Graham J. Mann

Prognostic and Clinicopathologic Associations of Oncogenic BRAF in Metastatic Melanoma

PURPOSE To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome. PATIENTS AND METHODS Consecutive BRAF-tested Australian patients with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted. RESULTS Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor. CONCLUSION V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.

Genome-wide association study identifies three loci associated with melanoma risk

We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 × 10−7. Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 × 10−27 for rs258322), 11q14-q21 encompassing TYR (P = 2.41 × 10−14 for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 × 10−7 for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: A consensus statement

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of familys mutations) and the Netherlands (c.225_243del19, 90% of familys mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.

A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma

So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case–control sample. Likewise, it was similarly associated in an independent case–control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents

Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. Methods: These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk. Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

Common sequence variants on 20q11.22 confer melanoma susceptibility

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 × 10−15). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: a consensus statement. Society of Surgical Oncology.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

Genome-wide association study identifies three new melanoma susceptibility loci

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10−5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10−3: an SNP in ATM (rs1801516, overall P = 3.4 × 10−9), an SNP in MX2 (rs45430, P = 2.9 × 10−9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10−10). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10−7 under a fixed-effects model and P = 1.2 × 10−3 under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Sunbed use during adolescence and early adulthood is associated with increased risk of early-onset melanoma

Sunbed use is associated with increased risk of melanoma. Younger people might be more susceptible to the carcinogenic effects of ultraviolet radiation. We investigated the association between sunbed use and risk of early‐onset cutaneous malignant melanoma. From the Australian Melanoma Family Study, a multicentre, population‐based, case‐control‐family study, we analysed data for 604 cases diagnosed between ages 18 and 39 years and 479 controls. Data were collected by interview. Associations were estimated as odds ratios (ORs) using unconditional logistic regression, adjusting for age, sex, city, education, family history, skin color, usual skin response to sunlight and sun exposure. Compared with having never used a sunbed, the OR for melanoma associated with ever‐use was 1.41 (95% confidence interval (CI) 1.01–1.96), and 2.01 (95% CI 1.22–3.31) for more than 10 lifetime sessions (Ptrend 0.01 with cumulative use). The association was stronger for earlier age at first use (Ptrend 0.02). The association was also stronger for melanoma diagnosed when aged 18–29 years (OR for more than 10 lifetime sessions = 6.57, 95% CI 1.41–30.49) than for melanoma diagnosed when 30–39 years (OR 1.60, 95% CI 0.92–2.77; Pinteraction 0.01). Among those who had ever used a sunbed and were diagnosed between 18 and 29 years of age, three quarters (76%) of melanomas were attributable to sunbed use. Sunbed use is associated with increased risk of early‐onset melanoma, with risk increasing with greater use, an earlier age at first use and for earlier onset disease.