Al-Saydalani Al-Jehani, Rajai Munir Ahmed Abduljalil; (1994) Genetic changes in human testicular germ cell tumours. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Most testicular germ cell tumours (TGCTs) have a modal chromosome number in the hypotriploid range and and tumour progression is thought to result from net loss of chromosomes from a near tetraploid carcinoma in situ cell. Around 1.5% of TGCTs occur in a familial form thus suggesting a possible role for tumour suppressor genes in testicular tumorigenesis. To find out whether particular areas of the TGCT genome show marked loss of heterozygosity (LOH) allele loss studies were carried out on tumours from 41 patients using a number of polymorphic ezyme and DNA RFLP markers covering 23 chromosome arms. In addition aneuploid cultures were successfully established from seven cases and the results from these cultures were compared with those from corresponding tumours. LOH at a frequency of >10% was found on the following chromosome arms; 3p (2 losses out of 18 informative individuals), 3q (1/8), 4 (1/10), 5q (6/33), 11p (4/13), 11q (4/24), 12p (1/7), 13q (3/18), 16p (3/24) and 18p (1/5). LOH at a fequency of <10% was found on 1p (2/37), 1q (3/34), 5p (1/30), 7p (1/27), 7q (2/22), 9q (1/19), 14q (2/22), 15 (1/23), 18q (2/25) and 20 (1/26). No losses were found on 6p (six informative individuals), 12q (33) and 17p (23). Additional losses on 1p, 1q, 3p, 9q, 11p, 11q, 14q, 18p and 18q were observed in the tumour cultures. The relatively high frequency of allele loss on 3p, 5q, 11p, 11q, 13q and 16p may indicate the presence of tumour suppressor genes on these chromosome arms which are important in the development of TGCTs. The extent of allele loss as defined by fractional allele loss was not found to be significantly different between the two histologic subtypes seminoma and nonseminoma. An examination of allele intensity in tumour DNA has demonstrated allelic evenness in over 70% of tumours for probes on 1p36, 3q, 4, 5p, 5q, 7q, 11p, 11q, 12q14, 13q and 15q. The only chromosome arm demonstrating an uneven pattern in more than 70% of tumours is 12p. These findings suggest that the changing pattern of genomic organization occuring during tumour progression is non-random. An isochromosome for the short arm of chromosome 12 is a highly specific cytogenetic abnormality found in the majority of TGCTs. The retention of heterozygosity for all informative markers on 12q suggests that formation of the i(12p) markers occurs following polyploidization. Mutations in the p53 gene which is located on 17p are considered to be among the most common genetic alterations in human cancers. The retention of heterozygosity for all informative 17p loci suggests that alterations in the p53 gene are not important for the predisposition and development of TGCTs. Consistent with this finding is the lack of any consistent change in p53 mRNA levels in TGCTs. Inactivation of the retinoblastoma (RB) tumour suppressor gene is associated with the development of several human malignancies. An investigation of RB mRNA revealed decreased levels in all TGCTs analysed but no alterations in transcript size. Rearrangemet of the RB gene was demonstrated in a single TGCT. These findings suggest regulation of transcription and/or transcript half- life or gene mutations may be responsible for the decreased RB mRNA levels in human TGCTs. Analysis of the H-ras oncogene mRNA revealed decreased levels in nearly all tumours examined. The reduced levels did not always coincide with LOH at this locus thus suggesting a decrease in the level of transcription and/or half-life of H-ras mRNA. There was no consistent change in the levels of N-ras and MCC40 mRNA levels.

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