1. ¹Department of Experimental Medicine and Pathology, University La Sapienza, Policlinico Umberto I, Viale Regina Elena, 324, 00161 Rome, Italy
2. ²Neuromed Institute, Pozzilli, Italy
3. ³Department of Experimental Medicine, University of L'Aquila, L7100 L'Aquila, Italy
4. ⁴Division of Exprimental Oncology 1, Centro Riferimento Oncologico-IRCCS, 33081 Aviano, italy
5. ⁵Department of Preclinical and Epidemiological Research, Centro Riferimento Oncologico-IRCCS, 33081 Aviano, Italy
6. ⁶Department of Gynecology, Catholic University, Rome, Italy
7. ⁷Pasteur Institute, Cenci-Bolognetti Foundation, 00161 Rome, Italy

Correspondence: G Giannini, E-mail: giuseppe.giannini@uniroma1.it

Received 1 October 2003; Revised 20 November 2003; Accepted 2 December 2003.

Abstract

Frequent mutations of coding nucleotide repeats are thought to contribute significantly to carcinogenesis associated with microsatellite instability (MSI). We have shown that shortening of the poly(T)11 within the polypyrimidine stretch/accessory splicing signal of human MRE11 leads to the reduced expression and functional impairment of the MRE11/NBS1/RAD50 complex. This mutation was selectively found in mismatch repair (MMR) defective cell lines and potentially identifies MRE11 as a novel target for MSI. Here, we examined 70 microsatellite unstable primary human cancers and we report that MRE11 mutations occur in 83.7 and 50% of the colorectal and endometrial cancers, respectively. In the colorectal cancer series, mutated MRE11 is more frequently associated with advanced age at diagnosis and A/B stages. Biallelic mutations were present in 38.8% of the cases and more frequently associated with lower (G1/G2) grade tumors. Impaired MRE11 expression was prevalent in primary colorectal tumors with larger and biallelic shortening of the poly(T)11. Immunohistochemistry confirmed the impaired MRE11 expression and revealed NBS1-defective expression in MRE11 mutated cancers. Together with the observation that perturbation of the MRE11/NBS1/RAD50 complex predisposes to cancer, our work highlights MRE11 as a new common target in the MMR deficient tumorigenesis and suggests its role in colorectal carcinogenesis.