SSAT - TWO PROTEIN COMBINATION OF CHITINASE 3-LIKE-1 AND MATRIX METALLOPROTEINASE 3 IMPROVES SENSITIVITY AND SPECIFICITY OF PLASMA ANALYSIS FOR DIAGNOSIS OF COLORECTAL CANCER

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TWO PROTEIN COMBINATION OF CHITINASE 3-LIKE-1 AND MATRIX METALLOPROTEINASE 3 IMPROVES SENSITIVITY AND SPECIFICITY OF PLASMA ANALYSIS FOR DIAGNOSIS OF COLORECTAL CANCER
H M C Shantha Kumara^*1, Hiromichi Miyagaki², Geoffrey Bellini¹, Abhinit Shah^1,3, Erica Pettke¹, Xiaohong Yan¹, Vesna Cekic¹, Nipa D. Gandhi¹, Richard L. Whelan¹
¹Department of Surgery, Mount Sinai West Hospital, New York 10019, NY; ²Department of Surgery, Saiseikai Senri Hospital, Suita, Osaka., Japan; ³Topiwala National Medical College, Mumbai,Maharashtra-400008, Dr A.L. Nair Road, Mumbai Central, India

Introduction: Chitinase 3-Like-1 (CHI3L1) and matrix metalloproteinase-3(MMP3) are over expressed in many cancers including colorectal cancer(CRC). CHI3L1 is a secreted glycoprotein that enhances macrophage production of IL8 and MCP-1 in the tumor microenvironment which promotes tumor angiogenesis and progression. CHI3L1 also promotes in vitro cancer cell proliferation, human endothelial cell migration and tube formation. MMP3 plays a role in the breakdown of extracellular matrix ( and connective tissue remodeling and is thought to facilitate solid tumor progression and metastasis. Biosynthesis of MMP3 is regulated by epidermal growth factor, TNF- α, and IL1. The active form of MMP3 stimulates the epithelial-mesenchymal transition during tumor development. Together with its activator matriptase, MMP3 has also been associated with the regulation of VEGF bioavailability. The goal of this study was to determine and compare preoperative (PreOp) plasma CHI3L1 and MMP3 levels in CRC and benign pathology (BP) patients (pts.). The study hypothesis was that these proteins hold promise as diagnostic markers for colorectal cancer.
Method: PreOp plasma samples from consenting CRC and BP pts. undergoing elective resection from an IRB approved tissue bank were studied. Plasma levels of CHI3L1 and MMP3 (ng/ml) were determined in duplicate via ELISA and reported as median + 95%CI. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to evaluate the diagnostic value of single and multiple plasma protein levels. Expression levels were also determined in the tumors and paired normal tissues of a subpopulation of study patients by QRT-PCR. The Mann-Whitney test was used for statistical analysis (significance p<0.05).
Results: Plasma from 71 BP (polyp 32%, diverticulitis 65%, other 3%) and 166 CRC (79% colon, 21% rectal) pts. were studied. The CRC stage distribution was: Stage-1, 23%; Stage-2, 39%, Stage-3,28%, Stage-4,10%. The CRC median preop plasma protein levels were significantly higher vs. the BP group results [CHI3L1;87.7, CI:80.5,115.3 vs 37.1,CI:30.3, 44.5;MMP3; 14.5,CI:13.2,16.0 vs 9.3,CI:8.5,10.8; P<0.0001). Plasma CHI3L1 levels in stage 4 and MMP3 levels in stage 3 were significantly higher vs their respective stage 1 pts.(p=0.03). The AUC value for the ROC curve for CHI3L1 and MMP3 were 0.80 and 0.75 respectively with 55% and 75% sensitivity. The AUC for the combination of these 2 proteins was 0.87 with 71% sensitivity and 90% specificity. Expression of CHI3L1 and MMP3were elevated in 92% of CRC tumors tested vs. paired normal tissues (n=12).
Conclusion: The median CHI3L1and MMP3values in CRC pts were significantly higher (136% and 55%) than BP levels. The two protein combination improved AUC, sensitivity& specificity vs single protein results and may have value as a diagnostic panel. Further study is warranted.

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