Dataset Information

The Genetic Germline Background of Single and Multiple Primary Melanomas.

ABSTRACT: Background: Melanoma has a complex molecular background and multiple genes are involved in its development and progression. The advent of next generation sequencing platforms has enabled the evaluation of multiple genes at a time, thus unraveling new insights into the genetics of melanoma. We investigated a set of germline mutations able to discriminate the development of multiple primary melanomas (MPM) vs. single site primary melanomas (SPM) using a targeted next generation sequencing panel. Materials and Methods: A total of 39 patients, 20 with SPM and 19 with MPM, were enrolled in our study. Next generation analysis was carried out using a custom targeted sequencing panel that included 32 genes known to have a role in several carcinogenic pathways, such as those involved in DNA repair, pigmentation, regulation of kinases, cell cycle control and senescence. Results: We found a significant correlation between PIK3CA:p.I391M and MPMs, compared to SPMs, p = 0.031 and a trend for the association between CYP1B1: p.N453S and SPMs, compared to MPMs (p = 0.096). We also found that both subgroups shared a spectrum of 9 alterations in 8 genes (CYP1B1: p.N453S, BAP1: p.C39fs, PIK3CA: p.I391M, CDKAL1: c.1226_1227TG, POLE: p.V1161fs, OCA2: p.R419Q, OCA2: p.R305W, MC1R: p.V60L, MGMT: p.L115F), which suggested that these genes may play a role in melanoma development. Conclusions: In conclusion, despite the small cohort of patients, we found that germline mutations, such as those of PIK3CAand CYP1B1, might contribute to the differential development of SPM and MPM.

SUBMITTER: De Summa S

PROVIDER: S-EPMC7973206 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Genetic Germline Background of Single and Multiple Primary Melanomas.

De Summa Simona S Lasorella Antonia A Strippoli Sabino S Giudice Giuseppe G Guida Gabriella G Elia Rossella R Nacchiero Eleonora E Azzariti Amalia A Silvestris Nicola N Guida Michele M Guida Stefania S Tommasi Stefania S Pinto Rosamaria R

Frontiers in molecular biosciences 20210305

<b>Background:</b> Melanoma has a complex molecular background and multiple genes are involved in its development and progression. The advent of next generation sequencing platforms has enabled the evaluation of multiple genes at a time, thus unraveling new insights into the genetics of melanoma. We investigated a set of germline mutations able to discriminate the development of multiple primary melanomas (MPM) vs. single site primary melanomas (SPM) using a targeted next generation sequencing p ...[more]

PMID: 33748184

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Project description:IntroductionMultiple primary melanomas (MPM) occur up to 8% of patients with cutaneous malignant melanoma (CMM). They are often sporadic harbouring several somatic mutations, but also familial cases harbouring a CDKN2A germline mutation have been describe in Caucasian populations. The aim of this study was to investigate the incidence, the distribution patterns and the impact of known and unknown germline and somatic mutations in patients with MPM from Italy.Materials and methodsOne-hundred and two MPM patients were enrolled for germline mutation analysis, and five patients with at least four MPMs were identified for somatic mutation analysis. The demographic, pathologic and clinical features were retrieved from medical records. Molecular analysis for both germline and somatic mutations was performed in genomic DNA from peripheral blood and tissue samples, respectively, through a next generation sequencing approach, using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup for somatic analysis and a commercial cancer hotspot panel for somatic analysis.ResultsCDKN2A mutations were detected in 6/16 (37.5%) and 3/86 (3.5%) MPM cases with and without family history for melanoma, respectively. Furthermore, multiple MC1R and, to a lesser extent, ATM variants have been identified. BAP1 variants were found only in MPM patients from southern Italy. The most frequent somatic variants were the pathogenic BRAFV600E and TP53, followed by KIT, PIK3CA, KDR, and NRAS. Single APC, ERBB4, MET, JAK3 and other variants with unknown function were also detected.ConclusionsCDNK2A mutation is the most relevant susceptibility mutation in Italian patients with MPM, especially those with a family history for CMM. The prevalence of this mutation and other sequence variants identified in this study varies among specific sub-populations. Furthermore, some heterogeneity in driver somatic mutations between sporadic MPMs has been observed, as well as in a number of associated sequence variants the clinical impact of which needs to be further elucidated.

Project description:ImportanceMelanoma is one of the most rapidly increasing forms of cancer worldwide. Most studies about survival among patients with melanoma consider only the primary tumor and disregard the potential effect of multiple primary tumors. A better understanding of the prognosis of patients with multiple primary melanoma is important for patient counselling and follow-up strategies.ObjectiveTo describe the epidemiologic features of multiple primary melanoma in patients from the Netherlands.Design, setting, and participantsThis retrospective, population-based cohort study included adults with histologically proven, primary, invasive cutaneous melanoma in the Netherlands between January 1, 2000, and December 31, 2014, with a median follow-up of 75.1 months, using data from PALGA, the Dutch Nationwide Network and Registry of Histopathology and Cytopathology. Follow-up data were retrieved from the Netherlands Cancer Registry. Statistical analysis was performed from August 1, 2018, to September 3, 2018.Main outcomes and measuresA multivariable Cox model with a time-varying covariate was performed to assess overall survival between patients with a single primary melanoma vs those with multiple primary melanomas. Secondary outcomes included incidence of multiple primary melanoma, differences in Breslow thickness, and time between first and second multiple primary melanoma.ResultsOf the 56 929 study patients, 31 916 (56.1%) were female, with a mean (SD) age of 56.4 (16.2) years. A total of 54 645 single primary melanomas and 4967 multiple primary melanomas in 2284 patients were included. The median Breslow thickness decreased from 0.90 mm (interquartile range, 0.55-1.70 mm) for the first melanoma to 0.65 mm (interquartile range, 0.45-1.10 mm) for the second melanoma (P < .001). For their second melanoma, 370 patients (16.2%) had a higher T stage, 1112 (48.7%) had the same T stage, and 802 (35.1%) had a lower T stage. In addition, 841 of 2284 second melanomas (36.8%) in patients with multiple primary melanomas were found during the first year of follow-up, whereas 624 of 2284 (27.3%) were found after 5 years of follow-up. These proportions did not vary when stratified for melanoma stage. Worse overall survival was seen among patients with multiple primary melanomas compared with patients with a single primary melanoma (hazard ratio, 1.31; 95% CI, 1.20-1.42; P < .001).Conclusions and relevanceA significant decrease in Breslow thickness between the first and second multiple primary melanoma was found, and overall survival among patients with multiple primary melanomas was significantly worse than that among patients with a single primary melanoma. These findings suggest that more strict follow-up strategies may be warranted for patients with multiple primary melanomas.

Project description:ImportanceLittle 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.ObjectiveTo 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.SettingThe 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.ParticipantsTwo thousand three hundred seventy-two patients with SPM and 1206 with MPM.ExposureDiagnosis with melanoma.Main outcomes and measuresMelanoma-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.ResultsMelanoma 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 relevanceAlthough 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.

Dataset Information

The Genetic Germline Background of Single and Multiple Primary Melanomas.

Publications

The Genetic Germline Background of Single and Multiple Primary Melanomas.

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