Alternative Lengthening of Telomeres in Human Carcinoma Subtypes.
Andrea Proctor Subhawong, Christopher Heaphy, Seung-Mo Hong, Michael Goggins, Elizabeth Montgomery, Edward Gabrielson, George Netto, William Westra, Pedram Argani, Christine Iacobuzio-Donahue, Ie-Ming Shih, Michael Torbenson, Alan Meeker. The Johns Hopkins University School of Medicine, Baltimore, MD
Background: Approximately 10-15% of human cancers do not show evidence of telomerase activity, and a subset of these maintain telomere lengths by a genetic recombination-based mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in certain sarcomas and germ cell tumors, has only rarely been reported in carcinomas. It has been suggested that telomerase expression is more stringently suppressed in mesenchymal tissues, potentially explaining the higher frequency of ALT in sarcomas; however, the prevalence of ALT has not been thoroughly assessed in carcinomas. Our lab recently reported ALT in a small subset of breast carcinomas; it has also been detected in some adrenal cortical carcinomas. The purpose of this study was to systematically investigate the frequency of ALT in epithelial tumors.
Design: We analyzed tissue microarrays (TMA) of carcinomas of breast (n= 116), salivary gland (n=31), lung (n=197), liver (n=91), kidney (n=114), ovarian serous (n=46), stomach (n=89), colon (n=104), small intestine (n=195), pancreas (n=432), and esophagus (n=88). The arrays included an assortment of primary and metastatic tumors. A sarcoma TMA (n=36) was used as a positive control. Telomere lengths were directly assessed using fluorescence in situ hybridization (FISH) with combined promyelocytic leukemia (PML) protein immunofluorescence.
Results: The ALT phenotype was identified in 7 of 91 primary liver carcinomas and 2 of 114 conventional renal cell carcinomas (1 primary, 1 metastatic). A fourth ALT-positive case was identified in a primary breast carcinoma, in addition to the 3 previously reported from our lab. In summary, 1,503 total carcinomas were analyzed yielding 13 cases of ALT (overall frequency = 0.86%).
Conclusions: This is the first observation of the ALT phenotype in liver and kidney tumors. ALT is very rare in carcinomas overall; observation in our study was restricted to 3 tumor types (breast, liver, and kidney). The telomere maintenance mechanism confers a poor prognosis in some cancers; further studies are needed to assess the prognostic significance and unique biology of carcinomas that express ALT. As cancers using the ALT pathway are predicted to be resistant to therapies based on telomerase inhibition, these results may have therapeutic consequences.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 219, Monday Morning