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Repeat Expansion Detection Analysis of (CAG)_n Tracts in Tumor Cell Lines, Testicular Tumors, and Testicular Cancer Families¹

Departments of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520-8040 [B. L. K., B. M. K.]; Department of Medical Biophysics and Institute of Medical Science, University of Toronto [H-Q. P., D. H.], and The Toronto Hospital [P. G.], Toronto, Ontario M5G 2C4, Canada; Ottawa Regional Cancer Centre, Ottawa, Ontario 1Y4K7, Canada [S. H.]; and Department of Urology, University of Minnesota Medical School, Minneapolis, Minnesota [D. B.] 55455

The mutational expansion of triplet repeat microsatellite sequences underlies the transmission of a number of heritable neurological disorders. However, this form of microsatellite instability has not previously been observed in association with malignant disease. Because trinucleotide expansions can dramatically alter gene expression and protein function, we hypothesized that they might occur in neoplastic cells as a mechanism through which to alter cancer genes. Accordingly, we used the repeat expansion detection technique to determine whether (CAG)_n triplet repeat expansions were present in DNA from malignant cells. No expansions were observed in a survey of 20 tumor cell lines derived from enoplasms of the breast, ovary, cervix, endometrium, lung, colon, placenta, or hematopoietic system. However, we did observe expanded (CAG)_n tracts in DNA from 5 of 11 testicular tumor cell lines and in 1 of 11 sporadic testicular tumors. Examination of the corresponding normal DNA, when available, revealed that some of the expansions were germline in nature. To assess the possibility that (CAG)_n expansions underlie some cases of inherited testicular cancer, we also analyzed germline DNA from members of five kindreds predisposed to this malignancy. An increase in (CAG)_n tract size was observed in all five families and was particularly striking in one large pedigree in which expansions were observed in three of four affected siblings. These observations raise the possibility that the germline transmission of expanded (CAG)_n tracts may play a role in testicular tumorigenesis.

¹ Supported by a Yale Critical Technologies Program Grant from the Mathers Foundation to B. L. K. and by a Terry Fox Research Grant from The National Cancer Institute of Canada to D. H.

² To whom requests for reprints should be addressed, at Department of Therapeutic Radiology, Hunter Radiation Building 303, Yale University School of Medicine, P. O. Box 208040, New Haven, CT 06520-8040.

Received 9/ 4/96. Accepted 12/ 3/96.

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