[689] Two-Antibody Screen with PMS2 and MSH6 Is Equally as Effective as Four Antibodies for Identification of Mismatch Repair Defects in 1000 Colorectal Cancers.

Mark Redston, Richard Lash. Caris Life Sciences, Newton, MA and Irving, TX

Background: Analysis of DNA mismatch repair (MMR) status in colorectal cancers (CRCs) is commonly undertaken utilizing immunohistochemical (IHC) analysis of MMR protein expression. Because MMR proteins function as heterodimers, abnormalities in MLH1 or MSH2 may be identified by corresponding loss of PMS2 or MSH6 respectively. We undertook this study to determine whether testing for MMR defects with only PMS2 and MSH6 is effective in identifying MMR defects in all four proteins.
Design: 1153 consecutive biopsies diagnosed with colorectal cancer at Caris Life Sciences from March 15 through August 31, 2010 were eligible for DNA MMR testing. 152 were excluded due to inadequate tissue (21), declination by clinician (73), or the presence of other conditions (13). IHC stains for MLH1, PMS2, MSH2, and MSH6 were reviewed by a single observer (MR). MSH6 and PMS2 stains were reviewed first, and scored as either Intact (retained nuclear expression) or Deficient, including 1) absent expression (no nuclear staining) or 2) markedly reduced expression (<20% of nuclei with 2-3+ staining). MLH1 and MSH2 were independently scored according to the same criteria.
Results: 887 (84.8%) of 1046 CRCs had intact PMS2 and MSH6 expression, and 159 (15.2%) had abnormal PMS2 or MSH6 expression, including 135 (12.9%) with absent PMS2, 18 (1.7%) with absent MSH6, 2 (0.2%) with markedly reduced MSH6, and 4 (0.4%) with absent PMS2 and absent or markedly reduced MSH6. Subsequent scoring of the additional MMR IHC stains revealed that all 887 cases with intact PMS2 and MSH6 also had intact MLH1 and MSH2, while 147 of the 159 cases with PMS2 or MSH6 abnormalities also had absent MLH1 or MSH2 expression. The only CRCs with discrepant results were 6 (0.6%) cases that had absent PMS2 only and 6 (0.6%) cases that had absent MSH6 only.

PMS2/MSH6 vs. MLH1/MSH2 MMR IHC Testing
Number of CRCsPMS2/MSH6 ResultMLH1/MSH2 Result
887 (84.8%)IntactIntact
147 (14.0%)DeficientDeficient
12 (1.2%)DeficientIntact

Conclusions: IHC analysis of PMS2 and MSH6 is as sensitive in identifying defective mismatch repair protein expression as a panel that also includes MLH1 and MSH2. MLH1 and MSH2 are only required for further characterization of those CRCs with PMS2 or MSH6 defects, respectively. Of note, 12 MMR deficient CRCs would not have been identified by screening with MLH1 and MSH2 alone. These results strongly support the less costly use of PMS2 and MSH6 only in the initial screening for MMR defects.
Category: Gastrointestinal

Monday, February 28, 2011 8:30 AM

Platform Session: Section E, Monday Morning


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