Conditional survival in patients with stage IB-IIIA melanoma undergoing sentinel node biopsy in Queensland: A longitudinal study.

BACKGROUND: Tumour characteristics such as thickness and ulceration, along with sentinel lymph node (SLN) status, have been essential in predicting survival in patients with locally invasive melanomas at the time of diagnosis. It is unclear if these prognostic factors are relevant 1, 2 or 5 years after diagnosis. OBJECTIVES: The key aim of this project was to analyse conditional survival in a cohort of Queensland patients with stage IB to IIIA melanomas (American Joint Committee on Cancer's staging system, 8th version) and to test the relevance of clinicopathological prognostic factors for melanoma outcome after varying intervals of survival time. METHODS: Patients with primary invasive cutaneous melanoma who were referred to a tertiary melanoma clinic and underwent SLN biopsy between 1994 and 2011 were ascertained. The effect of patient and tumour characteristics on melanoma survival were calculated using multivariate Cox proportional hazard models at diagnosis and at variable times after diagnosis. RESULTS: The final analysis included 651 patients (average age 49 years, 55.5% male) with stage IB to IIIA melanoma. At diagnosis, and after 1 and 2 years survived, SLN positivity, thickness and ulceration were predictive of 10-year survival since diagnosis. However, once patients survived 5 years, only SLN status was predictive. Overall conditional melanoma survival improved with increasing time survived. Five years after diagnosis, 10-year conditional melanoma survival (MSS) was 91% (95% CI 86%-95%) compared with 85% (82%-88%) predicted at diagnosis. The improvement in MSS was observed mainly for Stage II melanoma patients and not for those with a positive SLN biopsy. CONCLUSIONS: This study confirms the improvement of prognosis according to time survived since diagnosis suggesting that after 5 years survival the classic prognostic indicators may not have the same influence.

Associations of keratinocyte cancers with snp variants in the sonic hedgehog pathway.

BACKGROUND: Sonic Hedgehog (SHH) pathway dysregulation is implicated in basal cell carcinoma (BCC) development. To evaluate the possible wider role of SHH gene variants in skin carcinogenesis, we assessed associations of genes in the SHH pathway with lifetime development of any keratinocyte cancer (KC), and with developing either BCCs or squamous cell carcinomas (SCCs) exclusively, in a 25-year prospective, population-based study of 1,621 Australians. METHODS: We genotyped 795 unrelated adults with available blood samples: 311 cases with any KC (186 developing BCCs-only, 55 SCCs-only, 70 BCCs and SCCs) and 484 controls. We compared allele frequencies of 158 independent SNPs across 43 SHH genes between cases and controls, and performed a gene-based analysis. RESULTS: We found associations between SNP rs4848627 (GLI2) (related to DNA synthesis in keratinocytes) and development of any KC (OR = 1.53; 95% CI = 1.06-2.13, P < 0.01) and SCCs exclusively (OR = 2.12; 95%CI = 1.39-3.23, P < 0.01). SNP rs3217882 located in CCND2 was associated with exclusive BCC development (OR = 1.43, CI = 1.12-1.82, P < 0.01). The gene-based analysis suggested an association of PRKACG (protein kinase cAMP-activated catalytic subunit gamma) with any KC (P = 0.013). CONCLUSION: We conclude that variants located in genes in the SHH pathway may are involved in SCC as well as BCC development.

Dark Green Leafy Vegetable Intake, MTHFR Genotype, and Risk of Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Evidence suggests that consumption of dark green leafy vegetables may influence the decrease in the risk of cutaneous squamous cell carcinoma (SCC). Dark green leafy vegetables contain folate as a main component among other nutrients; thus, we hypothesised that their possible observed protective effect on SCC, observed in previous studies, would be more evident in persons with specific genotypes related to folate metabolism. METHODS: Genotyping of methylenetetrahydrofolate reductase (MTHFR) gene variants rs1801133 (C677T) and rs1801131 (A1298C) was carried out for 1,128 participants in an Australian community-based longitudinal study of skin cancer. Dietary intakes were assessed through repeated Food Frequency Questionnaires (1992-1996), and all incident skin cancers were recorded in 1992-2007 and histologically confirmed. We assessed associations between intake of dark green leafy vegetables and SCC development in strata defined by genotype, by calculating relative risks (RRs) with 95% confidence intervals (CIs) using generalised linear models with negative binomial distribution and person-years of follow-up as offset. RESULTS: High versus low intake of dark green leafy vegetables was associated with a lower risk of SCC tumours in carriers of the C677T variant allele (RR = 0.42, 95% CI = 0.23-0.75), and within wild-type A1298C homozygotes (RR = 0.43, 95% CI = 0.22-0.85). CONCLUSION: The protective effect of dark green leafy vegetables on cutaneous SCC may be genotype-dependent. Folate metabolism-related gene polymorphisms should be considered when assessing the relation of green leafy vegetables to cancer risk.

Combined analysis of keratinocyte cancers identifies novel genome-wide loci.

The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5-1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.

Host genetic polymorphisms associated with beta human papillomavirus seropositivity.

Human papillomaviruses (HPVs) cause superficial epidermal infections and are only cleared if they trigger an immunological response. We analysed SNPs that had previously been investigated for association with HPV infection to determine whether they play a role in the serological response to cutaneous beta-HPVs in an Australian population. Serum samples from 1,142 participants were analysed for seropositivity against the L1 protein of 21 beta-HPV types. Associations between seropositivity to beta-HPV types and the SNPs rs9264942 (HLA-C; HPV-9, p = 0.022, HPV-15, p = 0.043 and HPV-17, p = 0.004), rs12449858 (EVER1; HPV-23, p = 0.029), and rs2981451 (FGFR2; HPV-22, p = 0.049) were identified. We found that certain SNPs could be involved in the serological response to beta-HPVs.

Polyunsaturated fatty acids and risk of melanoma: A Mendelian randomisation analysis.

Melanoma is the deadliest form of skin cancer, mainly affecting populations of European ancestry. Some observational studies suggest that particular diets reduce melanoma risk, putatively through an increase in polyunsaturated fatty acid (PUFA) consumption. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To date, a randomized controlled trial has not been carried out to examine the relationship between PUFAs and melanoma. Hence, we performed a Mendelian randomisation (MR) study to evaluate the link between PUFAs and melanoma. To perform MR, we used summary results from the largest risk genome-wide association study (GWAS) meta-analysis of melanoma, consisting of 12,874 cases and 23,203 controls. As instrumental variables we selected SNPs associated with PUFA levels from a GWAS meta-analysis of PUFA levels, from the CHARGE consortium. We used the inverse variance weighted method to estimate a causal odds ratio. To aid interpretation, we established a benchmark "large" predicted change in PUFAs in which, for example, an increase in docosahexaenoic acid (DPA) of 0.17 units (equal to 1 standard deviation) moves a person from the 17th percentile to the median. Raising PUFA levels by a large amount (increasing DPA by 0.17 units) only negligibly changed melanoma risk: odds ratio [OR] = 1.03 (95% confidence interval [CI] = 0.96-1.10). Other PUFAs yielded similar results as DPA. Our MR analysis suggests that the effect of PUFA levels on melanoma risk is either zero or very small.

Weight Gain After Heart Transplantation in Adults: Systematic Review and Meta-Analysis.

Gain in weight is common after heart transplantation but the magnitude of usual weight gain and whether this varies by country is unknown. We systematically reviewed all relevant studies to quantify weight change among heart transplant recipients (HTRs) in the years after transplantation and assess variation with geographic location. We searched PubMed, Cumulative Index to Nursing and Allied Health Literature, and Excerpta Medica Database databases to September 2020. Eligible studies reported adult HTRs' mean/median weight and/or body mass index (BMI) up to time of transplantation (baseline) and posttransplantation in any language. Weighted mean differences (WMDs) (95% confidence intervals [CIs]) of weight/BMI from baseline to posttransplantation were estimated using a random-effects model. Ten studies met the inclusion criteria. Pooled analysis showed weight gain of 7.1 kg (95% CI, 4.4-9.8 kg) in HTRs 12 months posttransplant, with corresponding BMI increase of 1.69 kg/m 2 (95% CI, 0.83-2.55 kg/m 2 ). Greatest weight gain at 12 months posttransplant occurred in US HTRs (WMD weight 10.42 kg, BMI 3.25 kg/m 2 ) and least, in European HTRs (WMD weight 3.10 kg, BMI 0.78 kg/m 2 ). In conclusion, HTRs gain substantial weight in the years after transplantation, but varying widely by geographic location.

Multi-Trait Genetic Analysis Identifies Autoimmune Loci Associated with Cutaneous Melanoma.

Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multitrait analysis of GWAS (MTAG). We used bivariate linkage disequilibrium-score regression score regression to identify traits that are genetically correlated with clinically confirmed cutaneous melanoma and then used publicly available GWAS for these traits in a multitrait analysis of GWAS. Multitrait analysis of GWAS allows GWAS to be combined while accounting for sample overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci, 19 of them were not previously reported in the input cutaneous melanoma GWAS meta-analysis. Of these loci, 55 were replicated (P < 0.05/74, Bonferroni-corrected P-value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the, to our knowledge, previously unreported cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.

No Evidence for a Causal Relationship Between Cancers and Parkinson's Disease.

BACKGROUND: Epidemiological data suggest that cancer patients have a reduced risk of subsequent Parkinson's disease (PD) development, but the prevalence of PD in melanoma patients is often reported to be increased. Causal relationships between cancers and PD have not been fully explored. OBJECTIVE: To study causal relationship between different cancers and PD. METHODS: We used GWAS summary statistics of 15 different types of cancers and two-sample Mendelian randomization to study the causal relationship with PD. RESULTS: There was no evidence to support a causal relationship between the studied cancers and PD. We also performed reverse analyses between PD and cancers with available full summary statistics (melanoma, breast, prostate, endometrial and keratinocyte cancers) and did not find evidence of causal relationship. CONCLUSION: We found no evidence to support a causal relationship between cancers and PD and the previously reported associations could be a result of genetic pleiotropy, shared biology or biases.

Genetically determined risk of keratinocyte carcinoma and risk of other cancers.

BACKGROUND: Epidemiological studies have consistently documented an increased risk of developing primary non-cutaneous malignancies among people with a history of keratinocyte carcinoma (KC). However, the mechanisms underlying this association remain unclear. We conducted two separate analyses to test whether genetically predicted KC is related to the risk of developing cancers at other sites. METHODS: In the first approach (one-sample), we calculated the polygenic risk scores (PRS) for KC using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 16 896). The association between the KC PRS and each cancer site was assessed using logistic regression. In the secondary (two-sample) approach, we used genome-wide association study (GWAS) summary statistics identified from the most recent GWAS meta-analysis of KC and obtained GWAS data for each cancer site from the UK-Biobank participants only. We used inverse-variance-weighted methods to estimate risks across all genetic variants. RESULTS: Using the one-sample approach, we found that the risks of cancer at other sites increased monotonically with KC PRS quartiles, with an odds ratio (OR) of 1.16, 95% confidence interval (CI): 1.13-1.19 for those in KC PRS quartile 4 compared with those in quartile 1. In the two-sample approach, the pooled risk of developing other cancers was statistically significantly elevated, with an OR of 1.05, 95% CI: 1.03-1.07 per doubling in the odds of KC. We observed similar trends of increasing cancer risk with increasing KC PRS in the QSkin cohort. CONCLUSION: Two different genetic approaches provide compelling evidence that an instrumental variable for KC constructed from genetic variants predicts the risk of cancers at other sites.

Mendelian Randomization Study for Genetically Predicted Polyunsaturated Fatty Acids Levels on Overall Cancer Risk and Mortality.

BACKGROUND: Observational studies evaluating the link between polyunsaturated fatty acids (PUFA) and cancers have yielded mixed findings. We used Mendelian randomization (MR) to evaluate whether genetic evidence supports a causal role for PUFAs on overall cancer outcomes. METHODS: We identified genetic instruments for six PUFAs from previous literature and evaluated their association with overall cancer risk (46,155 cases, 270,342 controls) and cancer mortality (6,998 deaths, 270,342 controls) among the UK Biobank cohort. We used the inverse variance weighted model to combine SNP estimates, and derived log (OR) estimates per SD change in each PUFA. RESULTS: None of the six PUFAs showed association with overall cancer risk or mortality, with narrow confidence interval (CI) ruling out all but very small effects, for example, arachidonic acid (AA) overall cancer risk (OR, 1.02; 95% CI, 1.00-1.03). Sex-specific analysis revealed no associations except α-linolenic acid for potentially reducing cancer risk in men (OR, 0.92; 95% CI, 0.86-0.98; P = 0.02); however, this was nonsignificant after multiple testing correction. From individual cancers, only colorectal cancer showed evidence for a causal association for higher AA levels (OR, 1.05; 95% CI, 1.03-1.07), with similar results for the other correlated PUFAs. CONCLUSIONS: Our study provides no support for the hypothesis that PUFAs reduce overall cancer risk or mortality. Higher AA levels increased the risk for colorectal cancer. IMPACT: Our well-powered MR study provides robust causal inferences for the PUFAs on overall cancer risk and mortality. Future larger studies are warranted to replicate the individual cancer findings.