Survival for Patients With Single and Multiple Primary Melanomas: The Genes, Environment, and Melanoma Study

IMPORTANCE: Little is known about survival after a diagnosis of a second or higher-order (multiple) primary melanoma, and no study has explored survival in a population-based sample that included patients with single primary melanomas (SPMs) and multiple primary melanomas (MPMs) of any stage. Because people with a first primary melanoma are known to have an increased risk of being diagnosed with another, evidence for prognosis is needed. OBJECTIVE: To determine whether survival after diagnosis was better in patients with MPMs than with SPMs, as suggested in a recent study. DESIGN Survival analysis with median follow-up of 7.6 (range, 0.4-10.6) years. SETTING: The Genes, Environment, and Melanoma Study enrolled incident cases of melanoma from population-based cancer registries in Australia, Canada, Italy, and the United States. Multiple primary melanomas were ascertained during a longer period than SPM. PARTICIPANTS: Two thousand three hundred seventy-two patients with SPM and 1206 with MPM. EXPOSURE: Diagnosis with melanoma. MAIN OUTCOMES AND MEASURES: Melanoma-specific fatality hazard ratios (HR) and 95% confidence intervals associated with clinical and pathological characteristics of SPM, MPM, and both in Cox proportional hazards regression models. RESULTS: Melanoma thickness was the main determinant of fatality (HR for >4 mm, 7.68 [95% CI, 4.46-13.23]); other independent predictors were ulceration, mitoses, and scalp location. After adjustment for these other predictors, we found little difference in fatality between MPM and SPM (HR for MPM relative to SPM, 1.24 [95% CI, 0.91-1.69; P = .18]). Thicker SPM, however, had higher fatality (HR for >4 mm, 13.56 [95% CI, 6.47-28.40]) than thicker MPM (2.93 [1.17-7.30]). CONCLUSIONS AND RELEVANCE: Although overall fatalities due to SPM and MPM were similar, relative fatality for thicker SPM was greater than that for thicker MPM. This finding may offer support for a difference in outcome between patients with SPM and MPM related to factors other than closer surveillance and earlier diagnosis. The better outcomes are worth further exploration

Risk of non-Hodgkin lymphoma associated with occupational exposure to solvents,metals, organic dusts and PCBs (Australia)

Objective: Several studies have suggested that there is an occupational component to the causation of non-Hodgkin lymphoma (NHL). We aimed to use accurate means to assess occupational exposures to solvents, metals, organic dusts and polychlorinated biphenyls (PCBs) in a case-control study. Methods: Cases were incident NHLs during 2000 and 2001 in two regions of Australia. Controls were randomly selected from the electoral roll and frequency matched to cases by age, sex and region. A detailed occupational history was taken from each subject. For jobs with likely exposure to the chemicals of interest, additional questions were asked by telephone interview using modified job specific modules. An expert allocated exposures using the information in the job histories and the interviews. Odds ratios were calculated for each exposure adjusting for age, sex, region and ethnic origin. Results: 694 cases and 694 controls (70% and 45% respectively of those potentially eligible) participated. The risk of NHL was increased by about 30% for exposure to any solvent with a dose response relationship, subgroup analysis showed the finding was restricted to solvents other than benzene. Exposure to wood dust also increased the risk of NHL slightly. Exposures to other organic dusts, metals, and PCBs were not strongly related to NHL. Conclusions: The risk of NHL appears to be increased by exposure to solvents other than benzene and possibly to wood dust

A design for cancer case–control studies using only incident cases: experience with the GEM study of melanoma

BACKGROUND: The population-based case-control study is not suited to the evaluation of rare genetic (or environmental) factors. The use of a novel case-control design in which cases have second primaries and controls are cancer survivors has been proposed for this purpose. METHODS: We report results from an international study of melanoma that involved population-based ascertainment of incident cases of second or subsequent primary melanoma as the 'case' group and incident cases of first primary melanoma as the 'control' group. We evaluate the validity of the study design by comparing the results obtained for phenotypic factors that have been shown consistently to be associated with melanoma in previous conventional studies with the results from a conventional case-control study conducted in Connecticut and from literature reviews. RESULTS: All but one of the known risk factors for melanoma were shown to be significantly associated with melanoma in our study, though the individual odds ratios appear to be somewhat attenuated relative to the magnitudes typically observed in the literature. CONCLUSIONS: Patients with a second or subsequent primary cancer of a single type represent a potentially valuable and under-utilized resource for the study of cancer aetiology

CDKN2A Germline Mutations in Individuals with Cutaneous Malignant Melanoma

Cyclin-dependent kinase inhibitor type 2A (CDKN2A) has been identified as a major melanoma susceptibility gene based on the presence of germline mutations in high-risk melanoma families. In this study, we sought to identify and characterize the spectrum of CDKN2A mutations affecting p16 inhibitor of cyclin-dependent kinase type 4 (INK4a) in individuals with melanoma using a population-based study design. DNA samples from 1189 individuals with incident multiple primary melanoma (MPM) and 2424 with incident single primary melanoma unselected for family history of melanoma were available for screening of CDKN2A (p16INK4a) mutations. Variants were classified for functional impact based on intragenic position, existing functional data, sequence, and structural analysis. The impact of individual mutations and functional groupings was assessed by comparing frequencies in cases of MPM versus cases with a single first primary melanoma, and by comparing the reported incidence rates in first-degree relatives. Our results show that mutations occur infrequently in these high-risk groups, and that they occur mainly in exons 1alpha and 2. Rare coding variants with putative functional impact are observed to increase substantially the risk of melanoma. With the exception of the variant in position -34 of CDKN2A of known functional consequence, the remaining rare variants in the non-coding region have no apparent impact on risk

Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics

MC1R genotype may modify the effect of sun exposure on melanoma risk in the GEM study

We investigated whether MC1R genotype modifies the effect of sun exposure on melanoma risk in 1,018 cases with multiple melanomas (MPM) and 1,875 controls with one melanoma (SPM). There was some suggestion that MC1R genotype modified the effect of beach and water activities on MPM risk: ORs were 1.94 (95% CI 1.40–2.70) for any activities for no R variants and 1.39 (95% CI 1.05–1.84) with R variants (R151C, R160W, D294H, D84E) (p for interaction 0.08). MC1R modification of sun exposure effects appeared most evident for MPM of the head and neck: for early life ambient UV the OR was 4.23 (95% CI 1.76–10.20) with no R and 1.04 (95% CI 0.40–2.68) with R (p for interaction=0.01; p for three-way interaction=0.01). Phenotype modified the effect of sun exposure and MPM in a similar manner. We conclude that MC1R and pigmentary phenotype may modify the effects of sun exposure on melanoma risk on more continuously sun-exposed skin. Possible explanations include that risk may saturate with higher sun sensitivity for melanomas on continuously sun-exposed sites but continue to increase as sun exposure increases with lower sun sensitivity, or that sun sensitive people adapt their behaviour by increasing sun protection when exposed

MITF E318K's effect on melanoma risk independent of, but modified by, other risk factors

A rare germline variant in the MITF (microphthalmia-associated transcription factor) gene, E318K, has been reported as associated with melanoma. We confirmed its independent association with melanoma (odds ratio (OR) 1.7, 95% Confidence Interval (CI) = 1.1, 2.7, p = 0.03); adjusted for age, sex, center, age*sex interaction, pigmentation characteristics, family history of melanoma and nevus density). In stratified analyses, carriage of MITF E318K was associated with melanoma more strongly in people with dark hair than fair hair (p for interaction, 0.03) and in those with no moles than some or many moles (p for interaction, <0.01). There was no evidence of interaction between MC1R “red hair variants” and MITF E318K. Moreover, risk of melanoma among carriers with “low risk” phenotypes was as great or greater than among those with “at risk” phenotypes with few exceptions

Clinicopathologic Features of Incident and Subsequent Tumors in Patients with Multiple Primary Cutaneous Melanomas

0.6–12.7% of patients with primary cutaneous melanoma will develop additional melanomas. Pathologic features of tumors in patients with multiple primary cutaneous melanomas have not been well described. In this large international multi-center case-control study, we compared the clinicopathologic features of a subsequent melanoma with the preceding (usually the first) melanoma in patients with multiple primary cutaneous melanomas, and with those of melanomas in patients with single primary cutaneous melanomas