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Background Cutaneous melanoma tumour is classified into clinicohistopathological subtypes that may be associated with different genetic and host factors. Variation in the MC1R gene is one of the main factors of risk variation in sporadic melanoma. The relationship between MC1R variants and the risk of developing a specific subtype of melanoma has not been previously explored. Objectives To analyse whether certain MC1R variants are associated with particular melanoma subtypes with specific clinicohistopathological features. Methods An association study was performed between MC1R gene variants and clinicopathological subtypes of primary melanoma derived from 1679 patients. Results We detected 53 MC1 R variants (11 synonymous and 42 nonsynonymous). Recurrent nonsynonymous variants were p. V60L (30·0%), p. V92 M (11·7%), p. D294 H (9·4%), p. R151 C (8·8%), p. R160 W (6·2%), p. R163 Q (4·2%) p. R142 H (3·3%), p.I155 T (3·8%), p. V122 M (1·5%) and p. D84 E (1·0%). Melanoma subtypes showed differences in the total number of MC1 R variants ( P = 0·028) and the number of red hair colour variants ( P = 0·035). Furthermore, an association between p. R163 Q and lentigo maligna melanoma was detected under a dominant model of heritance (odds ratio 2·16, 95% confidence interval 1·07-4·37; P = 0·044). No association was found between p. R163 Q and Fitzpatrick skin phototype, eye colour or skin colour, indicating that the association was independent of the role of MC1 R in pigmentation. No association was observed between MC1 R polymorphisms and other melanoma subtypes. Conclusions Our findings suggest that certain MC1 R variants could increase melanoma risk due to their impact on pathways other than pigmentation, and may therefore be linked to specific melanoma subtypes. [ABSTRACT FROM AUTHOR]

Background The p33 ING1 b gene is involved in the p53-dependent response to DNA damage following exposure to ultraviolet radiation, and has recently been reported to be mutated in 20% of melanoma tumours. Objectives We sought to assess the p33 ING1 b mutation rate in our large panels of fresh melanomas and melanoma cell lines. Methods We screened 83 primary melanomas and 55 melanoma cell lines for mutations in p33 ING1 b by single-strand conformational polymorphism analysis and by direct sequencing. Results In contrast to previous reports, we found no somatic p33 ING1 b mutations in our panel of melanomas. We found that some of the discrepancy between our results and previously published studies may be due to inadvertent amplification of the ING1 pseudogene ( INGX), and/or contamination of some samples with murine Ing1. Conclusions p33 ING1 b mutations in melanoma are rare. We have highlighted the importance of allele-specific primer design to avoid pseudogene amplification, and also the necessity to confirm the genetic identity and species of origin of individual cell lines. Further studies are needed to clarify the possible role of p33ING1b in melanoma tumorigenesis. [ABSTRACT FROM AUTHOR]

Rodriguez-Revenga L, Badenas C, Sánchez A, Mallolas J, Carrió A, Pedrinaci S, Barrionuevo JL, Milà M. Cryptic chromosomal rearrangement screening in 30 patients with mental retardation and dysmorphic features. Mental retardation affects 1–3% of the general population, and the genetic causes in many cases are unknown. Cytogenetically undetected chromosomal imbalances have been indicated as an explanation. Nowadays, due to the development of molecular cytogenetic techniques, it is possible to identify cryptic rearrangements involving the ends of chromosomes. We report a screening using chromosome-specific telomere fluorescence in-situ hybridization (FISH) probes, in a group of 30 patients with a well-characterized phenotype including mental retardation, dysmorphic features, and a normal karyotype. Among them, two subtelomeric rearrangements have been detected and characterized. One of them is a de novo deletion of 1p36, which has been previously described as a new contiguous gene syndrome. The second is an unbalanced product of a cryptic translocation involving chromosomes 1 and 13, which results in a partial 1q trisomy and partial 13q monosomy. These findings highlight, the importance of searching for cryptic subtelomeric rearrangements in non-syndromic mentally retarded patients. [ABSTRACT FROM AUTHOR]

Summary: Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin Syndrome, affects only 1 in 56 000 people. It is usually inherited from a parent with the condition and affects both males and females equally (autosomal dominant inheritance). People with NBCCS may show characteristic features such as extra fingers or toes, irregular ribs, an unusually shaped face and large head. Tumours sometimes develop, particularly jaw cysts and basal cell carcinomas (BCCs) of the skin from which the syndrome is named. NBCCS is caused by mistakes (mutations) in a gene called PTCH1 located on the long arm of chromosome 9. PTCH1 acts as a brake on a set of chemical processes in cells called the Hedgehog (HH)/GLI signalling pathway. In NBCCS, mutations inactivate PTCH1 allowing excessive Hedgehog signalling. This loss of control results in the abnormal bones and tumours. Within an affected family, people with the same genetic mutation can have very different abnormalities. This group from Spain studied 22 unrelated Spanish people with NBCCS to see if they could discern any relationship between specific clinical abnormalities and specific genetic mutations. BCCs were very common, occurring in 96% of patients with 43% having more than 50; 77% had jaw cysts. Two abnormalities had not previously been recognised in NBCCS: double uterus and a benign nerve tumour. They found 19 PTCH1 mutations that had not previously been reported. However, they could not find any pattern relating the type of mutation to the clinical abnormalities. Presumably other factors besides the PTCH1 mutation causes the clinical features. [ABSTRACT FROM AUTHOR]

Background: Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark‐skinned individuals, are underrepresented. Objectives: We report a comprehensive pooled analysis of established high‐ and intermediate‐penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium. Methods: Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country. Results: We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3–19.7), >3 affected members (OR 2.6; 95% CI 1.3–5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4–9.4) in the family (AUC 0.76, 95% CI 0.71–0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0–2.0 and OR 4.3; 95% CI 1.2–14.6, respectively). Conclusions: Variants in known high‐penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the diagnosis of placental mesenchymal dysplasia (PMD) during the prenatal period with the use of chorionic villus sampling (CVS).

Background 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. Objectives To describe the dermoscopic features of MPM for each given patient, and to evaluate the characteristics eventually associated with similar or dissimilar appearance. Methods 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. Results 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%). Conclusions 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. [ABSTRACT FROM AUTHOR]

Background: Early detection of melanoma is the best way to improve prognosis. Digital follow-up (DFU) programs of populations at high risk could be an efficient strategy for detecting early melanomas with low morbidity.Objective: We sought to report the added value of the use of the "two-step method" (digital total body photography and digital dermatoscopy).Methods: This was an analysis of the surveillance of 618 patients at high risk for melanoma included in our DFU program from 1999 to 2008.Results: A total of 11,396 lesions were monitored (mean 18.44/patient) during a median follow-up of 96 months (median 10 visits/patient). A total of 1152 lesions, 1.86 per patient, were excised. Almost 70% (798) were lesions previously registered at least twice, whereas 356 (30%) were detected and removed in the same visit. During follow-up, 98 melanomas (8.5% of excised lesions) were diagnosed in 78 patients (12.6%). In all, 53 melanomas were in situ (53.3%), whereas invasive (45) showed a Breslow index of less than 1 mm (median 0.5 mm) and none were ulcerated.Limitations: Because there are no control groups we cannot determine if the combined use of total body photography and digital dermatoscopy is more beneficial than these techniques used separately.Conclusion: DFU with total body photography and dermatoscopy in a selected population at high risk demonstrated the early detection of melanomas with a low rate of excisions. Long-term follow-up is required to allow the detection of slow-growing melanomas. Based on our 10-year experience, melanomas can be diagnosed at any time, suggesting that in a population at high risk for melanoma, DFU should be maintained over time. [ABSTRACT FROM AUTHOR]

Background: Around 0.5% of cutaneous melanoma (CM) patients will present with synchronous melanomas when first seen. Moreover, 26–40% of patients with multiple primary melanomas present with synchronous lesions. Objectives: To assess the prevalence, clinical and histopathological characteristics, germline mutations and outcome in patients with synchronous melanoma. Methods: Clinical and histopathological data from 4703 melanoma patients were included. Clinical, histological and genetic mutational status information was analysed. Kaplan–Meier curves were used to investigate survival outcomes. Results: A total of 144 patients (3.06%) presented simultaneously with two or more primary melanomas. During follow‐up, 25.7% of patients with synchronous melanoma developed a new primary melanoma compared to 8.6% of patients diagnosed with single melanoma (P < 0.001). Germinal CDKN2A mutations were identified in 10.7% of patients with synchronous melanomas and genetic variants in MC1R in 72%. No significant differences in all survival outcomes between patients with synchronous melanomas and single melanomas were found. Conclusion: Synchronous melanomas are more frequent than previously reported and are more frequent in older patients compared to single melanomas. Moreover, these patients have a higher risk of developing a new primary melanoma during follow‐up and have higher rates of germline susceptibility variants. Nevertheless, these findings were not associated with worse outcomes. [ABSTRACT FROM AUTHOR]

Background The origin of melanoma has always been a debated subject, as well as the role of adjacent melanocytic naevi. Epidemiological and histopathological studies point to melanomas arising either de novo or from a naevus. Objectives To evaluate the presence of mutations in genes from well-known melanomagenesis pathways in a large series of naevus-associated melanomas. Materials and methods Sixty-one melanomas found in association with a pre-existing naevus were microdissected, after careful selection of cell subpopulations, and submitted to Sanger sequencing of the BRAF, NRAS, c- KIT, PPP6C, STK19 and RAC1 genes. Each gene was evaluated twice in all samples by sequencing or by sequencing and another confirmation method, allele-specific fluorescent polymerase chain reaction ( PCR) and capillary electrophoresis detection or by SNaPshot analysis. Only mutations confirmed via two different molecular methods or twice by sequencing were considered positive. Results The majority of cases presented concordance of mutational status between melanoma and the associated naevus for all six genes (40 of 60; 66·7%). Nine cases presented concomitant BRAF and NRAS mutations, including one case in which both the melanoma and the adjacent naevus harboured V600E and Q61K double mutations. In two cases, both melanoma and associated naevus located on acral sites were BRAF mutated, including an acral lentiginous melanoma. Conclusions To our knowledge this is the largest naevus-associated melanoma series evaluated molecularly. The majority of melanomas and adjacent naevi in our sample share the same mutational profile, corroborating the theory that the adjacent naevus and melanoma are clonally related and that the melanoma originated within a naevus. [ABSTRACT FROM AUTHOR]

Background The oligophrenin 1 gene ( OPHN1) is an Rho-GTPase-activating protein involved in the regulation of the G-protein cycle required for dendritic spine morphogenesis. Mutations in this gene are implicated in X-linked mental retardation (XLMR). Methods We report a deletion spanning exons 21 and 22 of the OPHN1 gene identified by a tiling path X-chromosome array comparative genomic hybridization (CGH) and multiplex ligation-dependent probe amplification, confirmed by polymerase chain reaction (PCR), in a family with four males with intellectual disabilities. Results Patients harbouring mutations in this gene share the same clinical manifestations reinforcing the idea of a syndromic XLMR. The most important neurological findings are cerebellar hypoplasia and ventriculomegaly. Conclusions We recommend screening of the OPHN1 gene in male patients with XLMR and cerebellar anomalies. This case highlights the value of high-resolution techniques as Multiplex Ligation Probe Amplification (MLPA) and CGH array for a better characterization of copy number changes and suggests that MLPA technology may be very useful for an initial screening of small deletions and duplications in XLMR patients. [ABSTRACT FROM AUTHOR]

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 > 99th 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 > 99th 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 > 99th 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 > 99th centile and no genetic anomaly. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Background The identification of BRAF mutations in melanoma led to the development and implementation of new and effective therapies. Few clinical and histological features have been associated with this mutational status. Objectives The main objective of this study was to investigate clinical, histopathological and dermoscopic characteristics of primary melanomas according to BRAF or NRAS mutational status. Methods An observational retrospective study including melanoma dermoscopy images assessed for somatic mutations in BRAF and NRAS. Results Seventy-two patients were included, 30 women (42%) and 42 men (58%), mean age was 59 ± 15·51 years. BRAF-mutated melanomas were more frequently located on the trunk ( n = 18, 64% for BRAF-mutated vs. n = 11, 29% for wild-type melanomas, P = 0·013). Histological ulceration was associated with the presence of BRAF mutations [odds ratio ( OR) 3·141; 95% confidence interval ( CI) 1·289-7·655; P = 0·002]. The Breslow index tended to be thicker in BRAF-mutated compared with wild-type ( P = 0·086). BRAF mutations were present in 28 (39%) patients and only four cases were positive for NRAS mutations (6%), BRAF and NRAS mutations being mutually exclusive. The presence of dermoscopic peppering was associated with MAPK mutations ( BRAF and NRAS) ( OR 1·68; 95% CI 1·089-2·581; P = 0·015). Dermoscopic ulceration was also associated with BRAF mutations excluding acral and facial melanomas ( OR 2·64; 95% CI 1·032-6·754). Conclusions This study showed a correlation between BRAF and NRAS status and dermoscopic findings of 'peppering' as an expression of regression and melanophages in the dermis, suggesting a morphological consequence of immune behaviour in BRAF-mutated melanomas. [ABSTRACT FROM AUTHOR]

Background UV radiation and the presence of melanocytic nevi are the main risk factors of sporadic melanoma (MM). Protection of skin by an oral photoprotective agent would have substantial benefits. Objective We investigated the possible role of an oral Polypodium leucotomos (PL) extract to improve systemic photoprotection in patients at risk of skin cancer analyzing the ability to decrease UV-induced erythema. We also studied the interaction among MC1R polymorphisms and CDKN2A status with the minimal erythematous dose (MED) and their influence in the response after oral PL. Methods A total of 61 patients (25 with familial and/or multiple MM, 20 with sporadic MM and 16 with atypical mole syndrome without history of MM) were exposed to varying doses of artificial UVB radiation without and after oral administration of a total dose of 1080mg of PL. Results Oral PL treatment significantly increased the MED mean in all group patients (0.123 to 0.161 J/cm2, p<0.05). Although not significant, we noticed a stronger effect of PL on the MED of patients with familial MM compared to those with MM ( U=273, p=0.06). Among the patients with familial MM, those exhibiting a mutated CDKN2A and/or polymorphisms in MC1R had the bigger differences in response to treatment with PL. Limitations Reduced number of patients. No control population. Conclusions Administration of PL leads to a significant reduction of sensitivity to UVR (p<0.05) in all patients. Dark-eye patients and patients with higher UVR sensibility (lower basal MED) would be the most benefited from oral PL treatment. [ABSTRACT FROM AUTHOR]

Summary Background 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. Objective 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. Methods 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. Results 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. Conclusions The results emphasize the complex relationship between the genetic defects and the biochemical phenotype in homozygous porphyria. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]