Genotypic Heterogeneity May Influence Tumor Immunologic Response in DNA Mismatch Repair Deficient Colorectal Carcinoma.
Gloria Q Young, David S Klimstra, Martin R Weiser, Laura H Tang, Efsevia Vakiani, Nora Katabi, Xiaoling Xiong, Zsofia K Stadler, Jinru Shia. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: DNA mismatch repair (MMR) deficiency in colorectal carcinoma (CRC) has been associated with tumor behavior and clinical outcome. It is believed that the mutator phenotype results in an increased immune response which may then account for the better outcome observed in MMR-deficient CRCs. It is unclear whether the nature and extent of the immune response differ among different genotypic alterations (e.g., germline mutation versus somatic change, or the specific gene that is mutated). Clarification of these issues may provide insights into the biology of MMR deficient CRCs and carry prognostic and therapeutic implications.
Design: Histological features with an emphasis on the type of inflammatory response were analyzed among MMR-deficient CRCs from 2 groups of patients: 1) Lynch syndrome (LS) cases with a defined pathogenic mutation in 1 of the 4 MMR genes; and 2) sporadic cases defined by personal/family history and/or MLH1 hypermethylation without germline mutation. For statistical analysis, proportions were compared by chi-square analysis and means compared by ANOVA.
Results: Group 1 had 33 cases (13 with mutations in MLH1, 15 in MSH2, 2 in MSH6 and 3 in PMS2) and group 2 had 23. No significant difference was seen between the 2 groups in terms of tumor stage, histologic type, presence of medullary, mucinous or heterogeneous components. Differences were seen regarding the presence of peritumoral lymphoid aggregates (PTLA) (group1 vs 2, 39% vs 4%, p=0.03), tumor associated neutrophils (TAN) (49% vs 17%, p=0.017), and tumor-infiltrating lymphocytes (TIL)/10HPFs (mean, 167 vs 88; p=0.057). Group 1 tumors were also more likely to have an expansile tumor border (82% vs 52%, p=0.018). Cases with MLH1 mutation differed from those with MSH2 mutation in PTLA (92% vs 60%, p=0.049).
Conclusions: Among the MMR-deficient CRCs studied, there was a more prominent immunologic response, manifested by PTLA, TANs and TILs, in LS cases than in sporadic ones. A difference in peritumoral lymphocytes was also seen between MLH1- mutated and MSH2-mutated LS CRCs. Such observations warrant further investigation about the effect of genotypic heterogeneity on the biology and clinical behavior of MMR-deficient CRCs.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 61, Wednesday Morning