Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd ...(alias Barttin) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290-deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity.
Introduction:
Adenoid cystic carcinoma (ACC), sinonasal undifferentiated carcinoma (SNUC), and esthesioneuroblastoma (EN) are rare malignant neoplasms of the skull base (SB) with a range of ...biological activities. These tumors present diagnostic and treatment challenges. The aim of this study was to determine if SB tumor prognosis may be predicted by tumor markers (TM): epidermal growth factor receptor (EGFR), neural cell adhesion molecule (NCAM), urokinase plasminogen receptor (uPAR), B-cell lymphoma protein 2 (BCL-2), and proliferating cell nuclear antigen (PCNA).
Methods:
Tissue specimens of 30 patients with ACC (11), SNUC (7), and EN (12) from the University of Michigan Department of Pathology were used to construct a tissue microarray (TMA). Immunohistochemistry was performed for each TM. TM expression was graded from 0 (no) to 4 + (intense) independently by two pathologists. Immunohistochemical results were compared with clinical data.
Results:
ACC specimens expressed all TM except NCAM. All of the SNUC specimens expressed EGFR, uPAR, and PCNA. However, none expressed NCAM and 71% expressed BCL-2. All EN expressed EGFR, uPAR, and PCNA. EN expressed BCL-2 and NCAM in 58% and 75% of specimens, respectively.
Conclusion:
This study was limited by the number of specimens and failed to show definitive correlations. However, there was a trend for uPAR expression and aggressive SNUC activity. Mean survival was greatest in patients with negative margins followed by positive margins with low uPAR expression. TM immunophenotypic profiles may be tumor-specific and correlate with outcomes for particular SB tumors. TM profiles may assist in targeting novel treatments in the future.