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.
•Rare earth elements help link sites with potential geological outcrops.•Decline in non-local raw materials suggest reduced mobility during the Mesolithic.•Growth in microburin technique linked to ...increases in backed points and geometrics.•Palaeolithic to Mesolithic transition marked by changes in technology and mobility.
Mobility represents one of the most important behavioural strategies of the Palaeolithic and Mesolithic, allowing groups to organise their use of landscapes by positioning themselves close to resources, as well as to regulate group size and social networks. One way of measuring the scale of this mobility is through the transport of lithic raw materials in the form of cores and finished artefacts. This paper aims to investigate settlement and mobility in Greece during the Late Upper Palaeolithic to Early Mesolithic transition, by using chipped stone technology and raw material transport as an index for wider subsistence and settlement changes associated with the Early Holocene. We take as a case study the Boila Rockshelter, located in the Voidomatis Basin in the rugged uplands of the Tymphi Massif, part of the Pindus Mountains in northwestern Greece.
Typological analysis of almost two-thirds of the Boila chipped stone assemblage was carried out, along with geochemical trace element analysis on chert samples from the site, as well as limestone exposures in the local area and further afield. The geochemical analysis was focused on rare earth and other elements, with the results from Boila and the geological samples then compared. These confirmed that the majority of the chert used at Boila was originally derived from outcrops within the Vikos Gorge and Voidomatis River Valley, with the best pieces from approximately 10 km to the southeast of the site. Abrasion on the surfaces of these indicates that the majority of pieces used at Boila were collected from secondary fluvial deposits, such as those immediately below the site. In contrast, the geochemical results suggested that the reddish-brown varieties which were recovered at low frequency at Boila were probably collected from deposits located further towards the south.
Synthesis of the results from the chipped stone and geochemical analyses suggested that during the Early Holocene at Boila, there was a change in the composition of the retouched tool assemblage. Backed bladelets continued to be made, but they were added to by increasing numbers of backed points and geometrics, along with a significant increase in the frequency of microburins. In parallel, the use of local black chert increased, albeit from a high level to begin with, while the poorer quality local greyish-white varieties declined, along with reddish-brown. The decline in greyish-white chert probably points to deliberate choice, favouring the better quality local black variety. The decline in reddish-brown chert, likely to have been collected further towards the south, suggests increasingly localised use of the landscape, possibly in response to improving conditions leading to increasing abundance, thus reducing the scale of mobility systems or the need for as frequent site relocation.
Although conventional amphotericin B was for many years the drug of choice and remains an important agent against invasive aspergillosis, reliable susceptibility breakpoints are lacking. Three ...clinical Aspergillus isolates (Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus) were tested in an in vitro pharmacokinetic-pharmacodynamic model simulating the biphasic 24-h time-concentration profile of free amphotericin B concentrations in human serum with free peak concentrations (fCmax) of 0.1, 0.3, 0.6, 1.2, and 2.4 mg/liter administered once daily. Drug concentrations were measured with a bioassay, and fungal growth was monitored for 72 h with galactomannan production. The fCmax/MIC corresponding to half-maximal activity (P50) was determined for each species, and the percentage of target attainment was calculated for different MICs for the standard (1 mg/kg of body weight) and a lower (0.6-mg/kg) dose of amphotericin B with Monte Carlo simulation analysis. The fCmax/MICs (95% confidence intervals) corresponding to P50 were 0.145 (0.133 to 0.158), 0.371 (0.283 to 0.486), and 0.41 (0.292 to 0.522) for A. fumigatus, A. flavus, and A. terreus, respectively. The median percentages of P50 attainment were ≥88%, 47%, and 0% for A. fumigatus isolates with MICs of ≤0.5, 1, and ≥2 mg/liter, respectively, and ≥81%, 24%, and 0% and ≥75%, 15%, and 0% for A. flavus and A. terreus isolates with MICs of ≤0.25, 0.5, and ≥1 mg/liter, respectively. The lower dose of 0.6 mg/kg would retain efficacy for A. fumigatus, A. flavus, and A. terreus isolates with MICs of ≤0.25, ≤0.125, and ≤0.125 mg/liter, respectively. The susceptibility, intermediate susceptibility, and resistance breakpoints of ≤0.5, 1, and ≥2 mg/liter for A. fumigatus and ≤0.25, 0.5, and ≥1 mg/liter for A. flavus and A. terreus were determined for conventional amphotericin B with a pharmacokinetic-pharmacodynamic model simulating free-drug serum concentrations.
Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is ...often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to Candida albicans. When ruxolitinib therapy (50 mg/kg of body weight/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-α) and interleukin 10 (IL-10) levels and IL-10/TNF-α ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-α ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.
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