Clinical Testing for Defective DNA Mismatch Repair in 335 Gynecologic Neoplasms
KM Rumilla, KA Mensink, A Brigl, SN Thibodeau, F Medeiros. Mayo Clinic, Rochester, MN; University of Minnesota, Minneapolis, MN
Background: Endometrial and ovarian tumors are included in the spectrum of Hereditary Non- Polyposis Colorectal Cancer (HNPCC) neoplasms. Neoplastic lesions in HNPCC often have defective DNA mismatch repair (dMMR) which is defined by the presence of high level of microsatellite instability (MSI-H) or by loss of protein expression of one or more of the 4 main DNA mismatch repair enzymes (MLH1, MSH2, MSH6 and PMS2) as detected by immunohistochemistry (IHC). The aim of this study is to analyze gynecologic neoplasms submitted for HNPCC screening by MSI and/or IHC and compare the screening results with follow-up sequencing.
Design: The study comprised 335 consecutive gynecologic neoplasms (263 endometrial and 72 ovarian) tested from January 2002 to June 2008. The data collected included tumor type, grade, MSI and/or IHC testing and germline testing.
Results: Of the endometrial neoplasms, 77 of 256 (30%) were MSI-H, 16 of 256 (6.3%) were MSI-L and 163 (63.4%) were MSS. Of the ovarian neoplasms, 8 of 72 (11.1%) were MSI-H, 12 of 72 (16.7%) were MSI-L and 52 were MSS. By IHC, 76 of 252 (30.2%) endometrial neoplasms showed loss of protein expression, while 176 of 252 (69.8%) were normal. Over half of the endometrial neoplasms with dMMR were caused by MLH1 loss (42 cases). Loss of MSH2/MSH6 occurred in 21 cases, MSH6 alone in 9 and PMS2 alone in 4 cases. For the ovarian neoplasms tested by IHC, 9 of 67 (13.4%) had loss of protein expression while 58 of 67 (86.6%) were normal. Loss of MSH2/MSH6 occurred in 6 cases, 1 case showed loss of MLH1/PMS2 and 2 showed loss of MSH6 alone. Of those cases for which both MSI and IHC had been performed, 3 of 312 (1%) were discordant - MSI testing was MSS or MSI-L and the IHC showed loss of protein expression. Follow-up germline testing in 34 patients with endometrial neoplasms yielded 14 mutations (6 in MSH2, 4 in MSH6, 4 in MLH1). Only 3 patients with ovarian neoplasms were sent for further testing and all 3 were found to have mutations (2 in MSH2, 1 in MSH6).
Conclusions: The rate of MSI-H was higher in endometrial than in ovarian tumors. The results show that occasional discordant cases are identified by performing both methods of DNA mismatch repair testing on gynecologic neoplasms. Of the patients with gynecologic neoplasms that underwent germline testing the majority (76%) were associated with MSH2 and MSH6 mutations.
Tuesday, March 10, 2009 8:45 AM
Platform Session: Section D, Tuesday Morning