Low frequency of <i>CDKN2</i> mutation in endometrial carcinomas

Peiffer, Stacia L.; Bartsch, Detlef K.; Whelan, Alison; Mutch, David G.; Herzog, Thomas J.; Goodfellow, Paul J.

doi:10.1002/mc.2940130403

Cited by 18 publications

(13 citation statements)

References 12 publications

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“…Our findings should be considered in light of previous reports regarding p16 and/or p15 in human uterine tumours (Hatta et al, 1995;Kelly et al, 1995;Peiffer et al, 1995;Hirama et al, 1996;Wong et al, 1997;Kim et al, 1998;Munirajan et al, 1998). Hatta et al (1995) found no mutations, deletions, or rearrangements in 15 endometrial carcinomas.…”

Section: Discussionsupporting

confidence: 74%

Alteration of p16 and p15 genes in human uterine tumours

et al. 1999

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A large variety of human tumours manifest a heterozygous or homozygous deletion in the 9p21 chromosome region. The list includes malignant melanoma, glioma, lung, bladder, pancreatic and renal cancers (Kamb et al, 1994;Nobori et al, 1994), as well as gynaecological tumours (reviewed by Wong et al, 1997). Two putative tumour suppressor genes have been identified in this region: p16 (also known as p16 INK4A , cyclin-dependent kinase 4 inhibitor, CDK4I, CDKN2, and MTS1), and p15 (p15 INK4B ).The p16 gene makes two different proteins, p16 and p19 ARF (p19 alternative reading frame), using different overlapping reading frames, starting with different first exons. The p16 protein uses exon 1α, and p19 ARF uses exon 1β; these two exons are alternatively spliced to the same second and third exons. The p16 and p15 proteins belong to a family of negative regulators of the cell cycle. Specific binding of p16 protein to the CDK4 or CDK6 cyclindependent protein kinases inhibits the phosphorylation activity of CDK-cyclin D complexes towards the nuclear RB/E2F protein complex (Serrano et al, 1993). p16 normally prevents phosphorylation of RB, resulting in RB's retention of E2F. Failure to release E2F at the late G1 checkpoint blocks the cell from entering the S phase (Hengstschläger et al, 1996;Lukas et al, 1996). The p19 ARF protein, although it has an unrelated amino acid sequence, has cell cycle arresting functions. It is the p16 protein that now appears to be the major target of mutations and deletions at the 9p21 loci.The p15 (MTS2) putative tumour suppressor gene is located 25 kb centromeric of the p16 gene on 9p. p15 contains sequences highly homologous to exon 2 of p16 and, like p16, inhibits both CDK4 and CDK6 kinase activities (Guan et al, 1994;Hannon and Beach, 1994). Homozygous deletions of p15 and hypermethylation-associated loss of p15 expression have been reported in glioblastomas (Jen et al, 1994).The p16/p19 ARF and p15 genes appear to play variably important roles in human tumorigenesis, with critical tissue specificities and uncertain implications for clinical prognoses. Little is currently known about the potential role of these genes in reproductive tract biology, and specifically in uterine tumours. We have begun to examine the expression of the p16 gene at the level of mRNA and protein, the methylation status of the 5′-CpG island of p16 exon 1α, and for p16 point mutations and homozygous deletions in these tumours. We have also analysed the p15 gene for mutations and homozygous deletions. We report that the inactivation of the p16 gene, either by homozygous gene deletion, mutation or loss of protein expression, occurs in a small but significant subset of these uterine tumours. Summary The roles of the p16 and p15 inhibitor of cyclin-dependent kinase tumour suppressor genes were examined in human uterine cervical and endometrial cancers. p16 mRNA, examined by reverse transcription polymerase chain reaction (RT-PCR), was significantly reduced in five of 19 (26%) cervical and four of 25 (16%) endometrial tu...

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Section: Discussionsupporting

confidence: 74%

Alteration of p16 and p15 genes in human uterine tumours

et al. 1999

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“…The low frequency of p16 alterations in the present series is in line with other studies. [11][12][13][14]16 We have previously reported that loss of nuclear p16 protein expression is associated with aggressive endometrial carcinomas and poor prognosis. 15 In line with this, we now demonstrate that alterations in the p16 gene also are associated with an aggressive phenotype, even though small numbers in the present series call for caution in the conclusion.…”

Section: Discussionmentioning

confidence: 99%

“…The median follow-up period for the survivors was 9 years (range [5][6][7][8][9][10][11][12][13][14]. None of the patients were lost due to insufficient follow-up data.…”

Section: Statisticsmentioning

confidence: 99%

“…10 In sporadic endometrial cancers, homozygous deletions have been reported in 2-8%, whereas rates have been 3-6% for p16 mutations and 1-4% for p16 promoter methylation. [11][12][13][14][15][16] Studies of loss of p16 protein expression, however, indicate that p16 inactivation might be more common, although the reported rates differ considerably from 14-74%. 12,14,15,17 We have previously reported a strong negative prognostic influence of loss of p16 expression in a large and population-based patient series.…”

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Low frequency of BRAF and CDKN2A mutations in endometrial cancer

Salvesen

Kumar

Stefansson

et al. 2005

Intl Journal of Cancer

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Several pathways have been implicated in the pathogenesis of endometrial carcinoma. Based on recent reports, BRAF mutations provide an alternative route for activation of the RAS signalling pathway. The CDKN2A (p16) tumour suppressor gene is also altered in several tumour types. We therefore wanted to assess the pattern and prognostic impact of BRAF mutations and p16 alterations in endometrial carcinomas. Only 1 of 48 tumours (2%) was found to have a BRAF mutation in exon 15, whereas 8 of 45 tumours (18%) had a K-ras mutation. Homozygous deletion, amplification, promoter region methylation or mutation of the p16 gene was seen in 6 cases (13%), and 18 cases (38%) carried polymorphisms in the p16 gene. All tumours with presence of p16 methylation, non-sense mutation, deletion or amplification exhibited loss of p16 expression as evaluated by immunohistochemistry. Presence of a p16 hit was significantly correlated with high FIGO stage ( p = 0.04), high histologic grade ( p = 0.02), estrogen receptor negativity ( p = 0.05), pathologic expression of p53 ( p = 0.02), pathologic expression of p16 (p = 0.05) and poor survival ( p = 0.02). There was also a significant correlation between loss of p16 expression and K-ras mutations, pathologic p53 expression and serous papillary/clear cell histologic types ( p = 0.05/p = 0.001/p = 0.002). In conclusion, BRAF mutation is an infrequent finding in endometrial carcinomas. Loss of p16 expression is seen in all cases with alterations of the p16 gene. The presence of a p16 hit might be important in a subset of endometrial carcinomas with aggressive clinical behaviour. However, the mechanism of p16 inactivation remains unclear for the majority of cases exhibiting loss of expression, but the interactions with K-ras and p53 should be further studied. ' 2005 Wiley-Liss, Inc.Key words: BRAF; K-ras; CDKN2A (p16); endometrial cancer; prognosis Several pathways have been implicated in the pathogenesis of endometrial carcinoma. 1 Ras mutations are common in human cancers and have previously been found in 14% within the present population-based patient series. 2 Recently, it has been reported that mutations of BRAF provide an alternative route for activation of the RAS-mediated MAP-kinase signalling pathway. Mutations in BRAF have been reported in melanomas, colorectal cancers and ovarian tumours. 3,4 These mutations of BRAF have also been linked to microsatellite instability (MSI) in colorectal carcinoma. 5 We wanted to investigate the frequency of BRAF mutations in endometrial cancer and in particular their relation to MSI and Ras mutations, especially since mutations in Ras are relatively few in this group of tumours.As evidenced from studies on melanoma, the mutations in the BRAF gene, though early, are not sufficient for tumour formation, for which an additional genetic hit is required. This is supported by characterization of overlapping BRAF mutations and CDKN2A aberrations in melanomas 6 and also occurrence of a high frequency of BRAF mutations in tumours from families with germline...

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“…Although the alternative exon 1␤, encoding parts of the ARF product, was not included in the analysis, our study does not support a role of CDKN2A/p16 or ARF inactivation in development of endometrial carcinomas, which is in agreement with the majority of previous studies. 36,37 However, the alternative mechanism of promoter hypermethylation or homologous deletion of the gene may be involved in these tumors. 66 Few tumors included in this study make it impossible to suggest a model for endometrial tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

Koul

Wïllén

Bendahl

et al. 2002

Cancer

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BACKGROUNDEndometrial carcinomas seem to carry a different prognosis depending on the presence or absence of concomitant complex atypical hyperplasia (hyperplasia). The molecular genetic profile of these two pathogenetic types, based on the genes reportedly mutated in these cancers, remains to be defined. Although microsatellite inability is reported in approximately 25% of endometrial carcinomas, its relation with the 2 pathogenetic types is not investigated.METHODSTo elucidate their underlying genetic changes, we analyzed 53 sporadic endometrial tumors, including 19 with and 34 without hyperplasia, for microsatellite instability (MSI), DNA ploidy (by flow cytometry), and for mutations in different genes.RESULTSMicrosatellite instability was present in 21%, DNA nondiploidy in 15%, and mutations in the PTEN, KRAS, CTNNB1/β‐catenin, TP53, and CDKN2A genes were detected in 32, 11, 13, 17, and 0% of the tumors, respectively. Microsatellite instability and mutations in these genes were present in tumors both with and without complex atypical hyperplasia. All cases with complex atypical hyperplasia were early stage (I–II) endometrioid tumors and associated with long progression free disease (P = 0.0004). Furthermore, most tumors with hyperplasia had low World Health Organization or International Federation of Gynecology and Obstetrics grade, had less myometrial invasion, and showed expression of estrogen receptors. All MSI tumors were diploid and had a significantly higher rate of PTEN mutations, but similar rates of KRAS, β‐catenin, and TP53 mutations compared with microsatellite stable tumors. TP53 mutations more often were found in nondiploid tumors but never in tumors with PTEN, KRAS, or β‐catenin mutations, and all PTEN mutations occurred in diploid tumors.CONCLUSIONSThus, PTEN, KRAS, β‐catenin, and TP53 mutations occurred in tumors both with and without hyperplasia, but PTEN and TP53 mutations were more common in tumors without hyperplasia. However, none of these genes seems to clearly distinguish tumors with and without hyperplasia, suggesting that other factors may be involved. Conversely, alterations in the PTEN and TP53 genes seem to define distinct subgroups of endometrial carcinoma, the former associated with diploidy and MSI, the latter with macroscopic chromosomal instability. Cancer 2002;94:2369–79. © 2002 American Cancer Society.DOI 10.1002/cncr.10498

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Low frequency of CDKN2 mutation in endometrial carcinomas

Cited by 18 publications

References 12 publications

Alteration of p16 and p15 genes in human uterine tumours

Alteration of p16 and p15 genes in human uterine tumours

Low frequency of BRAF and CDKN2A mutations in endometrial cancer

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

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