Increased Risk of Pancreatic Cancer in Melanoma-Prone Kindreds with<i>p16</i><sup>INK4</sup>Mutations

Goldstein, Alisa M.; Fraser, Mary C.; Struewing, Jeffery P.; Hussussian, Christopher J.; Ranade, Koustubh; Zametkin, Deborah P.; Fontaine, Laura; Organic, Sara M.; Dracopoli, Nicholas C.; Clark, Wallace H.; Tucker, Margaret A.

doi:10.1056/nejm199510123331504

Cited by 587 publications

(296 citation statements)

References 20 publications

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“…Indeed, these ®ve alleles (A73T, H98Y, V106M, R107C, P114S) were reported in malignant gliomas (Kyritsis et al, 1995(Kyritsis et al, , 1996 but each of these CDKN2A mutations was detected only in a small percentage of the tumor cells by individual colony sequencing and Southern hybridization, consistent with heterogeneous glioma cell populations (Kyritsis et al, 1996), in which the mutations do not appear to have been selected. While the biological signi®cance of these p16W mutations remains uncertain, this phenomenon was observed in other tumors such as malignant melanomas and pancreatic carcinomas (Goldstein et al, 1995;Ranade et al, 1995). One explanation may lie with p16b, a novel human p16 INK4a transcript (Duro et al, 1995;Mao et al, 1995;Stone et al, 1995) or an CDKN2A mutations in glioma W Arap et al unrelated protein from an alternative reading frame of the murine p16 INK4a gene (p19 ARF ) which has recently been reported and shown to be capable of inducing G 1 and also G 2 phase arrest independent of CDK4 or CDK6 (Quelle et al, 1995).…”

Section: Discussionmentioning

confidence: 98%

“…A novel in vivo assay of inhibition of RB phosphorylation was also used in our study. Based on the ability to induce G 1 arrest or their long term growth suppression, the CDKN2A alleles which behaved similarly to wildtype were classi®ed as p16W alleles, whereas the glioma-derived CDKN2A alleles exhibiting impaired function were classi®ed as p16M alleles (Goldstein et al, 1995). The p16W alleles (A73T, H98Y, V106M, R107C and P114S) a ected either growth suppression or cell cycle distribution to levels greater than 70% of the wild-type CDKN2A allele, while the p16M alleles (W110* and P114L) a ected each of the parameters by less than 30% relative to wild-type.…”

Section: Discussionmentioning

confidence: 99%

“…Second, structural analysis of 9p21 likely underestimates the importance of CDKN2A as a glioma suppressor gene since it does not address epigenetic mechanisms of p16 INK4a inactivation such as transcriptional silencing due to aberrant methylation (Costello et al, 1996;Merlo et al, 1995;Nishikawa et al, 1995) or modulation by other genes in the p16 INK4a pathway such as CDK4 ampli®cation and overexpression (He et al, 1994(He et al, , 1995Nishikawa et al, 1995;Schmidt et al, 1994). Third, a further level of complexity is created by examples of mutant CDKN2A alleles derived from familial cases of malignant melanomas and pancreatic carcinomas which do not seem to segregate with the tumors and appear to have only a minor impact on p16 INK4a function (Goldstein et al, 1995;Ranade et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Point mutations can inactivate in vitro and in vivo activities of p16INK4a/CDKN2A in human glioma

et al. 1997

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Deletions of chromosomal region 9p21 are among the most common genetic alterations observed during the clonal evolution of high grade malignant gliomas. Structural and functional evidence has suggested that homozygous deletion involving CDKN2A (the genetic locus encoding the cyclin-dependent kinase inhibitor p16 INK4a ) is a mechanism of inactivation of this gene and that it can be a growth suppressor in human gliomas. However, the presence of other potential suppressor genes in the 9p21 region and the relatively large sizes of the deletions has made it di cult to be certain that the CDKN2A gene is their actual target. Here, we tested this hypothesis by determining the growth suppressive e ects, cell cycle inhibitions, and the activities of seven naturally occurring glioma-derived CDKN2A alleles carrying point mutations and found that two of them were functionally compromised. To resolve discrepancies among the di erent existing functional assays, we developed an assay for p16 INK4a function that allowed us to demonstrate that the expression of wild-type CDKN2A, but not alleles with inactivating mutations, prevents pRB phosphorylation in vivo in human glioma cells. These data suggest that CDKN2A is a critical target for mutational inactivation in human malignant gliomas.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Point mutations can inactivate in vitro and in vivo activities of p16INK4a/CDKN2A in human glioma

et al. 1997

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“…R. Soc. B 370: 20140231 mutations develop melanoma and pancreatic cancer [41,42]. Clearly, the story of HS risk in dogs is only just beginning, and when combined with tumour genomics (see §3), there is still much to be learned to the benefit of both dogs and their human owners.…”

Section: Germline and Cancer Riskmentioning

confidence: 99%

Comparative oncology: what dogs and other species can teach us about humans with cancer

Schiffman

Breen

2015

Phil. Trans. R. Soc. B

316

315

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One contribution of 18 to a theme issue 'Cancer across life: Peto's paradox and the promise of comparative oncology'. Over 1.66 million humans (approx. 500/100 000 population rate) and over 4.2 million dogs (approx. 5300/100 000 population rate) are diagnosed with cancer annually in the USA. The interdisciplinary field of comparative oncology offers a unique and strong opportunity to learn more about universal cancer risk and development through epidemiology, genetic and genomic investigations. Working across species, researchers from human and veterinary medicine can combine scientific findings to understand more quickly the origins of cancer and translate these findings to novel therapies to benefit both human and animals. This review begins with the genetic origins of canines and their advantage in cancer research. We next focus on recent findings in comparative oncology related to inherited, or genetic, risk for tumour development. We then detail the somatic, or genomic, changes within tumours and the similarities between species. The shared cancers between humans and dogs that we discuss include sarcoma (osteosarcoma, soft tissue sarcoma, histiocytic sarcoma, hemangiosarcoma), haematological malignancies (lymphoma, leukaemia), bladder cancer, intracranial neoplasms (meningioma, glioma) and melanoma. Tumour risk in other animal species is also briefly discussed. As the field of genomics advances, we predict that comparative oncology will continue to benefit both humans and the animals that live among us.

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“…The frequency of INK4a-ARF mutations in melanoma probands increases with (i) the number of affected relatives, (ii) the presence of multiple melanomas in the same patient, (Soufir et al, 1998a;Holland et al, 1999) and (iii) a history of pancreatic cancer cases in the family (Goldstein et al, 1995).…”

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confidence: 99%

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

et al. 2004

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Germline anomalies of the INK4a-ARF and Cdk4 genes were sought in a series of 89 patients suspected of having a genetic predisposition to melanoma. Patients were selected based on the following criteria: (a) familial melanoma (23 cases), (b) multiple primary melanoma (MPM; 18 cases), (c) melanoma and additional unrelated cancers (13 cases), (d) age at diagnosis less than 25 years (21 cases), and (e) nonphoto-induced melanoma (NPIM; 14 cases). Mutations of INK4a-ARF and Cdk4 were characterised by automated sequencing, and germline deletions of INK4a-ARF were also examined by real-time quantitative PCR. Seven germline changes of INK4a-ARF, five of which were novel, were found in seven patients (8%). Four were very likely to be pathogenic mutations and were found in three high-risk melanoma families and in a patient who had a pancreatic carcinoma in addition to melanoma. Three variants of uncertain significance were detected in one MPM patient, one patient o25 years, and one NPIM patient. No germline deletion of INK4a-ARF was found in 71 patients, and no Cdk4 mutation was observed in the 89 patients. This study confirms that INK4a-ARF mutations are infrequent outside stringent familial criteria, and that germline INK4a-ARF deletions are rarely involved in genetic predisposition to melanoma.

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Increased Risk of Pancreatic Cancer in Melanoma-Prone Kindreds withp16^INK4Mutations

Abstract: The development of pancreatic cancer in kindreds prone to melanoma may require a p16M mutation. Genetic factors, such as the kind of mutation found in p16INK4, may explain the inconsistent occurrence of other cancers in these kindreds.

Cited by 587 publications

References 20 publications

Point mutations can inactivate in vitro and in vivo activities of p16INK4a/CDKN2A in human glioma

Point mutations can inactivate in vitro and in vivo activities of p16INK4a/CDKN2A in human glioma

Comparative oncology: what dogs and other species can teach us about humans with cancer

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

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Increased Risk of Pancreatic Cancer in Melanoma-Prone Kindreds withp16INK4Mutations

Abstract: The development of pancreatic cancer in kindreds prone to melanoma may require a p16M mutation. Genetic factors, such as the kind of mutation found in p16INK4, may explain the inconsistent occurrence of other cancers in these kindreds.

Cited by 587 publications

References 20 publications

Point mutations can inactivate in vitro and in vivo activities of p16INK4a/CDKN2A in human glioma

Point mutations can inactivate in vitro and in vivo activities of p16INK4a/CDKN2A in human glioma

Comparative oncology: what dogs and other species can teach us about humans with cancer

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

Contact Info

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Increased Risk of Pancreatic Cancer in Melanoma-Prone Kindreds withp16^INK4Mutations