Frequency of homozygous deletion at p16/CDKN2 in primary human tumours

Cairns, Paul; Polascik, Thomas J.; Eby, Yolanda; Tokino, Kaori; Califano, Joseph A.; Merlo, Adrian; Li, Mao; Herath, John F.; Jenkins, Robert B.; Westra, William H.; Rutter, Joni L.; Buckler, Alan; Gabrielson, Edward; Tockman, Melvyn S.; Cho, Kathleen R.; Hedrick, Lora; Bova, G. Steven; Isaacs, William B.; Koch, Wayne M.; Schwab, Donna; Sidransky, David

doi:10.1038/ng1095-210

Cited by 575 publications

(443 citation statements)

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“…Six cases had LOH for one of the markers, while one tumor showed LOH with two markers. For this latter cancer, both lost markers were centromeric to PTEN/MMAC1, which excludes the possibility of identifying homozygous deletion by LOH analysis (Cairns et al, 1995. The D10S581 marker was the most frequently deleted, having 15% LOH (4 of 26 informative cases).…”

Section: Resultsmentioning

confidence: 88%

PTEN/MMAC1 is infrequently mutated in pT2 and pT3 carcinomas of the prostate

et al. 1998

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Deletion of the q23-24 region of human chromosome 10 is one of the most frequent genetic alterations in prostate cancer, suggesting that inactivation of a tumor suppressor gene in this region is involved in the development or progression of this carcinoma. A candidate gene, PTEN/ MMAC1, has been identi®ed from this chromosomal region; mutations of this gene have been found in various advanced tumors and cell lines including those of prostate cancer. To further de®ne the role of PTEN/ MMAC1 in the development of prostate cancer and its spectrum of genetic alterations, we analysed 40 pT2 or pT3 prostate tumors for allelic loss, mutations, and homozygous deletions using PCR-based methods. Six tumors showed loss of heterozygosity for one of the ten markers analysed, while one tumor showed loss of two markers. None of the markers within PTEN/MMAC1 was lost. Direct sequencing of PCR ampli®ed exons and intron/exon junctions of all 40 tumors revealed three sequence variants, one of which was a point mutation in exon 9, while the other two were polymorphisms. Using multiplex PCR, no homozygous deletions were detected in any of the neoplasms. Our results showing a low frequency of alterations of PTEN/MMAC1 in pT2 and pT3 prostate cancers suggest that this gene plays an insigni®cant role in the development of most low stage carcinomas of the prostate.

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Section: Resultsmentioning

confidence: 88%

PTEN/MMAC1 is infrequently mutated in pT2 and pT3 carcinomas of the prostate

et al. 1998

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“…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%

“…Alterations of the CDKN2A (p16) gene have been involved in tumour development in several organs. 7,8 The CDKN2A gene encodes 2 proteins, p16 and ARF, from a partially shared sequence. The p16 protein encoded by the CDKN2A gene has been identified as a tumour suppressor.…”

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confidence: 99%

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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“…Deletions most frequently involve both p16 INK4a and p15 INK4b . Although p16 INK4a is thought as the main target for these deletions (Cairns et al, 1995), speci®c deletion of p15 INK4b has been found in some cases (Jen et al, 1994;Glendeling et al, 1995;Rasool et al, 1995). Inactivation of these genes occurs also by point mutations (Pollock et al, 1996) or by hypermethylation of their promoter region Herman et al, 1996).…”

Section: Introductionmentioning

confidence: 99%