TDP‐43 has been identified as the pathological protein in the majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). TARDBP mutations have so far been uniquely associated with familial and sporadic ALS. We describe clinicopathological and genetic findings in a carrier of the novel K263E TARDBP variation, who developed frontotemporal dementia, supranuclear palsy, and chorea, but no signs of motor neuron disease. Neuropathologic examination revealed neuronal and glial TDP‐43‐immunoreactive deposits, predominantly in subcortical nuclei and brainstem. This is the first report of a TARDBP variation associated with a neurodegenerative syndrome other than ALS. © 2009 Movement Disorder Society
Longstanding ulcerative colitis (UC) is associated with a high risk of developing UC-related colonic adenocarcinoma (UCC). These carcinomas originate from nonadenomatous dysplastic regions referred to as dysplasia associated lesion or mass (DALM). We evaluated chromosomal and microsatellite instability (MSI) in 21 DALM/UCCs. Chromosomal instability was determined by high-resolution array comparative genomic hybridization with a 3500-element BAC-PAC array. MSI was assessed with markers BAT25 and BAT26 and by immunohistochemical analysis of mismatch repair genes. Comparative genomic hybridization revealed frequent losses of array clones (>20% of tumors) at chromosome arms 4p, 5q, and 18q, frequent gains of array clones (>20% of tumors) were found at 1q, 5p, 6p, 7p, 7q, 8p, 8q, 11p, 11q, 12q, 14q, 17q, 19q, 20p, and 20q. The pattern of alterations is dominated by gains on 5p and 20q with loss of 4p, all of which were already present in a patient with carcinoma in situ. Immunohistochemical analysis of mismatch repair genes MLH1, PMS2, MSH2, and MSH6 showed negative immunostaining in 1 neoplasm (5%). MSI of BAT25 and BAT26 was seen in 3 tumors (14%) including the neoplasm with aberrant immunostaining. In conclusion, we constructed a genomic profile of DALM/UCC including several novel genetic alterations. Further, we found a low percentage of MSI. Thus, DALM/UCCs display profound chromosomal instability, but this is not associated with concurrent MSI.
Long-standing ulcerative colitis is associated with an elevated risk of developing colonic adenocarcinoma. A very limited group of patients present with multiple synchronous cancers. This could be due to either a multifocal presentation of the same neoplastic clone or different tumors arising in a large area of polyclonal dysplastic colonic mucosa ("field cancerization"). Here, we describe a patient with long-standing colitis and three different tumors in the rectosigmoid part of the large bowel. Clonal evaluation of the lesions was performed by array-based comparative genomic hybridization. These three neoplasms showed a comparable pattern of genomic alterations characterized by gains of chromosomes 12, 13, and 20. Noteworthy, dysplastic mucosa distal to the three cancers displayed a completely different pattern of genomic changes indicating that different cell lineages were present. In addition, all three carcinomas were microsatellite stable and revealed identical immunoprofiles for several cancer-associated genes. We conclude that these three multifocal tumors must have originated from the same preneoplastic lineage.
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