Prognostic significance of MTOR pathway component expression in neuroendocrine tumors
Zhi Rong Qian1, Monica Ter-Minassian, Jennifer A Chan
1Zhi Rong Qian, Monica Ter-Minassian, Jennifer A. Chan, Yu Imamura, Susanne M. Hooshmand, Aya Kuchiba, Teppei Morikawa, Lauren K. Brais, Anastassia Daskalova, Rachel Heafield, Charles S. Fuchs, Shuji Ogino, Matthew H. Kulke, Dana-Farber Cancer Institute and Harvard Medical School; Monica Ter-Minassian, Xihong Lin, David C. Christiani, Shuji Ogino, Harvard School of Public Health; David C. Christiani, Massachusetts General Hospital, Harvard Medical School; Charles S. Fuchs, Shuji Ogino, Brigham and Women's Hospital, Boston, MA.
Purpose:
Clinical studies have implicated the mechanistic target of rapamycin (serine/threonine kinase; MTOR) pathway in the regulation of neuroendocrine tumor (NET) growth. We explored whether expression of MTOR pathway components has prognostic significance in NET patients.
Patients And Methods:
We evaluated immunohistochemical expression of MTOR and phospho (p) -MTOR; its downstream targets RPS6KB1, RPS6, and EIF4EBP1; and its upstream regulators, in a cohort of 195 archival neuroendocrine tumors. We correlated expression levels with clinical outcomes, after adjusting for other prognostic variables.
Results:
We observed anticipated correlations between expression of upstream components of the MTOR pathway and their downstream targets. Expression of PIK3CA, MTOR, or p-EIF4EBP1 was associated with high MKI67 (Ki-67) labeling index. We failed to identify clinical correlations associated with expression of the upstream regulators TSC1, TSC2, AKT, p-AKT, PDPK1, PTEN, PIK3R1, or PIK3CA. In contrast, high expression of MTOR or its activated downstream targets p-RPS6KB1, p-RPS6, or p-EIF4EBP1 was associated with adverse clinical outcomes.
Conclusion:
Our observations suggest that expression of MTOR or its downstream targets may be adverse prognostic factors in neuroendocrine tumors.
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