The Cancer Testis Antigens Cabyr a/B and Caby C Are Expressed in a Subset of Colorectal Cancers and Hold Promise As Targets for Specific Immunotherapy
C. M. Shantha Kumara H*1, Otavia L. Caballero3, Tao Su2, Xiaohong Yan1, Aqeel Ahmed2, Sonali a C. Herath1, Vesna Cekic1, Daniel D. Kirchoff1, Andrew J. Simpson4, Carlos Cordon-Cardo2, Richard L. Whelan1
1Surgery, St Luke Roosevelt Hospital, New York, NY; 2Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY; 3Ludwig Collaborative Laboratory for Cancer Biology and Therapy Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD; 4Ludwig Institute for Cancer Research, New York, NY
Introduction: Human CABYR is a testis specific polymorphic calcium binding tyrosine phosphorylation regulative protein isolated from spermatozoa. This protein is localized to the sperm flagellum in association with the fibrous sheath; it can bind calcium after being phosphorylated during sperm capacitation. Six transcript variants of CABYR encoding five protein isoforms have been identified. Normally, CABYR is expressed in the human germ line but not in adult human tissues, thus, it is considered a cancer testis (CT) protein. A high frequency of expression in tumor tissues and restricted expression in normal tissues make CT proteins attractive cancer vaccine targets. Increased expression of CABYR a/b and c isoforms in lung cancers and isoforms c and d in brain tumors have been reported. The expression patterns of CABYR genes in colorectal cancer (CRC) are not well characterized. The aim of this study is to evaluate the expression of CABYR a/b and c in CRC tumors and to determine if they hold promise as vaccine targets.Method: Consenting CRC patients (pts) who underwent elective resection for whom tumor samples were available were included in the study. Demographic, clinical, and pathologic data were collected prospectively. Tissues were OCT embedded and stored at -80°C until analysis. Total purified RNA was isolated from tissue samples and cDNA synthesized. CABYR a/b and c expression was analyzed by quantitative PCR (QPCR) using the SYBR Green platform. Tumor and normal tissue expression levels were determined and compared as were tumor and testis CABYR expression levels. Tumors with expression levels 0.1% or more than the testis were considered positive. Expression of CABYR a/b and c in a set of normal human tissues was analyzed by RT-PCR.Results: A total of 47 paired CRC and normal tissue specimens (18 M/ 29 F, age 65+/-16.8) were studied (85% colon,15% rectal). Stage breakdown was as follows: Stage 2, 26; Stage 3, 19; and Stage 4, 2 pts. The percent of pts with a relative expression ratio of malignant to normal tissues (MN ratio) over 1 was 70% for CABYR a/b and 72% for CABYR-c. The percent with both a MN ratio over 1 and expression levels over 0.1% of testis was 23.4% for CABYR-a/b and 25.5% for CABYR-c. Except for very low expression of CABYR a/b in the brain, CABYR a/b or c was not expressed in normal tissues.Conclusion: RT-PCR analysis confirmed the frequent overexpression of CABYR a/b and c in most CRC tumors compared to adjacent normal tissues. In 23-26% of tumors expression was more than 0.1% of the expression level of testis. A larger and more diverse group of tumors (Stage 1-4) needs to be assessed to determine if CABYR expression correlates with T, N, or final tumor stage. Evaluation of blood for anti-CABYR antibodies is also needed. These results support CABYR as a potential therapeutic vaccine candidate in CRC.
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