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OBJECTIVE: the aim of our study was to assess the contribution of quantitative fluorescent polymerase chain reaction (QF-PCR) and pathology studies in the diagnosis of diandric triploidies/partial hydatidiform moles. METHODS: this study included all fet al triploidies diagnosed by QF-PCR in chorionic villi or amniotic fluid in the 2 centers of BCNatal in which a maternal saliva sample was used to establish its parental origin. Pathology studies were performed in products of conception and concordance between a partial hydatidiform mole diagnosis and the finding of a diandric triploidy was assessed. RESULTS: among 46 fetal triploidies, found in 13 ongoing pregnancies and in 33 miscarriages, there were 26 (56%) diandric triploidies. Concordant molecular (diandric triploidy) and pathology results (partial mole) were achieved in 14 cases (54%), while in 6 cases (23%) pathology studies were normal, and in the remaining 6 cases (23%) pathology studies could not be performed because miscarriage was managed medically. CONCLUSIONS: diandric triploidy is associated with partial hydatidiform mole and its diagnosis is crucial to prevent the development of persistent trophoblastic disease. QF-PCR analysis in chorionic villi or amniotic fluid provides a more accurate diagnosis of the parental origin of triploidy than the classical pathology studies.

Objective: To explore the use of a new molecular work-up based on the stepwise use of Quantitative Fluorescence PCR (QF-PCR) extended to eight chromosomes and single nucleotide polymorphism array (SNP-array) in chorionic villi obtained by chorionic villi sampling (CVS) offered to women experiencing an early pregnancy loss. Methods: During a 3-year period (January 2016-December 2018), CVS was offered to women experiencing an early pregnancy loss before the evacuation of the products of conception (POC) to retrieve chorionic villi, irrespective of the number of previous losses. A new molecular work-up was prospectively assayed encompassing a first QF-PCR round (with the 21, 18, 13, 7, X, and Y chromosomes), a second QF-PCR round (with the 15, 16, and 22 chromosomes), and a high resolution SNP-array in those cases with normal QF-PCR results. A control group in which POC were collected after surgical uterine evacuation was used to be compared with the intervention group. Results: Around 459 women were enrolled in the intervention group (CVS) and 185 in the control group (POC after uterine evacuation). The QF-PCR testing success rates were significantly higher in the intervention group (98.5%: 452/459) as compared to the control group (74%: 109/147; p < 0.001), while the chromosomal anomaly rate at the two QF-PCR rounds was similar between the two groups: 52% (234/452) in the intervention and 42% (46/109) in the control group (p = 0.073). The SNP-array was performed in 202 QF-PCR normal samples of the intervention group and revealed 67 (33%) atypical chromosomal anomalies (>10 Mb), 5 (2.5%) submicroscopic pathogenic copy number variants, and 2 (1%) variant of uncertain significance (VOUS). Conclusion: Eighty-two percent of women experiencing an early pregnancy loss opted for a CVS. The testing success rates were higher in the intervention group (CVS; 98%) as compared to the control group (POC; 74%). The overall yields were 52% by QF-PCR (including three complete hydatiform moles), and 16% by SNP-array, including 15% atypical chromosomal anomalies and 1.1% submicroscopic pathogenic copy number variants.

OBJECTIVE: To assess the frequency of atypical chromosomal and submicroscopic anomalies, as well as fetal structural abnormalities, observed on first-trimester ultrasound scan in fetuses with nuchal translucency (NT) thickness > 99(th) centile, in order to evaluate the suitability of using standard cell-free DNA (cfDNA) testing as the sole screening test in these pregnancies. METHODS: This was a retrospective cohort study of 226 fetuses with NT > 99(th) centile at 11-14 weeks' gestation, between January 2013 and December 2017, in a clinical setting in which greater than 95% of pregnant women receive first-trimester combined screening. All patients underwent genetic testing by means of quantitative fluorescence polymerase chain reaction and chromosomal microarray analysis, mainly in chorionic villus samples. We assessed the theoretical yield of two cfDNA testing models, targeted cfDNA (chromosomes 21, 18 and 13) and extended cfDNA (chromosomes 21, 18, 13 and sex chromosomes), and compared it with that of cytogenetic testing and ultrasound assessment in the first and second or third trimesters. RESULTS: In the 226 fetuses analyzed, cytogenetic testing revealed 84 (37%) anomalies, including 68 typical aneuploidies (involving chromosomes 13, 18 or 21), six sex chromosome aneuploidies (four cases of monosomy X and two of trisomy X), three clinically relevant atypical chromosomal anomalies (one trisomy 22, one trisomy 21 mosaicism and one unbalanced translocation), five submicroscopic pathogenic variants and two cases with Noonan syndrome. Targeted and extended cfDNA testing would miss at least 12% (10/84) and 19% (16/84), respectively, of genetic anomalies, accounting for 4.4% and 7.1% of the fetuses with an increased NT, respectively. Finally, of the 142 fetuses with no identified genetic anomaly, a major fetal malformation was observed in 15 (10.6%) fetuses at the early anomaly scan, and in 19 (13.4%) in the second or third trimester. CONCLUSIONS: cfDNA does not appear to be the appropriate genetic test in fetuses with NT > 99(th) centile, given that it would miss 12-19% of genetic anomalies in this group. Additionally, first-trimester ultrasound will identify a major structural abnormality in 11% of the fetuses with NT > 99(th) centile and no genetic anomaly. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Chromosomal microarray analysis (CMA) has now replaced karyotyping in the analysis of prenatal cases with a fetal structural anomaly, whereas in those pregnancies undergoing invasive prenatal diagnosis with a normal fetal ultrasound, conventional karyotyping is still performed. The aims of this study were to establish the diagnostic yield of CMA in prenatal diagnosis, and to provide new data that might contribute to reconsider current practices. We reviewed 2905 prenatal samples with a normal rapid aneuploidy detection test referred for evaluation by CMA testing. Our study revealed pathogenic and reported susceptibility copy number variants associated with syndromic disorders in 4.8% (n = 138/2905) of cases, being 2.8% (n = 81/2905) the estimated added diagnostic value of CMA over karyotyping. Clinically significant CMA abnormality was detected in 5.4% (107/1975) of the fetuses with ultrasound anomalies and in 1.4% (5/345) of those considered as low-risk pregnancies. Our series shows that in prenatal samples, CMA increases 2-fold the diagnostic yield achieved by conventional karyotyping.

To date, the genes involved in familial non-medullary thyroid cancer (FNMTC) remain poorly understood, with the exception of syndromic cases of FNMTC. It has been proposed that germline mutations in telomere-related genes, such as POT1, described in familial melanoma might also predispose individuals to thyroid cancer, requiring further research. We aimed to identify germline mutations in POT1 in selected FNMTC families (with at least three affected members) without a history of other cancers or other features, and to describe the clinical characteristics of these families. Sequencing of the 5 ' UTR and coding regions of POT1 was performed in seven affected people (index cases) from seven families with FNMTC. In addition, we performed whole-exome sequencing (WES) of DNA from 10 affected individuals belonging to four of these families. We did not find germline variants of interest in POT1 by Sanger sequencing or WES. We neither found putative causative mutations in genes previously described as candidate genes for FNMTC in the 4 families studied by WES. In our study, no germline potentially pathogenic mutations were detected in POT1, minimizing the possibilities that this gene could be substantially involved in non-syndromic FNMTC.

Background: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. Methods: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. Findings: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02–2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06–3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05–2·44; p=0·04) and Asp294His (2·15, 1·05–4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. Interpretation: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies. Funding: SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831. © 2019 Elsevier Ltd

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele., Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.

To assess the distribution of the parental origin of the retained X chromosome in monosomy X, either in miscarriages or in ongoing pregnancies.

BACKGROUND: Little information is available about the risk of microdeletion and microduplication syndromes in fetal growth restriction (FGR) with a normal karyotype. OBJECTIVE: To assess the incremental yield of genomic microarray over conventional karyotyping in fetuses with early growth restriction. STUDY DESIGN: Genomic microarray was prospectively performed in fetuses with early growth restriction defined as a fetal weight below the 3rd percentile estimated before 32 weeks of pregnancy, and a normal quantitative fluorescent polymerase chain reaction result. The incremental yield of genomic microarray was defined by the rate of fetuses presenting with a pathogenic copy number variant below 10 Mb. RESULTS: Among 133 fetuses with early FGR, a 6.8% (95% CI: 2.5-11.0) incremental yield of genomic microarray over karyotyping was observed. This incremental yield was 4.8% (95% CI: 0.2-9.3) in isolated FGR, 10% (95% CI: 0-20.7) in FGR with nonstructural anomalies, and 10.5% (95% CI: 0-24.3) in FGR with structural anomalies. CONCLUSION: Our multicenter study reveals that 6.8% of fetuses with early growth restriction present with submicroscopic anomalies after common aneuploidies were excluded. Even when FGR is observed as an isolated finding, genomic microarray analysis should be considered after or instead of karyotyping, due to its 4.8% incremental yield.

We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.

Summary Three children (two boys and one girl) from the same family presented with photosensitivity, hyperpigmentation, hypertrichosis, mild skin fragility, blistering and scarring in childhood. On examination, the cutaneous lesions were found to have improved since their previous examinations. Laboratory tests showed raised plasma and urine carboxyporphyrins and decreased uroporphyrinogen decarboxylase enzyme activity in red blood cells. Triggering factors for porphyria were not detected except for a hepatitis C virus infection in the younger boy. The girl's clinical symptoms recurred in late adolescence, after iron and oestrogen treatments. Mutation analysis of the UROD gene detected two missense mutations, 19 AG M1V (novel) and 703CT P235S (previously reported), in an uncommon compound heterozygous manner in the three siblings.

A series of studies has investigated epidemiological, clinical and genetic characteristics of patients with multiple primary melanoma (MPM). However, comparison of the clinical and dermoscopic features of MPM within a given individual has been described only in case reports.To describe the dermoscopic features of MPM for each given patient, and to evaluate the characteristics eventually associated with similar or dissimilar appearance.From the databases of three skin-lesion clinics in the U.S.A., Italy and Spain we collected the dermoscopic images of melanomas in patients diagnosed with MPM.Among 58 patients with MPM, we found that 53% of patients had dermoscopically similar melanomas and 47% of patients had dermoscopically different melanomas. In older patients 59% of melanomas were dermoscopically similar vs. 47% in younger patients (P=0·377). Similar thickness was associated with the occurrence of dermoscopically similar melanomas (19/30 cases, 63%; P=0·039). Most (65%) of the synchronous lesions were similar, compared with 36% of nonsynchronous lesions (P=0·029), and most (69%) of the melanomas on sun-damaged skin were similar, vs. 37% of melanomas on nonsun-damaged skin (P=0·015; odds ratio 3·88, 95% confidence interval 1·11-13·98). The percentage of dermoscopically different melanomas was higher in patients with a family history of melanoma (67% vs. 48%).MPMs in a given patient have almost the same chance of looking dermoscopically similar or different. However, a subset of elderly patients with sun-damaged skin may present multiple, similar, thin melanomas characterized by pigment-network and regression structures.

CDKN2A is the major melanoma susceptibility gene so far identified, but only 40% of three or more case families have identified mutations. A comparison of mutation detection rates was carried out by "blind" exchange of samples across GenoMEL, the Melanoma Genetics Consortium, to establish the false negative detection rates. Denaturing high performance liquid chromatography (DHPLC) screening results from 451 samples were compared to screening data from nine research groups in which the initial mutation screen had been done predominantly by sequencing. Three samples with mutations identified at the local centres were not detected by the DHPLC screen. No additional mutations were detected by DHPLC. Mutation detection across groups within GenoMEL is carried out to a consistently high standard. The relatively low rate of CDKN2A mutation detection is not due to failure to detect mutations and implies the existence of other high penetrance melanoma susceptibility genes.

Hepatoerythropoietic porphyria (HEP) is a rare form of porphyria that results from a deficiency of uroporphyrinogen decarboxylase (UROD). The disease is caused by homoallelism or heteroallelism for mutations in the UROD gene.To study a 19-year-old woman from Equatorial Guinea, one of the few cases of HEP of African descent and to characterize a new mutation causing HEP.Excretion of porphyrins and residual UROD activity in erythrocytes were measured and compared with those of other patients with HEP. The UROD gene of the proband was sequenced and a new mutation identified. The recombinant UROD protein was purified and assayed for enzymatic activity. The change of amino acid mapped to the UROD protein and the functional consequences were predicted.The patient presented a novel homozygous G170D missense mutation. Porphyrin excretion showed an atypical pattern in stool with a high pentaporphyrin III to isocoproporphyrin ratio. Erythrocyte UROD activity was 42% of normal and higher than the activity found in patients with HEP with a G281E mutation. The recombinant UROD protein showed a relative activity of 17% and 60% of wild-type to uroporphyrinogen I and III respectively. Molecular modelling showed that glycine 170 is located on the dimer interface of UROD, in a loop containing residues 167-172 that are critical for optimal enzymatic activity and that the carboxyl side chain from aspartic acid is predicted to cause negative interactions between the protein and the substrate.The results emphasize the complex relationship between the genetic defects and the biochemical phenotype in homozygous porphyria.

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 > or =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, > or =2 patients with MPM, median age at melanoma diagnosis or =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 > or =1 patient with MPM and age at diagnosis < or =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.

Pancreatic cysts are an uncommon extrarenal clinical feature of autosomal dominant polycystic kidney disease (ADPKD). The prevalence of pancreatic cysts, sonographically assessed in ADPKD and in the different typs of ADPKD (PKD1 and PKD2) has not been reported. We have studied 173 ADPKD patients and 160 non-affected family members and found a prevalence of pancreatic cysts, of 9% in ADPKD patients over 30 years of age. The presence of pancreatic cysts was related to the increasing age, to the female sex and to the type of ADPKD, found exclusively in PKD1 patients. No complications related to pancreatic cysts were recorded. Pancreatic cysts are an unusual feature of ADPKD and do not appear to contribute to morbidity or mortality.

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges.

Two genes causing autosomal dominant polycystic kidney disease (ADPKD), PKD1 and PKD2, have been described. In the present work we study, by means of linkage analysis, the genetic heterogeneity in our population as well as the clinical differences between PKD1 and PKD2.316 subjects belonging to 49 unrelated ADPKD families have been studied by means of 3 microsatellites for PKD1 and 3 for PKD2 to differentiate if they have ADPKD type 1 or 2. The techniques used to analyze the microsatellites have been the chemiluminescence and the silver satining techniques. All the subjects underwent a complete physical examination and a sonographic scan. Clinical and molecular results have been correlated.Genetic heterogeneity has been proved, with 85% of families linked to PKD1 and 15% to PKD2. The disease is more severe in PKD1, with an earlier age at diagnosis (27.4 vs. 41.4 years; p = 0.0002), a younger age at the onset of end stage renal disease (53.4 vs. 72.7 years, p0.00001), and earlier age at diagnosis of hypertension (34.8 vs. 49.7 years; p = 0.001) and a higher prevalence of hypertension for all groups of age. In both forms of ADPKD there were families showing anticipation (8/44 for PKD1 and 2/5 for PKD2) but this was not a widespread phenomenon. Our data do not support the phenomenon of genetic imprinting for this disease.In the population of Catalonia, Spain, PKD1 accounts for 85% of families with autosomal dominant polycystic kidney disease and PKD2 accounts for the remaining 15%. PKD1 form is more severe than PKD2.

Ferrari, Andrea/0000-0002-4724-0517; Pellegrini, Cristina/0000-0003-2168-8097; Migliano, Emilia/0000-0002-5316-8937; Maisonneuve, Patrick/0000-0002-5309-4704; Guida, Stefania/0000-0002-8221-6694; Pastorino, Lorenza/0000-0002-2575-8331; CARRERA, CRISTINA/0000-0003-1608-8820; Paillerets, Brigitte Bressac-de/0000-0003-0245-8608; Sekulovic, Lidija Kandolf/0000-0002-5221-5068; Caini, Saverio/0000-0002-2262-1102; Potrony, Miriam/0000-0003-2766-0765; Pizzichetta, Maria Antonietta/0000-0002-4201-8490; Little, Julian/0000-0001-5026-5531; Nagore, Eduardo/0000-0003-3433-8707; Polsky, David/0000-0001-9554-5289; Demenais, Florence/0000-0001-8361-0936; Nazzaro, Gianluca/0000-0001-8534-6497; gandini, sara/0000-0002-1348-4548; Cornelius, Lynn A/0000-0002-6329-2819; Palmieri, Giuseppe/0000-0002-4350-2276; Cotignola, Javier/0000-0003-4473-9854; Ghiorzo, Paola/0000-0002-3651-8173; Autier, Philippe/0000-0003-1538-5321; Bishop, Tim/0000-0002-8752-8785; Sera, Francesco/0000-0002-8890-6848; Newton-Bishop, Julia/0000-0001-9147-6802; Litchfield, Melisa/0000-0003-0002-7724, WOS: 000464254100018, PubMed: 30872112, Background Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. Methods in this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. Findings We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1.54, 95% CI 1.02-2.33), including when analysis was restricted to patients aged 18 years or younger (1.80, 1.06-3.07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1.60, 95% CI 1.05-2.44; p=0.04) and Asp294His (2.15, 1.05-4.40; p=0.04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. Interpretation Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies. Copyright (c) 2019 Elsevier Ltd. All rights reserved., [AIRC-MFAG-11831]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P30CA016086, P01CA206980, P30CA016086, P30CA016086] Funding Source: NIH RePORTER, SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.