Tracking functional changes in the cancer genome : a molecular genetic analysis of renal and prostatic carcinomas using PCR based techniques by a candidate chromosome and candidate gene approach
Author: Li, Chunde
Date: 1999-12-10
Location: Föreläsningssalen, Radiumhemmet
Time: 9.00
Department: Institutionen för kirurgisk vetenskap / Department of Surgical Science
Abstract
Renal cell carcinoma (RCC) is the most common malignancy occurring in the
adult kidney. Prostatic carcinoma is the most common male malignancy in
most Western countries. Several environmental factors have been suggested
to contributed to the tumor genesis but the involvement of genetic
factors is also recognized. Here we applied a variety of molecular
genetic techniques to characterize somatic and constitutional genetic
alterations in patients with these types of tumors. Von Hippel-Lindau
disease (VHL) is an autosomal dominant disorder predisposing to the
development of RCC. The disease is caused by the germline mutations of
the VHL gene located in chromosomal region 3p25. Using PCR /direct DNA
sequencing and Southern blot analysis, 7 germline mutations were
identified in 10 VHL families (Paper 1). We further showed the importance
of VHL mutation analysis both in prognosis of patient and presymptomatic
diagnosis of VHL mutation carriers. Particular note was emphasized on the
selection of kidney donors from relatives of a possible VHL patient
affected by bilateral RCCs.
Somatic deletions of the long arm of chromosome 10 were demonstrated in
24% of the RCC analyzed (Paper 2). As the deletion included the PTEN/MMAC
1 gene, mutation analysis was carried out using PCR/direct DNA
sequencing. Three single base changes were identified in 3/6 tumors
showing loss of the PTEN/MMAC1 region. A homozygous deletion coupled with
absent PTEN/MMAC1 expression was detected in the RCC line UOK147. The
result suggests the possible importance of PTEN/MMAC1 gene mutation in
clinical prognosis of a subset of RCCs.
Using PCR/LOH analysis we detected LOH of 13q markers in 18/36 prostatic
carcinomas analyzed (Paper 3). Two important regions of deletion were
defined, which did not included the Rb I locus at 13q14 or the BRCA2
locus at 13q12. Mutation analysis of the BRCA2 gene in six tumors did not
reveal any important mutations. Immunohistochemical analysis of the same
tumor materials showed that frequent aberrant pRb expression was
correlated with a tetraploid DNA content but not concordant with the loss
of the Rb1 gene. The data suggest the existence of yet unidentified tumor
suppressor genes on 13q that are important for prostate cancer
development.
In the same set of prostatic carcinomas, 16q deletions were demonstrated
in 75% of tumors (Paper4). Extensive deletions were found in all the
metastases while small deletions were also present in 54% of primary
tumors. Four important deleted regions were identified and the presence
of the terminal 16q deletion was closely correlated with grade, stage and
metastases. The location of tandemly arranged classical cadherin genes
was coincident with the four important deleted regions. We chose the CDH
I gene at 16q22.1 that encodes the E-cadherin protein as the first
candidate gene. Mutation analysis of all the 16 coding exons did not find
any mutations in the ten tumors showing LOH at the CDH I region. In
addition, we also detected frequent reduced or absent E-cadherin
expression in the same set of materials. The finding suggests that
chromosome 16q deletions are important in the development of prostate
cancer metastasis and could potentially be used as a prognostic marker.
Using a modified PCR/LOH analysis in sporadic prostatic carcinomas, we
found two possible deletions at the putative prostate cancer
susceptibility locus HPCX on Xq27-28 (Paper 5). These deletions caused a
complete loss of the DNA sequences in the region. The findings further
support the importance of this locus in sporadic tumors.
The association between the CAG repeats polymorphism in the androgen
receptor gene and prostatic carcinomas was analyzed in Swedish and
Japanese populations (Paper 6). Both sporadic and familial prostatic
carcinomas in Sweden showed association with short CAG repeats whereas
sporadic prostatic carcinomas in Japan showed association with long
repeats. In both populations the allele AR(CAG)22 showed negative
correlation with prostatic carcinomas, and the alleles AR(CAG)21 and
AR(CAG)23 showed positive correlation. Compared to Swedish populations,
Japanese males more frequently carried AR(CAG)22 and less frequently
AR(CAG)21 and AR(CAG)23. This difference in allelic distribution may be
part of the genetic background that determines a dramatically lower
incidence of clinical prostate cancer in Japan.
The present study may contribute to a better understanding of the genetic
mechanism for the development of renal and prostatic carcinoma. The
results also present the potential of molecular genetic analysis in
clinical diagnosis and prognosis of these two common types of urological
malignancies.
List of papers:
I. Li C, Weber G, Ekman P, Lagercrantz J, Norlen BJ, Akerstrom G, Nordenskjold M, Bergerheim US (1998). "Germline mutations detected in the von Hippel-Lindau disease tumor suppressor gene by Southern blot and direct genomic DNA sequencing." Hum Mutat Suppl 1: S31-33
Pubmed
II. Alimov A, Li C, Gizatullin R, Fredriksson V, Sundelin B, Klein G, Zabarovsky E, Bergerheim U (1999). "Somatic mutation and homozygous deletion of PTEN/MMAC1 gene of 10q23 in renal cell carcinoma. " Anticancer Res 19(5B): 3841-3846
Pubmed
III. Li C, Larsson C, Futreal A, Lancaster J, Phelan C, Aspenblad U, Sundelin B, Liu Y, Ekman P, Auer G, Bergerheim US (1998). "Identification of two distinct deleted regions on chromosome 13 in prostate cancer. " Oncogene 16(4): 481-487
Pubmed
IV. Li C, Berx G, Larsson C, Auer G, Aspenblad U, Pan Y, Sundelin B, Ekman P, Nordenskjold M, van Roy F, Bergerheim US (1999). "Distinct deleted regions on chromosome segment 16q23-24 associated with metastases in prostate cancer. " Genes Chromosomes Cancer 24(3): 175-182
Pubmed
V. Li C, Ekman P, Bergerheim U (1999). "Somatic deletion of FRAXE GGC repeats overlapping HPCX locus at Xq28 in sporadic prostate cancer." (Manuscript)
VI. Li C, Grönberg H, Matsuyama H, Weber G, Damber J-E, Bergh A, Larsson C, Naito K, Nordenskjöld M, Ekman P, Bergerheim U (1999). "Difference between Japanese and Swedish males in androgen receptor polymorphism associated with prostate cancer." (Submitted)
I. Li C, Weber G, Ekman P, Lagercrantz J, Norlen BJ, Akerstrom G, Nordenskjold M, Bergerheim US (1998). "Germline mutations detected in the von Hippel-Lindau disease tumor suppressor gene by Southern blot and direct genomic DNA sequencing." Hum Mutat Suppl 1: S31-33
Pubmed
II. Alimov A, Li C, Gizatullin R, Fredriksson V, Sundelin B, Klein G, Zabarovsky E, Bergerheim U (1999). "Somatic mutation and homozygous deletion of PTEN/MMAC1 gene of 10q23 in renal cell carcinoma. " Anticancer Res 19(5B): 3841-3846
Pubmed
III. Li C, Larsson C, Futreal A, Lancaster J, Phelan C, Aspenblad U, Sundelin B, Liu Y, Ekman P, Auer G, Bergerheim US (1998). "Identification of two distinct deleted regions on chromosome 13 in prostate cancer. " Oncogene 16(4): 481-487
Pubmed
IV. Li C, Berx G, Larsson C, Auer G, Aspenblad U, Pan Y, Sundelin B, Ekman P, Nordenskjold M, van Roy F, Bergerheim US (1999). "Distinct deleted regions on chromosome segment 16q23-24 associated with metastases in prostate cancer. " Genes Chromosomes Cancer 24(3): 175-182
Pubmed
V. Li C, Ekman P, Bergerheim U (1999). "Somatic deletion of FRAXE GGC repeats overlapping HPCX locus at Xq28 in sporadic prostate cancer." (Manuscript)
VI. Li C, Grönberg H, Matsuyama H, Weber G, Damber J-E, Bergh A, Larsson C, Naito K, Nordenskjöld M, Ekman P, Bergerheim U (1999). "Difference between Japanese and Swedish males in androgen receptor polymorphism associated with prostate cancer." (Submitted)
Issue date: 1999-11-19
Publication year: 1999
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