Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers

Abstract

A new tumor suppressor gene PTEN/MMAC1 was recently isolated at chromosome 10q23 and found to be inactivated by point mutation or homozygous deletion in glioma, prostate and breast cancer. PTEN/MMAC1 was also identi®ed as the gene predisposing to Cowden disease, an autosomal dominant cancer predisposition syndrome associated with an increased risk of breast, skin and thyroid tumors and occasional cases of other cancers including bladder and renal cell carcinoma. We screened 345 urinary tract cancers by microsatellite analysis and found chromosome 10q to be deleted in 65 of 285 (23%) bladder and 15 of 60 (25%) renal cell cancers. We then screened the entire PTEN/MMAC1 coding region for mutation in 25 bladder and 15 renal cell primary tumors with deletion of chromosome 10q. Two somatic point mutations, a frameshift and a splicing variant, were found in the panel of bladder tumors while no mutation was observed in the renal cell carcinomas. To screen for homozygous deletion, we isolated two polymorphic microsatellite repeats from genomic BAC clones containing the PTEN/MMAC1 gene. Using these new informative markers, we identi®ed apparent retention at the gene locus indicative of homozygous deletion of PTEN/MMAC1 in four of 65 bladder and 0 of 15 renal cell tumors with LOH through chromosome 10q. Identi®cation of the second inactivation event in six bladder tumors with LOH of 10q implies that the PTEN/MMAC1 gene is occasionally involved in bladder tumorigenesis. However, the low frequency of biallelic inactivation suggests that either PTEN/MMAC1 is inactivated by other mechanisms or it is not the only target of chromosome 10q deletion in primary bladder and renal cell cancer.

Intragenic PTEN/MMAC1 Loss of Heterozygosity in Conventional (Clear-Cell) Renal Cell Carcinoma is Associated with Poor Patient Prognosis

“…While Steck et al (11) reported mutations in one of four primary renal carcinomas, later, larger studies have found no, or very few, PTEN/MMAC1 mutations in RCC (13)(14)(15)(16)(17). Furthermore, observations in other human tumor types have also shown few PTEN/MMAC1 mutations despite high LOH rates at the gene locus (22,23).…”

“…Initial screens of 9 RCCs seemed to support this hypothesis, showing loss of heterozygosity (LOH) in 40% of tumors and mutations in 15% of tumors (11,12). However, two subsequent larger studies failed to detect any mutations (13,14). Recently, Alimov et al (15) reported a 34% LOH rate at 10q23-25 but found only three mutations when they screened the subset of tumors that displayed LOH for mutations; Kondo et al (16) detected only five mutations, some of which were heterozygote, in a series of 68 sporadic renal cell carcinomas; and Sukosd et al (17) found high rates of 10q23.3 LOH in chRCC, but only in 2 of 50 cRCC, and detected no PTEN/MMAC1 mutations in the tumors with LOH.…”

Promoter Methylation and Silencing of PTEN in Gastric Carcinoma

“…In particular, the mutation of PTEN appears with a frequency of up to 50% in endometrial cancer (Tashiro et al, 1997) compared with other cancers, including glioblastoma (28%), prostate cancer (30%), and melanoma (15%) (Dahia, 2000). Abnormalities in the expression of the PTEN gene have been shown in esophageal cancer, melanoma, and prostate cancer (Cairns et al, 1997;Whang et al, 1998). Gene silencing by promoter methylation of PTEN has been reported in endometrial and prostate cancer (Salvesen et al, 2001).…”

The role of PTEN signaling perturbations in cancer and in targeted therapy

“…Among these mutations are structural rearrangements within the PTEN gene (intragenic inversions, insertions, deletions and duplications known as gross PTEN mutations) that occur in BRCA1-associated basal-like breast cancer (Saal et al, 2008). PTEN mutation frequencies affecting both alleles in various cancers are: endometrial (B50%), glioblastoma (B30%), prostate (B10%), and breast (B5%) (Cairns et al, , 1998Steck et al, 1997;Tashiro et al, 1997;Wang et al, 1997;Chiariello et al, 1998;Duerr et al, 1998;Lin et al, 1998;Shao et al, 1998;Ali et al, 1999;Zhou et al, 2002;Saal et al, 2005). The monoalleleic loss of PTEN is regularly observed in a considerable fraction of malignancies at the following frequencies: glioma (B75%), breast (B40-50%), colon (B20%), lung (B37%), prostate (B42%) (Teng et al, 1997;Bose et al, 1998;Feilotter et al, 1998;Lin et al, 1998;Rubin et al, 2000).…”

“…Sequencing of the PTEN gene in tumors found it to be one of the most commonly mutated tumor suppressors in human malignancies Rasheed et al, 1997;Tashiro et al, 1997;Wang et al, 1997Wang et al, , 1998Cairns et al, 1998;Duerr et al, 1998;Shao et al, 1998). The hereditary loss of PTEN leads to numerous autosomal dominant disorders: Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome and Proteuslike syndrome, which are characterized by the presence of developmental defects, benign hamartomas and an increased risk of cancer Marsh et al, 1997;Zhou et al, 2000Zhou et al, , 2001.…”