Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have ...been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear.
From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set.
LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018).
This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.
Melanoma represents an important public health problem, due to its high case-fatality rate. Identification of individuals at high risk would be of major interest to improve early diagnosis and ...ultimately survival. The aim of this study was to evaluate whether
variants predicted melanoma risk independently of at-risk phenotypic characteristics.
Data were collected within an international collaboration - the M-SKIP project. The present pooled analysis included data on 3,830 single, primary, sporadic, cutaneous melanoma cases and 2,619 controls from seven previously published case-control studies. All the studies had information on
gene variants by sequencing analysis and on hair color, skin phototype, and freckles, ie, the phenotypic characteristics used to define the red hair phenotype.
The presence of any
variant was associated with melanoma risk independently of phenotypic characteristics (OR 1.60; 95% CI 1.36-1.88). Inclusion of
variants in a risk prediction model increased melanoma predictive accuracy (area under the receiver-operating characteristic curve) by 0.7% over a base clinical model (
=0.002), and 24% of participants were better assessed (net reclassification index 95% CI 20%-30%). Subgroup analysis suggested a possibly stronger role of
in melanoma prediction for participants without the red hair phenotype (net reclassification index: 28%) compared to paler skinned participants (15%).
The authors suggest that measuring the
genotype might result in a benefit for melanoma prediction. The results could be a valid starting point to guide the development of scientific protocols assessing melanoma risk prediction tools incorporating the
genotype.
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.
Background
A polygenic inheritance involving high, medium and low penetrance genes has been suggested for melanoma susceptibility in adults, but genetic information is scarce for paediatric patients.
...Objective
We aim to analyse the major high and intermediate melanoma risk genes, CDKN2A, CDK4, POT1, MITF and MC1R, in a large multicentre cohort of Italian children and adolescents in order to explore the genetic context of paediatric melanoma and to reveal potential differences in heritability between children and adolescents.
Methods
One‐hundred‐twenty‐three patients (<21 years) from nine Italian centres were analysed for the CDKN2A, CDK4, POT1, MITF, and MC1R melanoma predisposing genes. The rate of gene variants was compared between sporadic, familial and multiple melanoma patients and between children and adolescents, and their association with clinico‐pathological characteristics was evaluated.
Results
Most patients carried MC1R variants (67%), while CDKN2A pathogenic variants were found in 9% of the cases, the MITF E318K in 2% of patients and none carried CDK4 or the POT1 S270N pathogenic variant. Sporadic melanoma patients significantly differed from familial and multiple cases for the young age at diagnosis, infrequent red hair colour, low number of nevi, low frequency of CDKN2A pathogenic variants and of the MC1R R160W variant. Melanoma in children (≤12 years) had more frequently spitzoid histotype, were located on the head/neck and upper limbs and had higher Breslow thickness. The MC1R V92M variant was more common in children than in adolescents. CDKN2A common polymorphisms and MC1R variants were associated with a high number of nevi.
Conclusion
Our results confirm the scarce involvement of the major high‐risk susceptibility genes in paediatric melanoma and suggest the implication of MC1R gene variants especially in the children population.
Linked Commentary: H. Helgadottir. J Eur Acad Dermatol Venereol 2022; 36: 167–168. https://doi.org/10.1111/jdv.17879.
Summary
Background
Several pieces of evidence indicate that a complex relationship exists between constitutional telomere length (TL) and the risk of cutaneous melanoma. Although the general ...perception is that longer telomeres increase melanoma risk, some studies do not support this association. We hypothesize that discordant data are due to the characteristics of the studied populations.
Objectives
To evaluate the association of TL with familial and sporadic melanoma.
Materials and methods
TL was measured by multiplex quantitative polymerase chain reaction in leukocytes from 310 patients with melanoma according to familial/sporadic and single/multiple cancers and 216 age‐matched controls.
Results
Patients with sporadic melanoma were found to have shorter telomeres compared with those with familial melanoma. In addition, shorter telomeres, while tending to reduce the risk of familial melanoma regardless of single or multiple tumours, nearly trebled the risk of single sporadic melanoma.
Conclusions
This is the first time that TL has been correlated to opposite effects on melanoma risk according to the presence or absence of familial predisposition. Individual susceptibility to melanoma should be taken into account when assessing the role of TL as a risk factor.
What's already known about this topic?
The role of telomere biology in tumorigenesis is complex and influenced by multiple mechanisms, even acting in opposite directions.
What does this study add?
Constitutive telomere length is significantly different between familial and sporadic melanoma.
Short telomeres increase the risk of single sporadic melanoma, but decrease that of familial melanoma.
What is the translational message?
Individual susceptibility to cancer should be taken into account when assessing the role of telomere length as a cancer risk factor.
Linked Comment: Barrett. Br J Dermatol 2016; 175:865–866.
Plain language summary available online
The incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma ...may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date.
From 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors.
The overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status odds ratio (OR) = 3.23, 3.15, 2.43, P < 0.05. Conversely, age > 60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together.
Gene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas.
•Gene panel testing doubles germline variants detection rate compared to CDKN2A-only testing.•If only two melanoma events at > 60 years of age are reported, eligibility to genetic testing requires careful consideration.•Pancreatic cancer is a strong predictor of germline status.
Background Multiple primary melanomas (MPM) occur in up to 20% of melanoma patients, and subsequent tumours seem to have a favourable histopathological pattern.
Objective A prospectively collected ...cohort of 194 patients with MPM was retrospectively reviewed to investigate clinical and histopathological features of first and subsequent melanomas.
Methods Patients with MPM who were diagnosed at our Department (1985–2011) and who attended at least a follow‐up control yearly were identified.
Results The number of nevi was <10, 10–50 and >50 in 8.7%, 41% and 50.3% of patients respectively. Histopathological dysplastic nevi have been diagnosed in 105 patients. During a median follow‐up of 58 months, 159 (81.9%), 24 (12.3%), 7 (3.6%) and 4 (2%) patients developed 2, 3, 4 and ≥5 melanomas, respectively. The median time to second primary melanoma was 45 months. The second primary melanoma was diagnosed within 1‐year and after 5‐year from the first melanoma in 36.6% and 17.3% of patients respectively. First and second primary melanomas were in situ in 41 (21%) and 104 (54%) patients respectively (P < 0.001). Among patients with ≥2 invasive melanomas (N = 80), median tumour thickness and ulceration of first and second primaries were 0.91 and 0.44 mm (P < 0.001), and 32% and 7.7% (P = 0.001) respectively.
Conclusions Subsequent melanomas occurred within 1‐year from the appearance of the first melanoma in 36% of patients with MPM, while a late melanoma diagnosis was detected in 17% of cases. Second primary melanoma had favourable histopathological features. Our findings support long‐term skin surveillance to detect subsequent melanomas at an early stage.
RESUMO A espécie Solidago chilensis Meyen, Asteraceae é conhecida como erva-lanceta ou arnica-brasileira, sendo utilizada popularmente como antimicrobiana e para o tratamento de inflamações tópicas. ...No entanto, estudos fitoquímicos e farmacológicos para as partes aéreas são escassos. Neste trabalho, realizou-se a determinação de flavonoides por espectrofotometria de UV/Vis, prospecção fitoquímica da fração acetato de etila visando o isolamento do constituinte químico majoritário e validação analítica por cromatografia líquida de alta eficiência (CLAE). O teor de flavonoides totais foi de 5,42%, representados como hiperosídeo. O fracionamento químico utilizando métodos cromatográficos (cromatografia líquida em coluna gel de sílica; CHCl3:EtOH; 8:2 v/v) e espectroscópicos (1H RMN,13C RMN e ESI-MS) revelou o isolamento de quercetina-3-O-α-L-ramnosídeo(quercitrina). A sensibilidade e a linearidade (r = 0,999) da validação analítica, utilizando a quercitrina isolada do extrato hidroalcoólico da planta, revelaram um rendimento de 5,29% do analito em relação à droga vegetal. Precisão, recuperação e robustez, além dos valores estabelecidos para os limites de detecção (LOD) e de quantificação (LOQ), poderão ser utilizados como parâmetros de qualidade para extratos à base de S. chilensis.
Background:BRCA1 and BRCA2 are the two major genes responsible for the breast and ovarian cancers that cluster in families with a genetically determined predisposition. However, regardless of the ...mutation detection method employed, the percentage of families without identifiable alterations of these genes exceeds 50%, even when applying stringent criteria for family selection. A small but significant increase in mutation detection rate has resulted from the discovery of large genomic alterations in BRCA1. A few studies have addressed the question of whether BRCA2 might be inactivated by the same kinds of alteration, but most were either done on a relatively small number of samples or employed cumbersome mutation detection methods of variable sensitivity. Objective: To analyse 121 highly selected families using the recently available BRCA2 multiplex ligation dependent probe amplification (MLPA) technique. Results: Three different large genomic deletions were identified and confirmed by analysis of the mutant transcript and genomic characterisation of the breakpoints. Conclusions: Contrary to initial suggestions, the presence of BRCA2 genomic rearrangements is worth investigating in high risk breast or ovarian cancer families.
Lymphomas of different histologic type can occur in the same patient. Two types of lymphomas can be diagnosed in the same lymph node (composite lymphoma) or in different sites. In the latter case, ...terms as simultaneous and sequential have been proposed to define the detection of two lymphomas at the same time or at different times, respectively.
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