger. Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression and its extracellular secretion can be detected in blood.

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Section: Introductionmentioning

confidence: 99%

Cancer-Specific Production of N-Acetylaspartate via NAT8L Overexpression in Non–Small Cell Lung Cancer and Its Potential as a Circulating Biomarker

Lou

Sethuraman

Dospoy

et al. 2016

Cancer Prevention Research

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“…Metabolic markers have gained increased interest recently, as they are recognized as proximal markers to the disease phenotype in comparison to other ‘omics’ markers (44–46). The footprint that products of altered tumor metabolism may leave in non-invasively collected biospecimens serves as a great opportunity for biomarker discovery.…”

Section: Discussionmentioning

confidence: 99%

Urinary Metabolite Risk Biomarkers of Lung Cancer: A Prospective Cohort Study

Haznadar

Cai

Krausz

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Lung cancer is a major health burden causing 160,000 and 1.6 million deaths annually in the United State and worldwide, respectively. Methods Seeking to identify stable and reproducible biomarkers in non-invasively collected biofluids, we assessed whether previously identified metabolite urinary lung cancer biomarkers, creatine riboside (CR), N-acetylneuraminic acid (NANA), cortisol sulfate and indeterminate metabolite 561+ were elevated in the urines of subjects prior to lung cancer diagnosis in a well-characterized prospective Southern Community Cohort Study (SCCS). Urine was examined from 178 patients and 351 non-diseased controls, confirming that one of four metabolites was associated with lung cancer risk in the overall case-control set, whereas two metabolites were associated with lung cancer risk in European-Americans. Results Odds ratio of lung cancer associated with elevated CR levels, and adjusted for smoking and other potential confounders, was 2.0 (95%CI 1.2–3.4;P=0.01). In European-Americans, both CR and NANA were significantly associated with lung cancer risk (OR=5.3 (95%CI 1.6–17.6; P=0.006 and OR=3.5 (95%CI 1.5, 8.4;P=0.004), respectively). However, race itself did not significantly modify the associations. Receiver Operating Characteristic (ROC) analysis showed that adding CR and NANA to a model containing previously established lung cancer risk factors led to a significantly improved classifier (P=0.01). Increasing urinary levels of CR and NANA displayed a positive association with increasing tumor size, strengthening a previously established link to altered tumor metabolism. Conclusion and Impact These replicated results provide evidence that identified urinary metabolite biomarkers have a potential utility as non-invasive, clinical screening tools for early diagnosis of lung cancer.

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“…Glycosylation changes have been observed in many cancers, including but not limited to liver[13–16], pancreas[17–20], lung [21, 22], breast [23], ovarian[24], colon[25] and prostate cancer[26, 27]. In many, proteins that contain these glycan changes have been identified.…”

Section: Discussionmentioning

confidence: 99%

Identification of IgM as a contaminant in lectin-FLISA assays for HCC detection

Wang

Comunale

Herrera

et al. 2016

Biochemical and Biophysical Research Communications

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Liver disease, in the form of hepatocellular carcinoma (HCC) accounts for >700,000 deaths worldwide. A major reason for this is late diagnosis of HCC. The currently used biomarker, serum alpha-fetoprotein (AFP) is elevated in 40–60% of those with HCC and other markers that can either compliment or replace AFP are desired. Our previous work has identified a number of proteins that contain altered glycans in HCC. Specifically, these altered glycans were increased levels of core and outer arm fucosylation. To determine the clinical usefulness of those identified glycoproteins, a plate based assay was developed that allowed for the detection of fucosylated glycoforms. While this method was applicable to a number of independent patient sets, it was unable to specifically detect fucosylated glycoforms in many patient samples. That is, some material was present in serum that led to non-specific signal in the lectin-fluorescence-linked immunosorbent assay (lectin-FLISA). To address this issue, a systematic process was undertaken to identify the material. This material was found to be increased levels of lectin reactive IgM. Removal of both IgG and IgM using a multi-step protein A/G incubation and filtration step removed the contaminating signal and allowed for the analysis of specific protein glycoforms. This assay was subsequently used on two sample sets, one that was shown previously to be unable to be tested via a lectin FLISA and in a larger independent sample set. The clinical usefulness of this assay in the early detection of HCC is discussed.

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Metabolomic Markers of Altered Nucleotide Metabolism in Early Stage Adenocarcinoma

Cited by 87 publications

References 54 publications

Cancer-Specific Production of N-Acetylaspartate via NAT8L Overexpression in Non–Small Cell Lung Cancer and Its Potential as a Circulating Biomarker

Cancer-Specific Production of N-Acetylaspartate via NAT8L Overexpression in Non–Small Cell Lung Cancer and Its Potential as a Circulating Biomarker

Urinary Metabolite Risk Biomarkers of Lung Cancer: A Prospective Cohort Study

Identification of IgM as a contaminant in lectin-FLISA assays for HCC detection

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