Rates of
            <i>p16</i>
            (
            <i>MTS1</i>
            ) Mutations in Primary Tumors with 9p Loss

Cairns, Paul; Li, Mao; Merlo, Adrian; Lee, DJ; Schwab, Donna; Eby, Yolanda; Tokino, Kaori; Riet, Peter van der; Blaugrund, JE; Sidransky, David

doi:10.1126/science.8023167

Cited by 437 publications

(257 citation statements)

References 13 publications

(2 reference statements)

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“…Others indicate that LOH on p21 less frequently results in the absence of functional MTs 1 product in bladder cancer (Packenham et al, 1995;Orlow et al, 1995). It appears that the frequency of the MTS 1 gene involvement in TCC is much lower than that reported for cell lines (Cairns et al, 1994;Spruck et al, 1994). An alternative mechanism of transcriptional silencing of the MTS 1 gene by hypermethylation has been postulated, but it appears to play a minor role in bladder cancer (Merlo et al, 1995;Reed et al, 1996;Wong et al, 1997).…”

Section: Discussionmentioning

confidence: 92%

“…An area corresponding to 9p21-22 is of particular interest, as the putative tumor suppressor genes (MTS 1 and 2) were mapped to this region (Kamb et al, 1994). The MTS genes may not, however, represent ultimate targets of deletions in the 9p21-22 region and other distinct loci on chromosome 9 could be altered in speci®c pathogenetic subsets of human tumors (Coleman et al, 1994;Olopade et al, 1993;Cairns et al, 1994). Some of these alterations may play a role in the development of clinically occult precursor conditions such as dysplasia and carcinoma in situ (Kishimoto et al, 1995;Simoneau et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer

et al. 1999

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The evolution of alterations on chromosome 9, including the putative tumor suppressor genes mapped to the 9p21-22 region (the MTS genes), was studied in relation to the progression of human urinary bladder neoplasia by using whole organ superimposed histologic and genetic mapping in cystectomy specimens and was veri®ed in urinary bladder tumors of various pathogenetic subsets with longterm follow-up. The applicability of chromosome 9 allelic losses as non-invasive markers of urothelial neoplasia was tested on voided urine and/or bladder washings of patients with urinary bladder cancer. Although sequential multiple hits in the MTS locus were documented in the development of intraurothelial precursor lesions, the MTS genes do not seem to represent a major target for p21-23 deletions in bladder cancer. Two additional tumor suppressor genes involved in bladder neoplasia located distally and proximally to the MTS locus within p22-23 and p11-13 regions respectively were identi®ed. Several distinct putative tumor suppressor gene loci within the q12-13, q21-22, and q34 regions were identi®ed on the q arm. In particular, the pericentromeric q12-13 area may contain the critical tumor suppressor gene or genes for the development of early urothelial neoplasia. Allelic losses of chromosome 9 were associated with expansion of the abnormal urothelial clone which frequently involved large areas of urinary bladder mucosa. These losses could be found in a high proportion of urothelial tumors and in voided urine or bladder washing samples of nearly all patients with urinary bladder carcinoma.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer

et al. 1999

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“…The existence of one or more additional tumor suppressor genes on 9p21 has also been suggested by others. This possibility has been based on the fact that LOH of 9p21 is common in bladder cancers, but homozygous deletion and mutation directly e ecting the MTS-1 gene is much less frequent (Cairns et al, 1994;Spruck et al, 1994;Packenham et al, 1995;Orlow et al, 1995). Nevertheless, others have suggested not only that p16 loss of function is a common event in bladder cancer, but also that it is the major target for deletion at 9p21 in bladder cancer (Williamson et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

et al. 1999

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Recent studies have shown that patients whose bladder cancer exhibit overexpression of RB protein as measured by immunohistochemical analysis do equally poorly as those with loss of RB function. We hypothesized that loss of p16 protein function could be related to RB overexpression, since p16 can induce transcriptional downregulation of RB and its loss may lead to aberrant RB regulation. Conversely, loss of RB function has been associated with high p16 protein expression in several other tumor types. In the present study RB negative bladder tumors also exhibited strong nuclear p16 staining while each tumor with strong, homogeneous RB nuclear staining were p16 negative, supporting our hypothesis. To expand on these immunohistochemical studies additional cases were selected in which the status of the p16 encoding gene had been determined at the molecular level. Absent p16 and high RB protein expression was found in the tumors having loss of heterozygosity within 9p21 and a structural change (mutation or deletion) of the remaining p16 encoding gene allele, con®rming the staining results. These results strongly support the hypothesis that the RB nuclear overexpression recently associated with poor prognosis in bladder cancer is also associated with loss of p16 function and implies that loss of p16 function could be equally deleterious as RB loss in bladder and likely other cancers.

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“…Indeed, it has been demonstrated that p16 and p15 genes are frequently deleted in many tumor cell lines and in some primary tumors. 5,6,[8][9][10] In hematological malignancies, homozygous deletion of p16 and p15 genes is frequently found exclusively in malignancies with lymphoid lineage. Myeloid leukemias rarely show the aberrations of p16 or p15 gene.…”

Section: Introductionmentioning

confidence: 99%

Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features

et al. 1997

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p16 and p15 genes are putative tumor suppressor genes located on chromosome 9p21. In acute leukemias, alterations of p16 and p15 genes have been reported to occur exclusively in lymphoid lineage. We analyzed alterations of p16 and p15 genes in 46 acute leukemias with MLL gene rearrangements by Southern blot analysis, and investigated the association with clinical characteristics. We identified homozygous deletion of p16 and p15 genes in five (19%) of 27 acute lymphoblastic leukemias (ALLs) and in two (11%) of 19 acute myeloid leukemias (AMLs). Patients with homozygous deletion of p16 and p15 genes showed higher average leukocyte counts (343 × 10 9 /l vs 271 × 10 9 /l) and lower estimated 2-year survival rates than those with normal p16 and p15 genes (14.3 vs 30.7%), although the differences were not statistically significant. In addition, we investigated mutation of p16 gene by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) in 31 patients, but no mutation was found in the patients tested. Our results suggest that alterations of p16 and p15 genes are involved in a subset of acute leukemias with MLL gene rearrangement not only of lymphoid but also of myeloid phenotype. Homozygous deletion of p16 and p15 genes may be a possible adverse prognostic factor, although further analysis would be needed to confirm it.

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Rates of p16 ( MTS1 ) Mutations in Primary Tumors with 9p Loss

Abstract: less steel tube attached to a tungsten microwire recording electrode while TAN activity was recorded 0.6 mm beyond the outlet of the tube.

Cited by 437 publications

References 13 publications

Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer

Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features

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