Abnormal Gene Expression Profiles in Unaffected Parents of Patients with Hereditary-Type Retinoblastoma

Abstract

The hereditary form of retinoblastoma (Rb) is associated with a germ line mutation in one RB allele and is characterized by the occurrence of multiple, bilateral Rb tumors and a predisposition to the development of second cancers. In an earlier study, we observed an unexpected hypersensitivity to ionizing radiation in skin fibroblasts derived from unaffected parents of children with hereditary Rb. In at least four of these five families, there was no family history of Rb, indicating a new germ line mutation. We hypothesize that the increased parental cell sensitivity to radiation may reflect the presence of an as yet unrecognized genetic abnormality occurring in one or both parents of children with Rb. In the present study, we use DNA microarray technology to determine whether differences in gene expression profiles occurred in the unaffected parents of patients with hereditary Rb relative to normal individuals. Microarray analyses were validated by quantitative reverse transcription-PCR measurements. A distinct difference was observed in the patterns of gene expression between unaffected Rb parents and normal controls. By use of the prediction analysis for microarrays and principal component analysis methodologies, significant differences between the two groups were identified when as few as nine genes were analyzed. Further study of this phenomenon may offer a new insight into the genetic mechanisms of Rb and perhaps more broadly in cancer biology. (Cancer Res 2006; 66(7): 3428-33)

Reduced mRNA and Protein Expression of the Genomic Caretaker RAD9A in Primary Fibroblasts of Individuals with Childhood and Independent Second Cancer

“…Compared to the enormous efforts to characterize the transcriptomes and proteomes of tumor cells, there are relatively few studies searching for gene expression differences in normal somatic cells of tumor patients [13], [14]. To test the hypothesis that differences in DNA repair pathways may influence the risk for developing a second tumor following treatment of childhood cancer, we compared the constitutive levels of DNA repair-associated proteins in primary fibroblasts of matched two-cancer and one-cancer patients.…”

“…Fibroblasts of breast and thyroid cancer patients were found to have defective repair and/or cell cycle regulation [13]. Abnormal gene expression in somatic cells of the unaffected parents of retinoblastoma patients are also consistent with an inherited predisposition to cancer development [14].…”

Gene expression profiles of post-Chernobyl thyroid cancers

“…Is this unique to these rare syndromes, or are these syndromes the extremes of variability in oncologically relevant radiosensitivity in the general population? The microarray profiles of lymphocytes drawn from the unaffected parents of patients with retinoblastoma could be distinguished from those of the parents of healthy controls [34]. Cells from parents of patients with retinoblastoma were also found to be hypersensitive in a low dose-rate g-H2AX assay [35 ].…”

Serendipity and chance in one’s life and scientific career

“…In Although much of this research involves the bystander effect, I have also become involved in research being carried out by Joel Bedford and his colleagues at the Colorado State University concerning genetic susceptibility to radiation (13). This has been based on an observation we made just prior to my retirement that skin fibroblasts from all of the unaffected parents of 5 children with hereditary-type retinoblastoma were abnormally sensitive to ionizing radiation.…”