Tumor Buds Show Reduced Expression of Laminin-5 Gamma 2 Chain in DNA Mismatch Repair Deficient Colorectal Cancer

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Abstract

Purpose:

Tumor budding at the invasive margin of colorectal cancer is an important adverse prognostic factor. The subset of colorectal cancer that is deficient in DNA mismatch repair has been associated with a good prognosis. It is hypothesized that tumor budding in this subset may lack biologic aggressiveness because it is not associated with aberrant expression of the independent prognostic factor, laminin-5 gamma 2.

Methods:

Eighty colorectal cancers with high-grade tumor budding were studied, including nine sporadic colorectal cancers with immunohistochemical loss of expression of MLH1 (MLH1(−)), seven colorectal cancers from patients with hereditary nonpolyposis colorectal cancer, and 64 sporadic colorectal cancers expressing both MLH1 and MSH2 (MLH1(+)). Two regulatory mechanisms for laminin-5 gamma 2 expression were explored, including aberrant nuclear expression of β-catenin by immunohistochemistry and promoter methylation of laminin-5 gamma 2 by methylation-specific polymerase chain reaction.

Results:

Only three of nine MLH1(−) colorectal cancers showed expression of laminin-5 gamma 2 compared with 46 of 64 MLH1(+) colorectal cancers (P= 0.05). Only two of seven hereditary nonpolyposis colorectal cancers expressed laminin-5 gamma2 compared with MLH1(+) colorectal cancers (P= 0.03). Expression of nuclear β-catenin was more frequent (58 percent) in MLH1(+) colorectal cancers compared with MLH1(−) colorectal cancers (11 percent,P= 0.01). Methylation of laminin-5 gamma 2 was found in 5 of 38 (13 percent) cases but did not differ among colorectal cancer subsets. Four of five colorectal cancers with methylation of laminin-5 gamma 2 were scored as negative for laminin-5 gamma 2 by immunohistochemistry.

Conclusions:

The reduced expression of laminin-5 gamma 2in colorectal cancers with deficient DNA mismatch repair may underlie a variant of tumor budding that is relatively nonaggressive.

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