The CDKN2A database: Integrating allelic variants with evolution, structure, function, and disease association

Murphy, Joan A.; Barrantes-Reynolds, Ramiro; Kocherlakota, Rama; Bond, Jeffrey P.; Greenblatt, Marc S.

doi:10.1002/humu.20083

Cited by 29 publications

(31 citation statements)

References 33 publications

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“…As noted in previous reports [Murphy et al, 2004], there has been significant variability between authors regarding mutation nomenclature for mutations at certain gene loci; standardization was imperative for meaningful analysis. Included in Supplementary …”

Section: Data Extractionmentioning

confidence: 95%

“…We used the LSDBs for TP53 [Olivier et al, 2002] and CDKN2A [Murphy et al, 2004] and analyzed our UVB-signature rates at these two loci relative to non-skin cancers (NSCs; defined as cancers in the locus-specific databases (LSDBs) arising from tissue other than ''SKIN,'' and ''HEAD & NECK'') and another non-melanoma skin cancer, cutaneous squamous cell carcinomas (SCCs). Uncultured cutaneous melanomas had a greater percentage of UVB-signature mutations (Fig.…”

Section: Comparison Of Uvb-signature Mutations Between Melanoma and Omentioning

confidence: 99%

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Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants

2007

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Despite the large body of mutational data available for melanoma and epidemiological studies linking this cancer to ultraviolet radiation (UVR), the fundamental carcinogenic mechanisms involved in melanoma remain largely unknown. To this end, we systematically reviewed, extracted, and analyzed mutational data from the extant melanoma literature in an effort to gain more insight into its early pathogenic events. We searched PubMed (1966-January 2006) using the words "mutation" AND "melanoma" in the title or abstract. Out of 2,095 returned results, there were 203 eligible studies that were subsequently analyzed. We cataloged 8,201 somatic and cultured melanoma specimens and annotated 2,041 reported somatic sequence variants. The single BRAF c.1799T>A (p.Val600Glu) alteration is the most prevalent variant while other A:T>T:A transversions were uncommon. Four highly-recurrent, non-ultraviolet B (UVB) changes account for most of the NRAS and BRAF variants. CDKN2A, PTEN/MMAC1, and TP53 harbored statistically higher rates of UVB signature changes (64.2%, 52.4%, and 69.2%, respectively) than oncogenic loci (NRAS: 15.3% and BRAF: 2.4%). More specifically, cutaneous melanomas showed a significantly higher proportion of UVB signature mutations at both TP53 and CDKN2A when compared to non-skin cancers using data from their respective locus-specific databases. Superficial spreading and nodular melanomas had the highest rates of BRAF (53.4%) and NRAS (28.0%) mutations. In melanoma, there is sufficient mutational evidence to support a role for direct UVB participation, especially at TP53 and CDKN2A. For oncogenes, the role for UVB is less clear since functionally-activating changes are uncommon and are subject to sequence constraints.

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Section: Data Extractionmentioning

confidence: 95%

Section: Comparison Of Uvb-signature Mutations Between Melanoma and Omentioning

confidence: 99%

Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants

2007

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“…The small region (<42kb in Hapmap II) including p16 INK4a / ARF and p15 INK4b is amongst the most frequent lost in human cancer (Kim and Sharpless, 2006) and germline mutations of p16 INK4a /ARF are linked to melanoma and other malignancies (Murphy et al, 2004;Lang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

A common variant of the p16INK4a genetic region is associated with physical function in older people

Melzer

Frayling

Murray

et al. 2007

Mechanisms of Ageing and Development

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Abstractp16 INK4a is active in cell senescence, ageing and tumor suppression. Deletion of the small p16 INK4a / ARF / p15 INK4b region occurs in many cancers. We screened 25 common polymorphisms across the region and 3 related genes for associations with physical functioning in older people.In an initial sample of 938 (aged 65 to 80yrs) from the EPIC study (Norfolk, UK) the rs2811712 SNP minor allele (located between the shared p16 INK4a / ARF locus and p15 INK4b ) was associated with reduced physical impairment. This association remained after testing an additional 1319 EPICNorfolk samples (p-value=0.013, total n=2257), and on independent replication in the InCHIANTI Study (n=709, p=0.015), and at one sided significance in Iowa-EPESE (n=419, p=0.079). Overall (n=3372) the prevalence of severely limited physical function was 15.0% in common homozygotes and 7.0% in rare homozygotes (per minor allele Odds Ratio=1.48 95%CI: 1.17−1.88, p =0.001, adjusted for age, sex and study). This estimate was similar excluding screening set 1 (OR=1.45: 95% CI 1.09−1.92, p=0.010, n=2434).These findings require further replication, but provide the first direct evidence that the p16 INK4a / ARF / p15 INK4b genetic region and the senescence machinery are active in physical ageing in heterogeneous human populations. The mechanism involved may be via greater cellular restorative activity and reduced stem cell senescence.

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“…This is happening because it is acknowledged that curation of mutations in genes is best done by experts in that gene or disease [Cotton, 2000], rather than by workers at central databases who collect information from the literature. This notion has been underscored recently by Gout et al [2007], who, using their expertise as LSDB curators, documented 5% errors in the literature, and Murphy et al [2004] found that 43% of CDKN2A mutations had at least one error in the report. Obviously, these errors cannot be tolerated since serious decisions, such as abortion and radical therapy, are being made on published data.…”

Section: Introductionmentioning

confidence: 98%

Recommendations for locus-specific databases and their curation

et al. 2007

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Communicated by Mark H. PaalmanExpert curation and complete collection of mutations in genes that affect human health is essential for proper genetic healthcare and research. Expert curation is given by the curators of gene-specific mutation databases or locusspecific databases (LSDBs). While there are over 700 such databases, they vary in their content, completeness, time available for curation, and the expertise of the curator. Curation and LSDBs have been discussed, written about, and protocols have been provided for over 10 years, but there have been no formal recommendations for the ideal form of these entities. This work initiates a discussion on this topic to assist future efforts in human genetics. Further discussion is welcome. Hum Mutat 29(1), 2-5, 2008.

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The CDKN2A database: Integrating allelic variants with evolution, structure, function, and disease association

Cited by 29 publications

References 33 publications

Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants

Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants

A common variant of the p16INK4a genetic region is associated with physical function in older people

Recommendations for locus-specific databases and their curation

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