Shawn A Ritchie, Bassirou Chitou, Qingan Zheng, Dushmanthi Jayasingthe, Wei Jin, Asuka Mochizuki and Dayan B Goodenowe.
In this paper, we investigated the levels of the biomarker PC-594 among North American pancreatic cancer patients. PC-594 is a fatty acid in the blood that we have previously shown to be reduced in Japanese pancreatic cancer patients. The study consisted of 99 disease-free control subjects and 84 pancreatic patients. PC-594 levels in blood were determined using the PanaSeeTM tandem mass spectrometry assay. Our results showed that 86% of North American patients, but only 9% of the disease-free group, had low PC-594 levels. There was no correlation between the levels of PC-594 and tumor stage, gender, age, treatment status, or ethnicity. No improvement in PC-594 levels following treatment, and no further reduction in late versus early-stage disease suggested that the reduction of PC-594 was not caused by the tumor. We hypothesize from this that the reduction in PC-594 occurs before the cancer develops, and could potentially represent an underlying causal mechanism. We also compared PC-594 levels to the biomarker CA19-9, which is often used in the management of pancreatic cancer. Our results showed that PC-594 performance was superior to CA19-9, with PC-594 detecting 21% more cases of cancer than CA19-9. We conclude from the results that PC-594 levels are also affected in North American patients, and that measuring PC-594 status represents a new approach for identifying subjects with increased pancreatic cancer risk.
Ritchie SA, Akita H, Takemasa I, Eguchi H, Pastural E, Nagano H, Monden M, Doki Y, Mori M, Jin W, Sajobi TT, Jayasinghe D, Chitou B, Yamazaki Y, White T, Goodenowe DB. Metabolic system alterations in pancreatic cancer patient serum: potential for early detection. BMC Cancer. 2013 Sep 12;13:416.
This paper reports on the metabolomic discovery of multiple metabolic system imbalances in the blood of 40 pancreatic cancer patients and 50 controls from Japan. We used high-resolution mass spectrometry to first identify the metabolites, followed by tandem mass spectrometry to confirm their identity. We then used a multivariate approach to select PC-594 as the top-discriminating metabolite, and designed the first-generation PanaSee™ test. The paper concludes with validation of PC-594 reduction in a small number of North American samples, and clinical decision curve analysis demonstrating a significant net clinical benefit of using PC-594 to pre-stratify subjects based on risk.
Ritchie SA, Tonita J, Alvi R, Lehotay D, Elshoni H, Myat S, McHattie J, Goodenowe DB. Low-serum GTA-446 anti-inflammatory fatty acid levels as a new risk factor for colon cancer. Int J Cancer. Jan 15, 2013; 132(2):355-62.
This paper describes the results of our 5000-patient prospective trial in Saskatchewan. In this paper, we show that 87% of early stage (I/II) and 85% of late stage (III/IV) colorectal cancer patients show a low GTA-446 level based on a 10% positivity rate in age-defined low-risk subjects.
Ritchie SA,Jayasinghe D, Davies GF, Ahiahonu P, Ma H, Goodenowe DB. Human serum-derived hydroxyl long-chain fatty acids exhibit anti-inflammatory and anti-proliferative activity. Journal of Experimental & Clinical Cancer Research. 30:59, 2011.
In this paper, we showed that GTA metabolites, including GTA-446, can protect against inflammation and induce apoptosis in vitro. The data showed that GTA-446 suppresses expression of the transcription factor NFkappaB, which is involved in mediating the expression of numerous pro-inflammatory cytokines such as interferons and cytokines. The paper concludes with a detailed discussion about mechanisms by which GTA-446 could decline with age, and how this decline could represent a driving force for cancer development.
Ritchie SA, Heath D, Yamazaki Y, Grimmalt B, Kavianpour A, Krenitsky K, Elshoni H, Takemasa I, Miyake M, Sekimoto M, Monden M, Tomonaga T, Matsubara M, Sogawa S, Matsushita K, Nomura F, Goodenowe DB. Reduction of novel circulating long-chain fatty acids in colorectal cancer patients is independent of tumor burden and correlates with age. BMC Gastroenterology. Nov. 2010; 10:140.
This paper shows that the presence of colorectal tumors are not responsible for low GTA-446 levels by comparing results prior to, and following, surgery. This paper was also our first report of an age-related decline in GTA-446 levels, as well as longitudinal stability analysis of GTA-446 in both colorectal cancer and healthy subjects. The paper concludes with a model comparing GTA-446 risk-based testing to FIT-based screening on colonoscopy burden and colorectal cancer detection rates.
Ritchie SA, Ahiahonu PW, Jayasinghe D, Heath D, Liu J, Lu Y, Jin W, Kavianpour A, Yamazaki Y, Khan AM, Hossain M, Su-Myat KK, Wood PL, Krenitsky K, Takemasa I, Miyake M, Sekimoto M, Monden M, Matsubara H, Nomura F, Goodenowe DB. Reduced levels of hydroxylated, polyunsaturated ultra long-chain fatty acids in the serum of colorectal cancer patients: implications for early screening and detection. BMC Medicine. Feb 2010; 8: 13.
This was our first publication describing the discovery of GTA metabolites, including GTA-446, and its reduction in the serum of colorectal cancer patients using non-targeted metabolomics technology. We report independent discovery populations, as well as validation results on the first-generation Cologic® tandem mass spectrometry assay.