High-resolution genomic alterations in Barrett's metaplasia of patients who progress to esophageal dysplasia and adenocarcinoma.

The main risk factor for esophageal dysplasia and adenocarcinoma (DAC) is Barrett's esophagus (BE), characterized by intestinal metaplasia. The critical genomic mechanisms that lead to progression of nondysplastic BE to DAC remain poorly understood and require analyses of longitudinal patient cohorts and high-resolution assays. We tested BE tissues from 74 patients, including 42 nonprogressors from two separate groups of 21 patients each and 32 progressors (16 in a longitudinal cohort before DAC/preprogression-BE and 16 with temporally concurrent but spatially separate DAC/concurrent-BE). We interrogated genome-wide somatic copy number alterations (SCNAs) at the exon level with high-resolution SNP arrays in DNA from formalin-fixed samples histologically confirmed as nondysplastic BE. The most frequent abnormalities were SCNAs involving FHIT exon 5, CDKN2A/B or both in 88% longitudinal BE progressors to DAC vs. 24% in both nonprogressor groups (p = 0.0004). Deletions in other genomic regions were found in 56% of preprogression-BE but only in one nonprogressor-BE (p = 0.0004). SCNAs involving FHIT exon 5 and CDKN2A/B were also frequently detected in BE temporally concurrent with DAC. TP53 losses were detected in concurrent-BE but not earlier in preprogression-BE tissues of patients who developed DAC. CDKN2A/p16 immunohistochemistry showed significant loss of expression in BE of progressors vs. nonprogressors, supporting the genomic data. Our data suggest a role for CDKN2A/B and FHIT in early progression of BE to dysplasia and adenocarcinoma that warrants future mechanistic research. Alterations in CDKN2A/B and FHIT by high-resolution assays may serve as biomarkers of increased risk of progression to DAC when detected in BE tissues.

FBXW7 mutations in melanoma and a new therapeutic paradigm.

BACKGROUND: Melanoma is a heterogeneous tumor with subgroups requiring distinct therapeutic strategies. Genetic dissection of melanoma subgroups and identification of therapeutic agents are of great interest in the field. These efforts will ultimately lead to treatment strategies, likely combinatorial, based on genetic information. METHODS: To identify "driver" genes that can be targeted therapeutically, we screened metastatic melanomas for somatic mutations by exome sequencing followed by selecting those with available targeted therapies directed to the gene product or its functional partner. The FBXW7 gene and its substrate NOTCH1 were identified and further examined. Mutation profiling of FBXW7, biological relevance of these mutations and its inactivation, and pharmacological inhibition of NOTCH1 were examined using in vitro and in vivo assays. RESULTS: We found FBXW7 to be mutated in eight (8.1%) melanoma patients in our cohort (n = 103). Protein expression analysis in human tissue samples (n = 96) and melanoma cell lines (n = 20) showed FBXW7 inactivation as a common event in melanoma (40.0% of cell lines). As a result of FBXW7 loss, we observed an accumulation of its substrates, such as NOTCH1. Ectopic expression of mutant forms of FBXW7 (by 2.4-fold), as well as silencing of FBXW7 in immortalized melanocytes, accelerated tumor formation in vivo (by 3.9-fold). Its inactivation led to NOTCH1 activation, upregulation of NOTCH1 target genes (by 2.6-fold), and promotion of tumor angiogenesis and resulted in tumor shrinkage upon NOTCH1 inhibition (by fivefold). CONCLUSIONS: Our data provides evidence on FBXW7 as a critical tumor suppressor mutated and inactivated in melanoma that results in sustained NOTCH1 activation and renders NOTCH signaling inhibition as a promising therapeutic strategy in this setting.

Giant medial parameniscal cyst in an osteoarthritic knee.

Medial parameniscal cysts of the knee are typically 0.3 to 9 mm in diameter. Few cases of unusually large medial parameniscal cysts have been reported. We describe the treatment of a patient with osteoarthritis of the knee who presented with an extraordinarily large, ipsilateral, medial parameniscal cyst, 10 cm in diameter. We believe this to be the largest medial parameniscal cyst reported in the English literature. Based on the patient's severe tricompartmental arthritis and associated symptoms, total knee arthroplasty (TKA) was indicated with simultaneous excision of the parameniscal cyst. Perioperativley, the cyst was found to have penetrated beyond the menisco-capsular attachments that were adjacent to a degenerative posterior horn horizontal medial meniscal tear. Following excision of the cyst, the mass was measured with surgical tape to be 10x10x5 cm. After complete excision of the parameniscal cyst, TKA was performed. Histological examination confirmed a benign parameniscal synovial cyst. At 2-year follow-up, the patient was ambulating unassisted without difficulty. The wound had completely healed with no evidence of recurrence of the cyst. The patient's range of motion was 0 degrees to 110 degrees with no signs of instability. Our patient's pathology was most significant for the heretofore unseen large size of the paramensical cyst. Open excision of this giant parameniscal cyst followed by TKA was effective in treating the patient's degenerative joint disease and extraordinarily large, painful soft tissue mass.