Molecular Changes Including the Status of Mismatch Repair Proteins in Malignant Mesothelioma.
Heather M Sumner, Mark J Mentrikoski, Henry F Frierson, Mark R Wick, Edward B Stelow. University of Virginia, Charlottesville
Background: Malignant pleural mesothelioma (MM) is an uncommon malignancy, which has a well-known association with environmental asbestos exposure. Aside from a few recurrent cytogenetic abnormalities, the molecular changes of MM have been incompletely described. Furthermore, although above baseline asbestos exposure is one of the only well-defined risk factors for the development of the disease, familial clustering of cases has suggested to some that genetic predisposition may play some role in MM oncogenesis. Here, we explore the status of p16 and the related cyclin dependent kinase 4 (CDK4) as well as the mismatch repair proteins in a large series of pleural MM.
Design: Fifty-nine cases of MM were identified and clinical histories obtained. The cases were classified as epithelioid (35/59), sarcomatoid (10/59), or mixed (14/59). A tissue microarray was constructed. Immunohistochemistry was performed with antibodies to MLH1, PMS2, MSH2, MSH6, p16, and CDK4. Presence or absence of staining in tumor cells and intensity was recorded.
Results: Patients included 44 men and 15 women and the mean age at diagnosis was 65 years. Forty percent (24/59) of patients had a documented history of asbestos exposure within their medical record and twenty percent (12/59) of patients had a noted first-degree relative with a previous epithelial malignancy. No loss of staining for MLH1, PMS2, MSH2, or MSH6 was observed in any cases. p16 loss was identified in all but 9 cases (83%) including 100% of sarcomatoid MM. CDK4 overexpression (both nuclear and cytoplasmic) was identified in 54 cases (92%) (figures 1 and 2).
Conclusions: Defects in the mismatch repair proteins do not appear to be involved in the oncogenesis of pleural MM. Alterations in p16 are common and most MM show overespression of CDK4, a protein typically regulated by p16.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 229, Monday Morning