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Nicholas K Hayward

Publications and source records attributed to Nicholas K Hayward.

13 recordsLinked to original sources
PubMed2026

Phenotypic and genotypic risk factors for uveal melanoma in a high ambient UV radiation environment.

BACKGROUND: Most evidence regarding risk factors for uveal melanoma (UM) derives from case-control studies prone to recall bias, and its rarity has limited prospective research. To address these gaps, we applied a population-based case-control design incorporating polygenic risk scores and Mendelian randomization to explore genetic and phenotypic determinants of UM risk. METHODS: The study was conducted in Queensland, Australia. Incident UM cases diagnosed between 2011 and 2022 were recruited through specialist ocular oncology clinics. Controls were participants in the QSkin Sun and Health Study, a prospective cohort of 43,794 adults aged 40-69 at baseline (2010-2011). Demographic, phenotypic, and sun exposure factors were harmonized across studies. Polygenic risk scores were calculated for pigmentation traits and nevi characteristics using genome-wide association study datasets, and Mendelian randomization was used to assess potential causal relationships with UM risk. RESULTS: Among 485 UM cases and 43,724 controls, several phenotypic traits were strongly associated with UM risk: male sex, blue or light eye color, inability to tan, freckling, and high nevus density. A family history of cutaneous melanoma and a personal history of keratinocyte cancer were also associated with higher risk. Polygenic risk score analyses confirmed significant associations for eye color and freckling. Mendelian randomization analyses supported causal relationships between lighter eye color, freckling propensity, reduced tanning ability and UM risk. CONCLUSIONS: These findings provide genetic evidence supporting a causal role for pigmentation-related traits in UM susceptibility. IMPACT: This evidence may help refine risk assessment and inform counselling for individuals with suspicious ocular lesions.

Journal Article↗
PubMed2003

Tumor necrosis factor haplotype analysis amongst schizophrenia probands from four distinct populations in the Asia-Pacific region.

A single nucleotide polymorphism (TNF(-308A)) within the promoter region of the gene encoding tumor necrosis factor (TNF), has been significantly associated with schizophrenia in a study of Italian patients and control subjects Boin et al. [2001: Mol Psychiatry 6:79-82]. We have applied case-control analyses to examine TNF promoter haplotypes (containing TNF(-308) and two additional promoter variants: TNF(-376) and TNF(-238)) in four schizophrenia cohorts drawn from Australian, Indian Fijian, Indigenous Fijian, and Brahmin populations. In addition, we have applied the sibling transmission disequilibrium (STD) test to promoter haplotypes within 81 trios drawn from Australian Caucasian pedigrees with multiple schizophrenia cases, and 86 trios drawn from the Brahmin population of Tamil Nadu province in Southern India. Within each of these cohorts, we found no evidence of recombination between these tightly linked promoter variants, supporting previous studies which demonstrated that only a subset of the eight possible haplotypes exist. Of the four observed haplotypes, we and others have observed only one carries the TNF(-308A) variant allele. We report no significant differences in TNF promoter haplotype frequencies between the patient and control groups within each population, although the Indian Fijian cohort showed a trend towards reduced TNF(-308A) alleles amongst schizophrenia cases (P = 0.07). We found no evidence of bias in TNF promoter haplotype transmission to schizophrenia probands. Very similar results were obtained when only the TNF(-308) polymorphism was considered. Taken together, these data provide no support for the involvement of TNF promoter variants TNF(-308), TNF(-376), and TNF(-238) in schizophrenia susceptibility within four ethnically distinct cohorts.

Australia↗
PubMed2003

Chromosomal gains and losses in ocular melanoma detected by comparative genomic hybridization in an Australian population-based study.

To define the location of potential oncogenes and tumor suppressor genes in ocular melanoma we carried out comparative genomic hybridization (CGH) analysis on a population-based series of 25 formalin-fixed, paraffin-embedded primary tumors comprising 17 choroidal, 2 ciliary body, 4 iris, and 2 conjunctival melanomas. Twelve (48%) of the 25 melanomas showed no chromosomal changes and 13 (52%) had at least one chromosomal gain or loss. The mean number of CGH changes in all tumors was 3.3, with similar mean numbers of chromosomal gains (1.5) and losses (1.8). The highest number of chromosomal changes (i.e., nine) occurred in a conjunctival melanoma and included four changes not observed in tumors at any other ocular site (gains in 22q and 11p and losses in 6p and 17p). The most frequent gains in all primary ocular melanomas were on chromosome arm 8q (69%), 6p (31%) and 8p (23%) and the most frequent losses were on 6q (38%), 10q (23%), and 16q (23%). The most common pairing was gain in 8p and gain in 8q, implying a whole chromosome copy number increase; gains in 8p occurred only in conjunction with gains in 8q. The smallest regions of copy number alteration were mapped to gain of 8q21 and loss of 6q21, 10q21, and 16q22. Sublocalization of these chromosomal changes to single-band resolution should accelerate the identification of genes involved in the genesis of ocular melanoma.

Adolescent↗
PubMed2003

Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma.

BACKGROUND: Some melanomas form on sun-exposed body sites, whereas others do not. We previously proposed that melanomas at different body sites arise through different pathways that have different associations with melanocytic nevi and solar keratoses. We tested this hypothesis in a case-case comparative study of melanoma patients in Queensland, Australia. METHODS: We randomly selected patients from among three prespecified groups reported to the population-based Queensland Cancer Registry: those with superficial spreading or nodular melanomas of the trunk (n = 154, the reference group), those with such melanomas of the head and neck (n = 77, the main comparison group), and those with lentigo maligna melanoma (LMM) (n = 75, the chronic sun-exposed group). Each participant completed a questionnaire, and a research nurse counted melanocytic nevi and solar keratoses. We calculated exposure odds ratios (ORs) and 95% confidence intervals (CIs) to quantify the association between factors of interest and each melanoma group. RESULTS: Patients with head and neck melanomas, compared with patients with melanomas of the trunk, were statistically significantly less likely to have more than 60 nevi (OR = 0.34, 95% CI = 0.15 to 0.79) but were statistically significantly more likely to have more than 20 solar keratoses (OR = 3.61, 95% CI = 1.42 to 9.17) and also tended to have a past history of excised solar skin lesions (OR = 1.87, 95% CI = 0.89 to 3.92). Patients with LMM were also less likely than patients with truncal melanomas to have more than 60 nevi (OR = 0.32, 95% CI = 0.14 to 0.75) and tended toward more solar keratoses (OR = 2.14, 95% CI = 0.88 to 5.16). CONCLUSIONS: Prevalences of nevi and solar keratoses differ markedly between patients with head and neck melanomas or LMM and patients with melanomas of the trunk. Cutaneous melanomas may arise through two pathways, one associated with melanocyte proliferation and the other with chronic exposure to sunlight.

Cell Division↗
PubMed2003

Genetics of melanoma predisposition.

Predisposition to melanoma is genetically heterogeneous. Two high penetrance susceptibility genes, CDKN2A and CDK4, have so far been identified and mapping is ongoing to localize and identify others. With the advent of a catalogue of millions of potential DNA polymorphisms, attention is now also being focused on identification of genes that confer a more modest contribution to melanoma risk, such as those encoding proteins involved in pigmentation, DNA repair, cell growth and differentiation or detoxification of metabolites. One such pigmentation gene, MC1R, has not only been found to be a low penetrance melanoma gene but has also been shown to act as a genetic modifier of melanoma risk in individuals carrying CDKN2A mutations. Most recently, an environmental agent, ultraviolet radiation, has also been established as a modifier of melanoma risk in CDKN2A mutation carriers. Hence, melanoma is turning out to be an excellent paradigm for studying gene-gene and gene-environment interactions.

Cyclin-Dependent Kinase 4↗
PubMed2003

Vegfb gene knockout mice display reduced pathology and synovial angiogenesis in both antigen-induced and collagen-induced models of arthritis.

OBJECTIVE: To determine the role of vascular endothelial growth factor B (VEGF-B) in 2 mouse models of arthritis, antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA). METHODS: For AIA studies, monarticular AIA was induced by methylated bovine serum albumin (mBSA) priming of Vegfb gene knockout (Vegfb(-/-)) and wild-type (Vegfb(+/+)) mice, followed by intraarticular injection of mBSA or saline control 8 days later. CIA was induced in Vegfb(-/-) and Vegfb(+/+) mice by intradermal injection of chick type II collagen in adjuvant. Arthritis was monitored in both models using defined criteria (clinical and histologic). Angiogenesis was measured by synovial vessel density in diseased and control joints. RESULTS: In AIA studies, Vegfb(+/+) mice displayed significant knee joint swelling and synovial inflammation 7 days after intraarticular injection of antigen. Synovial inflammation was associated with angiogenesis, since vessel density in AIA synovium was significantly higher in arthritic than in control joints from the same animal. Knee joint swelling, synovial inflammation, and inflammation-associated vessel density in arthritic joints were reduced in Vegfb(-/-) mice compared with arthritic joints from Vegfb(+/+) mice. Similarly, in CIA, both disease incidence and mean clinical severity scores were significantly reduced in Vegfb(-/-) mice compared with Vegfb(+/+) mice. Mean histologic severity scores and mean synovial vessel density were reduced in diseased joints from Vegfb(-/-) mice when compared with diseased joints from Vegfb(+/+) mice. CONCLUSION: The reduction in inflammation-associated synovial angiogenesis in Vegfb(-/-) mice implicates VEGF-B in pathologic vascular remodeling in inflammatory arthritis. VEGF-B may be an attractive target in the design of anti-angiogenic therapies for rheumatoid arthritis.

Angiogenesis Inducing Agents↗
PubMed2003

eMelanoBase: an online locus-specific variant database for familial melanoma.

A proportion of melanoma-prone individuals in both familial and non-familial contexts has been shown to carry inactivating mutations in either CDKN2A or, rarely, CDK4. CDKN2A is a complex locus that encodes two unrelated proteins from alternately spliced transcripts that are read in different frames. The alpha transcript (exons 1alpha, 2, and 3) produces the p16INK4A cyclin-dependent kinase inhibitor, while the beta transcript (exons 1beta and 2) is translated as p14ARF, a stabilizing factor of p53 levels through binding to MDM2. Mutations in exon 2 can impair both polypeptides and insertions and deletions in exons 1alpha, 1beta, and 2, which can theoretically generate p16INK4A-p14ARF fusion proteins. No online database currently takes into account all the consequences of these genotypes, a situation compounded by some problematic previous annotations of CDKN2A-related sequences and descriptions of their mutations. As an initiative of the international Melanoma Genetics Consortium, we have therefore established a database of germline variants observed in all loci implicated in familial melanoma susceptibility. Such a comprehensive, publicly accessible database is an essential foundation for research on melanoma susceptibility and its clinical application. Our database serves two types of data as defined by HUGO. The core dataset includes the nucleotide variants on the genomic and transcript levels, amino acid variants, and citation. The ancillary dataset includes keyword description of events at the transcription and translation levels and epidemiological data. The application that handles users' queries was designed in the model-view-controller architecture and was implemented in Java. The object-relational database schema was deduced using functional dependency analysis. We hereby present our first functional prototype of eMelanoBase. The service is accessible via the URL www.wmi.usyd.edu.au:8080/melanoma.html.

Computer Security↗
PubMed2002

High frequency of BRAF mutations in nevi.

To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.

Cell Transformation, Neoplastic↗
PubMed2002

Vascular endothelial growth factor-B-deficient mice show impaired development of hypoxic pulmonary hypertension.

OBJECTIVE: To test the hypothesis that Vegf-B contributes to the pulmonary vascular remodelling, and the associated pulmonary hypertension, induced by exposure of mice to chronic hypoxia. METHODS: Right ventricular systolic pressure, the ratio of right ventricle/[left ventricle+septum] (RV/[LV+S]) and the thickness of the media (relative to vessel diameter) of intralobar pulmonary arteries (o.d. 50-150 and 151-420 microm) were determined in Vegfb knockout mice (Vegfb(-/-); n=17) and corresponding wild-type mice (Vegfb(+/+); n=17) exposed to chronic hypoxia (10% oxygen) or housed in room air (normoxia) for 4 weeks. RESULTS: In Vegfb(+/+) mice hypoxia caused (i) pulmonary hypertension (a 70% increase in right ventricular systolic pressure compared with normoxic Vegfb(+/+) mice; P<0.001), (ii) right ventricular hypertrophy (a 66% increase in RV/[LV+S]; P<0.001) and (iii) pulmonary vascular remodelling (a 27-36% increase in pulmonary arterial medial thickness; P<0.05). In contrast, in Vegfb(-/-) mice hypoxia did not cause any increase in either right ventricular systolic pressure or pulmonary arterial medial thickness; also right ventricular hypertrophy (41% increase in RV/[LV+S]; P<0.001) was less pronounced (P<0.05) than in Vegfb(+/+) mice. CONCLUSION: Vegf-B may have a role in the development of chronic hypoxic pulmonary hypertension in mice by contributing to pulmonary vascular remodelling. If so, the effect of Vegf-B appears to be different from that of Vegf-A which is reported to protect against, rather than contribute to, hypoxia-induced pulmonary vascular remodelling.

Animals↗
PubMed2002

Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma.

Germline mutations of the PTEN tumor-suppressor gene, on 10q23, cause Cowden syndrome, an inherited hamartoma syndrome with a high risk of breast, thyroid and endometrial carcinomas and, some suggest, melanoma. To date, most studies which strongly implicate PTEN in the etiology of sporadic melanomas have depended on cell lines, short-term tumor cultures and noncultured metastatic melanomas. The only study which reports PTEN protein expression in melanoma focuses on cytoplasmic expression, mainly in metastatic samples. To determine how PTEN contributes to the etiology or the progression of primary cutaneous melanoma, we examined cytoplasmic and nuclear PTEN expression against clinical and pathologic features in a population-based sample of 150 individuals with incident primary cutaneous melanoma. Among 92 evaluable samples, 30 had no or decreased cytoplasmic PTEN protein expression and the remaining 62 had normal PTEN expression. In contrast, 84 tumors had no or decreased nuclear expression and 8 had normal nuclear PTEN expression. None of the clinical features studied, such as Clark's level and Breslow thickness or sun exposure, were associated with cytoplasmic PTEN expressional levels. An association with loss of nuclear PTEN expression was indicated for anatomical site (p = 0.06) and mitotic index (p = 0.02). There was also an association for melanomas to either not express nuclear PTEN or to express p53 alone, rather than both simultaneously (p = 0.02). In contrast with metastatic melanoma, where we have shown previously that almost two-thirds of tumors have some PTEN inactivation, only one-third of primary melanomas had PTEN silencing. This suggests that PTEN inactivation is a late event likely related to melanoma progression rather than initiation. Taken together with our previous observations in thyroid and islet cell tumors, our data suggest that nuclear-cytoplasmic partitioning of PTEN might also play a role in melanoma progression.

Aged↗
PubMed2002

Pathways to melanoma development: lessons from the mouse.

Because of subtle differences between mouse and human skin, mice have traditionally not been an ideal model to study melanoma development. Understanding of the molecular mechanisms of melanoma predisposition, however, has been greatly improved by modeling various pathway defects in the mouse. This review analyzes the latest developments in mouse models of melanoma, and summarizes what these may indicate about the development of this neoplasm in humans. Mutations of genes involved in human melanoma have been recapitulated with some unexpected results, particularly with respect to the role of the two transcripts (Ink4a and Arf) encoded by the Cdkn2a locus. Both the Ink4a/pRb and Arf/p53 pathways are involved in melanoma development in mice, and possible mechanisms of cross-talk between the two pathways are discussed. We also know from mouse models that Ras/mitogen-activated protein kinase pathway activation is very important in melanoma development, either through direct activation of Ras (e.g., Hras G12V), or via activation of Ras-effector pathways by other oncogenes (e.g., Ret, Hgf/Sf). Ras can cooperate with the Arf/p53 pathway, and probably the Ink4a/Rb pathway, to induce melanoma. These three growth regulation pathways (Ink4a/pRb, Arf/p53, and Ras/mitogen-activated protein kinase) seem to represent three major "axes" of melanoma development in mice. Finally, we summarize experiments using genetically modified mice that have given indications of the intensity and timing of ultraviolet radiation exposure that may be most responsible for melanoma development.

Animals↗