Publications by authors named "Chiara Menin"

45 Publications

The Interplay between Nevi and Melanoma Predisposition Unravels Nevi-Related and Nevi-Resistant Familial Melanoma.

Genes (Basel) 2021 Jul 16;12(7). Epub 2021 Jul 16.

Immunology and Diagnostic Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy.

Genetic susceptibility to nevi may affect the risk of developing melanoma, since common and atypical nevi are the main host risk factors implicated in the development of cutaneous melanoma. Recent genome-wide studies defined a melanoma polygenic risk score based on variants in genes involved in different pathways, including nevogenesis. Moreover, a predisposition to nevi is a hereditary trait that may account for melanoma clustering in some families characterized by cases with a high nevi density. On the other hand, familial melanoma aggregation may be due to a Mendelian inheritance of high/moderate-penetrance pathogenic variants affecting melanoma risk, regardless of the nevus count. Based on current knowledge, this review analyzes the complex interplay between nevi and melanoma predisposition in a familial context. We review familial melanoma, starting from Whiteman's divergent pathway model to overall melanoma development, distinguishing between nevi-related (cases with a high nevus count and a high polygenic risk score) and nevi-resistant (high/moderate-penetrance variant-carrier cases) familial melanoma. This distinction could better direct future research on genetic factors useful to identify high-risk subjects.
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http://dx.doi.org/10.3390/genes12071077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303673PMC
July 2021

Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.

Fam Cancer 2021 Jul 3. Epub 2021 Jul 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, EPS 7106, Bethesda, MD, 20892, USA.

While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.
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http://dx.doi.org/10.1007/s10689-021-00267-9DOI Listing
July 2021

The Molecular Landscape of Primary Acral Melanoma: A Multicenter Study of the Italian Melanoma Intergroup (IMI).

Int J Mol Sci 2021 Apr 7;22(8). Epub 2021 Apr 7.

Pathological Anatomy Unit, Padua University Hospital, 35128 Padua, Italy.

Acral melanoma (AM) is a rare and aggressive subtype of melanoma affecting the palms, soles, and nail apparatus with similar incidence among different ethnicities. AM is unrelated to ultraviolet radiation and has a low mutation burden but frequent chromosomal rearrangements and gene amplifications. Next generation sequencing of 33 genes and somatic copy number variation (CNV) analysis with genome-wide single nucleotide polymorphism arrays were performed in order to molecularly characterize 48 primary AMs of Italian patients in association with clinicopathological and prognostic features. was the most commonly mutated gene, followed by and , whereas promoter, , and were less frequently mutated. Gains and losses were recurrently found in the 1q, 6p, 7, 8q, 20 and 22 chromosomes involving , , , , , , and genes, and in the 6q, 9, 10, 11q and 16q chromosomes including , , and genes, respectively. This study confirmed the variety of gene mutations and the high load of CNV in primary AM. Some genomic alterations were associated with histologic prognostic features. mutations, found with a higher rate than previously reported, correlated with a low Breslow thickness, low mitotic count, low CNV of the AMs, and with early-stage of disease.
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http://dx.doi.org/10.3390/ijms22083826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067752PMC
April 2021

Gender-specific associations between polymorphisms of the circadian gene RORA and cutaneous melanoma susceptibility.

J Transl Med 2021 02 6;19(1):57. Epub 2021 Feb 6.

Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy.

Background: Melanoma is the deadliest of skin cancers and has an increasing annual incidence worldwide. It is a multi-factorial disease most likely arising from both genetic predisposition and environmental exposure to ultraviolet light. Genetic variability of the components of the biological circadian clock is recognized to be a risk factor for different type of cancers. Moreover, two variants of a clock gene, RORA, have been associated with melanoma patient's prognosis. Our aim is to test the hypothesis that specific single nucleotide polymorphisms (SNPs) of the circadian clock genes may significantly influence the predisposition to develop cutaneous melanoma or the outcome of melanoma patients.

Methods: We genotyped 1239 subjects, 629 cases of melanoma and 610 healthy controls in 14 known SNPs of seven selected clock genes: AANAT, CLOCK, NPAS2, PER1, PER2, RORA, and TIMELESS. Genotyping was conducted by q-PCR. Multivariate logistic regression was employed for susceptibility of melanoma assessment, modeled additively. Subgroup analysis was performed by gender. For the female subgroup, a further discrimination was performed by age. For prognosis of melanoma assessment, multivariate Cox proportional hazard regression was employed. The Benjamini-Hochberg method was utilized as adjustment for multiple comparisons.

Results: We identified two RORA SNPs statistically significant with respect to the association with melanoma susceptibility. Considering the putative role of RORA as a nuclear steroid hormone receptor, we conducted a subgroup analysis by gender. Interestingly, the RORA rs339972 C allele was associated with a decreased predisposition to develop melanoma only in the female subgroup (OR 0.67; 95% CI 0.51-0.88; P = 0.003) while RORA rs10519097 T allele was associated with a decreased predisposition to develop melanoma only in the male subgroup (OR 0.62; 95% CI 0.44-0.87; P = 0.005). Moreover, the RORA rs339972 C allele had a decreased susceptibility to develop melanoma only in females aged over 50 years old (OR 0.67; 95% CI 0.54-0.83; P = 0.0002). None of the studied SNPs were significantly associated with the prognosis.

Conclusions: Overall, we cannot ascertain that circadian pathway genetic variation is involved in melanoma susceptibility or prognosis. Nevertheless, we identified an interesting relationship between melanoma susceptibility and RORA polymorphisms acting in sex-specific manner and which is worth further future investigation.
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http://dx.doi.org/10.1186/s12967-021-02725-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866430PMC
February 2021

Genetic Variants of the Gene, Telomere Length, and Circulating as Prognostic Markers in Rectal Cancer Patients.

Cancers (Basel) 2020 Oct 25;12(11). Epub 2020 Oct 25.

Section of Oncology and Immunology, Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Gattamelata 64, 35128 Padova, Italy.

Single-nucleotide polymorphisms (SNPs) in the gene can affect telomere length and expression and have been associated with risk and/or outcome for several tumors, but very few data are available about their impact on rectal cancer. Eight SNPs (rs2736108, rs2735940, rs2736098, rs2736100, rs35241335, rs11742908, rs2736122 and rs2853690), mapping in regulatory and coding regions of the gene, were studied in 194 rectal cancer patients to evaluate their association with constitutive telomere length, circulating mRNA levels, response to neoadjuvant chemoradiotherapy (CRT) and disease outcome. At diagnosis, the rs2736100CC genotype was associated with longer telomeres measured pre-CRT, while the rs2736100CC, rs2736108TT and rs2735940AA were associated with greater telomere erosion evaluated post-CRT. The rs2736108CC and rs2853690AA/GG genotypes, respectively associated with lower telomere erosion and lower levels of circulating post-CRT, were also independently associated with a better response to therapy [OR 4.6(1.1-19.1) and 3.0(1.3-6.9)]. Overall, post-CRT, low levels (≤ median value) of circulating and its stable/decreasing levels compared to those pre-CRT, were independently associated with a better response to therapy [OR 5.8(1.9-17.8) and 5.3(1.4-19.4), respectively]. Furthermore, post-CRT, patients with long telomeres (>median value) and low levels of circulating had a significantly lower risk of disease progression [HR 0.4(0.1-0.9) and 0.3(0.1-0.8), respectively]. These findings suggest that SNPs could be a useful tool for improving the selection of patients who could benefit from CRT and support the role of telomere length and circulating mRNA levels as useful markers for monitoring the response to therapy and disease outcome in rectal cancer patients.
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http://dx.doi.org/10.3390/cancers12113115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692334PMC
October 2020

MC1R variants and cutaneous melanoma risk according to histological type, body site, and Breslow thickness: a pooled analysis from the M-SKIP project.

Melanoma Res 2020 10;30(5):500-510

Departments of Dermatology.

Little is known on whether melanocortin 1 receptor (MC1R) associated cutaneous melanoma (CM) risk varies depending on histological subtype and body site, and whether tumour thickness at diagnosis (the most important prognostic factor for CM patients) differs between MC1R variant carriers and wild-type individuals. We studied the association between MC1R variants and CM risk by histological subtype, body site, and Breslow thickness, using the database of the M-SKIP project. We pooled individual data from 15 case-control studies conducted during 2005-2015 in Europe and the USA. Study-specific, multi-adjusted odds ratios were pooled into summary odds ratios (SOR) and 95% confidence intervals (CI) using random-effects models. Six thousand eight hundred ninety-one CM cases and 5555 controls were included. CM risk was increased among MC1R variant carriers vs. wild-type individuals. The increase in risk was comparable across histological subtypes (SOR for any variant vs. wild-type ranged between 1.57 and 1.70, always statistical significant) except acral lentiginous melanoma (ALM), for which no association emerged; and slightly greater on chronically (1.74, 95% CI 1.47-2.07) than intermittently (1.55, 95% CI 1.34-1.78) sun-exposed skin. CM risk was greater for those carrying 'R' vs. 'r' variants; correlated with the number of variants; and was more evident among individuals not showing the red hair colour phenotype. Breslow thickness was not associated with MC1R status. MC1R variants were associated with an increased risk of CM of any histological subtype (except ALM) and occurring on both chronically and intermittently sun-exposed skin.
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http://dx.doi.org/10.1097/CMR.0000000000000668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479262PMC
October 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

TERT Promoter Mutations Differently Correlate with the Clinical Outcome of MAPK Inhibitor-Treated Melanoma Patients.

Cancers (Basel) 2020 Apr 11;12(4). Epub 2020 Apr 11.

Immunology and Diagnostic Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, 35128 Padua, Italy.

Resistance is a major challenge in the management of mitogen-activated protein kinase inhibitor (MAPKi)-treated metastatic melanoma. Tumor genetic alterations can cause MAPK pathway reactivation, leading to lack of response and poor outcome. Characterization of the mutational profile in patients with melanoma might be crucial for patient-tailored treatment choices. Mutations in the promoter region of the telomerase reverse transcriptase gene (TERTprom) lead to increased TERT expression and telomerase activity and are frequent in BRAF mutant melanoma. Reportedly, TERTprom, and BRAF mutations cooperate in driving cancer progression and aggressiveness. We evaluated the effect of the TERTprom status on the clinical outcome in 97 MAPKi-treated melanoma patients. We observed that patients with the c.-146C > T mutation showed a significantly worse progression-free survival (PFS) compared to those carrying the c.-124C > T mutation and a two-fold increased risk of progression (median 5.4 vs. 9.5 months; hazard ratio (HR) 1.9; 95% confidence interval (CI) 1.2-3.2; = 0.013). This trend was also observed for the overall survival (OS); melanoma patients with the c.-146C > T mutation showed a poorer prognosis compared to those with the c.-124C > T mutation (median 13.3 vs. 25.5 months; HR 1.9, 95% CI 1.1-3.3, 0.023). Our results disclose a different correlation of the two TERTprom mutations with MAPKi-treated melanoma patient outcome, highlighting a different impact of the pathway blockade.
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http://dx.doi.org/10.3390/cancers12040946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226422PMC
April 2020

Loss of BAP1 in Pheochromocytomas and Paragangliomas Seems Unrelated to Genetic Mutations.

Endocr Pathol 2019 Dec;30(4):276-284

Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padova, Italy.

Breast cancer-associated protein 1 (BAP1) gene is a broad-spectrum tumor suppressor. Indeed, its loss of expression, due to biallelic inactivating mutations or deletions, has been described in several types of tumors including melanoma, malignant mesothelioma, renal cell carcinoma, and others. There are so far only two reports of BAP1-mutated paraganglioma, suggesting the possible involvement of this gene in paraganglioma (PGL) and pheochromocytoma (PCC) pathogenesis. We assessed BAP1 expression by immunohistochemistry (IHC) in a cohort of 56 PCC/PGL patients (and corresponding metastases, when available). Confirmatory Sanger sequencing (exons 1-17) of BAP1 has been performed in those samples which resulted negative by IHC. BAP1 nuclear expression was lost in 2/22 (9.1%) PGLs and in 12/34 (35.3%) PCCs, five of which harboring a germline mutation predisposing the development of such tumors (MENIN, MAX, SDHB, SDHD, and RET gene). Confirmatory Sanger sequencing revealed the wild-type BAP1 status of all the analyzed samples. No heterogeneity between primary and metastatic tissue was observed. This study documents that the loss of BAP1 nuclear expression is quite a frequent finding in PCC/PGL, suggesting a possible role of BAP1 in the pathogenesis of these tumors. Gene mutations do not seem to be involved in this loss of expression, at least in most cases. Other genetic and epigenetic mechanisms need to be further investigated.
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http://dx.doi.org/10.1007/s12022-019-09595-0DOI Listing
December 2019

Contribution of Common Genetic Variants to Familial Aggregation of Disease and Implications for Sequencing Studies.

PLoS Genet 2019 11 15;15(11):e1008490. Epub 2019 Nov 15.

Biostatistics Branch: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America.

Despite genetics being accepted as the primary cause of familial aggregation for most diseases, it is still unclear whether afflicted families are likely to share a single highly penetrant rare variant, many minimally penetrant common variants, or a combination of the two types of variants. We therefore use recent estimates of SNP heritability and the liability threshold model to estimate the proportion of afflicted families likely to carry a rare, causal variant. We then show that Polygenic Risk Scores (PRS) may be useful for identifying families likely to carry such a rare variant and therefore for prioritizing families to include in sequencing studies with that aim. Specifically, we introduce a new statistic that estimates the proportion of individuals carrying causal rare variants based on the family structure, disease pattern, and PRS of genotyped individuals. Finally, we consider data from the MelaNostrum consortium and show that, despite an estimated PRS heritability of only 0.05 for melanoma, families carrying putative causal variants had a statistically significantly lower PRS, supporting the idea that PRS prioritization may be a useful future tool. However, it will be important to evaluate whether the presence of rare mendelian variants are generally associated with the proposed test statistic or lower PRS in future and larger studies.
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http://dx.doi.org/10.1371/journal.pgen.1008490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881075PMC
November 2019

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.

Lancet Child Adolesc Health 2019 05 12;3(5):332-342. Epub 2019 Mar 12.

Department of Pathophysiology and Transplantation, University of Milan, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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.
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http://dx.doi.org/10.1016/S2352-4642(19)30005-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942319PMC
May 2019

MelaNostrum: a consensus questionnaire of standardized epidemiologic and clinical variables for melanoma risk assessment by the melanostrum consortium.

J Eur Acad Dermatol Venereol 2018 Dec 14;32(12):2134-2141. Epub 2018 Sep 14.

Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Many melanoma observational studies have been carried out across different countries and geographic areas using heterogeneous assessments of epidemiologic risk factors and clinical variables.

Aim: To develop a consensus questionnaire to standardize epidemiologic and clinical data collection for melanoma risk assessment.

Methods: We used a stepwise strategy that included: compilation of variables from case-control datasets collected at various centres of the MelaNostrum Consortium; integration of variables from published case-control studies; consensus discussion of the collected items by MelaNostrum members; revision by independent experts; addition of online tools and image-based charts; questionnaire testing across centres and generation of a final draft.

Results: We developed a core consensus questionnaire (MelanoQ) that includes four separate sections: A. general and demographic data; B. phenotypic and ultraviolet radiation exposure risk factors and lifestyle habits; C. clinical examination, medical and family history; and D. diagnostic data on melanoma (cases only). Accompanying online tools, informative tables, and image-based charts aid standardization. Different subsections of the questionnaire are designed for self-administration, patient interviews performed by a physician or study nurse, and data collection from medical records.

Conclusions: The MelanoQ questionnaire is a useful tool for the collection and standardization of epidemiologic and clinical data across different studies, centres, cultures and languages. This will expedite ongoing efforts to compile high-quality data for pooled analyses or meta-analyses and offer a solid base for the design of clinical, epidemiologic and translational studies on melanoma.
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http://dx.doi.org/10.1111/jdv.15208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100361PMC
December 2018

Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma.

Hum Mol Genet 2018 12;27(23):4145-4156

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12 874 melanoma cases and 23 203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3102 cases and 2301 controls from the MelaNostrum consortium for validation. We estimated adjusted odds ratios (ORs) for melanoma risk using traditional melanoma risk factors and the PRS with the largest area under the receiver operator characteristics curve (AUC). We estimated absolute risks combining the PRS and other risk factors, with age- and sex-specific melanoma incidence and competing mortality rates from Italy as an example. The best PRS, including 204 SNPs (AUC = 64.4%; 95% confidence interval (CI) = 63-65.8%), developed using winner's curse estimate corrections, had a per-quintile OR = 1.35 (95% CI = 1.30-1.41), corresponding to a 3.33-fold increase comparing the 5th to the 1st PRS quintile. The AUC improvement by adding the PRS was up to 7%, depending on adjusted factors and country. The 20-year absolute risk estimates based on the PRS, nevus count and pigmentation characteristics for a 60-year-old Italian man ranged from 0.5 to 11.8% (relative risk  = 26.34), indicating good separation.
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http://dx.doi.org/10.1093/hmg/ddy282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240742PMC
December 2018

variants as melanoma risk factors independent of at-risk phenotypic characteristics: a pooled analysis from the M-SKIP project.

Cancer Manag Res 2018 14;10:1143-1154. Epub 2018 May 14.

Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

Purpose: 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.

Materials And Methods: 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.

Results: 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%).

Conclusion: 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.
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http://dx.doi.org/10.2147/CMAR.S155283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958947PMC
May 2018

Gene Copy Number and Mutant Allele Frequency Correlate with Time to Progression in Metastatic Melanoma Patients Treated with MAPK Inhibitors.

Mol Cancer Ther 2018 06 6;17(6):1332-1340. Epub 2018 Apr 6.

Diagnostic Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.

Metastatic melanoma is characterized by complex genomic alterations, including a high rate of mutations in driver genes and widespread deletions and amplifications encompassing various chromosome regions. Among them, chromosome 7 is frequently gained in -mutant melanoma, inducing a mutant allele-specific imbalance. Although amplification is a known mechanism of acquired resistance to therapy with MAPK inhibitors, it is still unclear if copy-number variation and mutant allele imbalance at baseline can be associated with response to treatment. In this study, we used a multimodal approach to assess copy number and mutant allele frequency in pretreatment melanoma samples from 46 patients who received MAPK inhibitor-based therapy, and we analyzed the association with progression-free survival. We found that 65% patients displayed gains, often supported by chromosome 7 polysomy. In addition, we observed that 64% patients had a balanced -mutant/wild-type allele ratio, whereas 14% and 23% patients had low and high mutant allele frequency, respectively. Notably, a significantly higher risk of progression was observed in patients with a diploid status versus those with gains [HR, 2.86; 95% confidence interval (CI), 1.29-6.35; = 0.01] and in patients with low percentage versus those with a balanced mutant allele percentage (HR, 4.54; 95% CI, 1.33-15.53; = 0.016). Our data suggest that quantitative analysis of the gene could be useful to select the melanoma patients who are most likely to benefit from therapy with MAPK inhibitors. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-1124DOI Listing
June 2018

Germline variation of circadian pathway genes and prognosis of gastric cancer patients.

Gut 2018 Apr 8;67(4):779-780. Epub 2017 Aug 8.

Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy.

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http://dx.doi.org/10.1136/gutjnl-2017-314740DOI Listing
April 2018

Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI.

Hum Mutat 2017 09 16;38(9):1042-1050. Epub 2017 May 16.

Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, Maryland.

Correct phenotypic interpretation of variants of unknown significance for cancer-associated genes is a diagnostic challenge as genetic screenings gain in popularity in the next-generation sequencing era. The Critical Assessment of Genome Interpretation (CAGI) experiment aims to test and define the state of the art of genotype-phenotype interpretation. Here, we present the assessment of the CAGI p16INK4a challenge. Participants were asked to predict the effect on cellular proliferation of 10 variants for the p16INK4a tumor suppressor, a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene. Twenty-two pathogenicity predictors were assessed with a variety of accuracy measures for reliability in a medical context. Different assessment measures were combined in an overall ranking to provide more robust results. The R scripts used for assessment are publicly available from a GitHub repository for future use in similar assessment exercises. Despite a limited test-set size, our findings show a variety of results, with some methods performing significantly better. Methods combining different strategies frequently outperform simpler approaches. The best predictor, Yang&Zhou lab, uses a machine learning method combining an empirical energy function measuring protein stability with an evolutionary conservation term. The p16INK4a challenge highlights how subtle structural effects can neutralize otherwise deleterious variants.
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http://dx.doi.org/10.1002/humu.23235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561474PMC
September 2017

Human IgGs induce synthesis and secretion of IgGs and neonatal Fc receptor in human umbilical vein endothelial cells.

Immunobiology 2016 12 4;221(12):1329-1342. Epub 2016 Aug 4.

Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Pharmacology Building, L.go E. Meneghetti 2, 35131 Padua, Italy. Electronic address:

Human IgGs are increasingly used in the therapy of many different immune and inflammatory diseases, however their mechanism of action still remains unclear in most diseases. To gain insight into the mechanism by which IgGs might also exert their effects on endothelial cells, we tested human IgGs on human umbilical vein endothelial cells (HUVECs). IgGs induced a time-dependent increase in the synthesis and secretion of IgGs, together with a marked angiogenic-like transformation of HUVECs that was maximal after a 20-h incubation. IgGs stimulated IG gene transcription without affecting the process of gene rearrangement, already present in control HUVECs. The mechanism involved the activation of transcription factors with the increased expression of HSP90, HSP70 and inactive MMP-9 responsible for the phenotypic differentiation associated with the most intense IgG synthesis and secretion. However, even a short incubation with IgGs followed by recovery of cells was sufficient to trigger and sustain in time the synthesis and secretion of new IgGs, independently of the angiogenic-like transformation visible only when cells were continuously exposed to IgGs. Under the stimulus of IgGs, specific secretory pathways were also activated in HUVECs together with the expression of FcRn, which was always associated with IgGs of new synthesis, forming complexes that were also secreted. Our results disclose a so far unknown and unexpected mechanism of IgGs on HUVECs that behave as Ig-producing immune cells. Results might have relevance for the effects that IgGs also exert in vivo in physiological conditions.
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http://dx.doi.org/10.1016/j.imbio.2016.08.002DOI Listing
December 2016

TLR7 Gln11Leu single nucleotide polymorphism and susceptibility to cutaneous melanoma.

Oncol Lett 2016 Jul 16;12(1):275-280. Epub 2016 May 16.

Department of Medicine, Dermatology Unit, University of Padua, Padua I-35121, Italy.

Cutaneous melanoma is a life-threatening skin cancer. Its incidence is rapidly increasing, and early diagnosis is the main factor able to improve its poor prognosis. Toll-like receptors (TLRs) are transmembrane glycoproteins that recognize pathogen- and damage-associated molecular patterns, against which TLRs activate the innate immune response and initiate the adaptive immune response. Genetic variations of these receptors may alter the immune system, and are involved in evolution and susceptibility to various diseases, including cancer. The aim of the present study was to evaluate whether the presence of TLR7 glutamine (Gln) 11 leucine (Leu) polymorphism confers an increased susceptibility to cutaneous melanoma. For that purpose, a case-control study was performed with 182 melanoma cases and 89 controls. To highlight the possible association between the aforementioned polymorphism and the susceptibility to melanoma, 93 cases of single melanoma and 89 cases of multiple primary melanoma (MPM) were compared in the present study. Since the TLR7 gene is localized on the chromosome X, the allelic frequency of the Gln11Leu polymorphism was analyzed separately in males and females. The distribution of allele frequencies between melanoma cases and controls (P=0.245) and between single melanoma and MPM cases (P=0.482) was not significant. Therefore, the present results do not suggest an association between TLR7 Gln11Leu polymorphism and susceptibility to cutaneous melanoma. Further studies are required to analyze the influence of other TLR polymorphisms on the susceptibility to malignant melanoma and the involvement of innate immunity in this malignancy.
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http://dx.doi.org/10.3892/ol.2016.4584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906938PMC
July 2016

Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup.

J Am Acad Dermatol 2016 Feb;74(2):325-32

Dermatology Unit, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.

Background: Multiple primary melanoma (MPM), in concert with a positive family history, is a predictor of cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A) germline mutations. A rule regarding the presence of either 2 or 3 or more cancer events (melanoma and pancreatic cancer) in low or high melanoma incidence populations, respectively, has been established to select patients for genetic referral.

Objective: We sought to determine the CDKN2A/CDK4/microphthalmia-associated transcription factor mutation rate among Italian patients with MPM to appropriately direct genetic counseling regardless of family history.

Methods: In all, 587 patients with MPM and an equal number with single primary melanomas and control subjects were consecutively enrolled at the participating centers and tested for CDKN2A, CDK4, and microphthalmia-associated transcription factor.

Results: CDKN2A germline mutations were found in 19% of patients with MPM versus 4.4% of patients with single primary melanoma. In familial MPM cases the mutation rate varied from 36.6% to 58.8%, whereas in sporadic MPM cases it varied from 8.2% to 17.6% in patients with 2 and 3 or more melanomas, respectively. The microphthalmia-associated transcription factor E318K mutation accounted for 3% of MPM cases altogether.

Limitations: The study was hospital based, not population based. Rare novel susceptibility genes were not tested.

Conclusion: Italian patients who developed 2 melanomas, even in situ, should be referred for genetic counseling even in the absence of family history.
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http://dx.doi.org/10.1016/j.jaad.2015.09.053DOI Listing
February 2016

The CDKN2A/p16(INK) (4a) 5'UTR sequence and translational regulation: impact of novel variants predisposing to melanoma.

Pigment Cell Melanoma Res 2016 Mar 17;29(2):210-21. Epub 2015 Dec 17.

Department of Internal Medicine and Medical Specialties, DiMI, University of Genoa, Genoa, Italy.

Many variants of uncertain functional significance in cancer susceptibility genes lie in regulatory regions, and clarifying their association with disease risk poses significant challenges. We studied 17 germline variants (nine of which were novel) in the CDKN2A 5'UTR with independent approaches, which included mono and bicistronic reporter assays, Western blot of endogenous protein, and allelic representation after polysomal profiling to investigate their impact on CDKN2A mRNA translation regulation. Two of the novel variants (c.-27del23, c.-93-91delAGG) were classified as causal mutations (score ≥3), along with the c.-21C>T, c.-34G>T, and c.-56G>T, which had already been studied by a subset of assays. The novel c.-42T>A as well as the previously described c.-67G>C were classified as potential mutations (score 1 or 2). The remaining variants (c.-14C>T, c.-20A>G, c.-25C>T+c.-180G>A, c.-30G>A, c.-40C>T, c.-45G>A, c.-59C>G, c.-87T>A, c.-252A>T) were classified as neutral (score 0). In conclusion, we found evidence that nearly half of the variants found in this region had a negative impact on CDKN2A mRNA translation, supporting the hypothesis that 5'UTR can act as a cellular Internal Ribosome Entry Site (IRES) to modulate p16(INK) (4a) translation.
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http://dx.doi.org/10.1111/pcmr.12444DOI Listing
March 2016

Association of CDK4 germline and BRAF somatic mutations in a patient with multiple primary melanomas and BRAF inhibitor resistance.

Melanoma Res 2015 Oct;25(5):443-6

Departments of aPlastic and Reconstructive Surgery bPathological Anatomy cMedicine, Section of Dermatology, Azienda Ospedaliera Universitaria Integrata, Verona dUnit of Immunology and Molecular Oncology, Veneto Institute of Oncology, IOV-IRCCS eDepartment of Surgery, Oncology and Gastroenterology, Section of Oncology and Immunology, University of Padova, Padova, Italy.

Many genetic alterations, including predisposing or somatic mutations, may contribute toward the development of melanoma. Although CDKN2A and CDK4 are high-penetrance genes for melanoma, MC1R is a low-penetrance gene that has been associated most consistently with the disease. Moreover, BRAF is the most frequently somatically altered oncogene and is a validated therapeutic target in melanoma. This paper reports a case of multiple primary melanoma with germline CDK4 mutation, MC1R variant, and somatic BRAF mutation in nine out of 10 melanomas, indicating that a common pathogenesis, because of a predisposing genetic background, may be shared among distinct subsequent melanomas of probable clonal origin. After 3 months of targeted therapy with BRAF inhibitor, our patient developed resistance with rapid progression of the disease leading to death. This is the first case in which early resistance to BRAF inhibitor has been reported in a patient with CDK4 germline mutation.
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http://dx.doi.org/10.1097/CMR.0000000000000173DOI Listing
October 2015

CDKN2A unclassified variants in familial malignant melanoma: combining functional and computational approaches for their assessment.

Hum Mutat 2014 Jul 21;35(7):828-40. Epub 2014 May 21.

Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy.

CDKN2A codes for two oncosuppressors by alternative splicing of two first exons: p16INK4a and p14ARF. Germline mutations are found in about 40% of melanoma-prone families, and most of them are missense mutations mainly affecting p16INK4a. A growing number of p16INK4a variants of uncertain significance (VUS) are being identified but, unless their pathogenic role can be demonstrated, they cannot be used for identification of carriers at risk. Predicting the effect of these VUS by either a "standard" in silico approach, or functional tests alone, is rather difficult. Here, we report a protocol for the assessment of any p16INK4a VUS, which combines experimental and computational tools in an integrated approach. We analyzed p16INK4a VUS from melanoma patients as well as variants derived through permutation of conserved p16INK4a amino acids. Variants were expressed in a p16INK4a-null cell line (U2-OS) and tested for their ability to block proliferation. In parallel, these VUS underwent in silico prediction analysis and molecular dynamics simulations. Evaluation of in silico and functional data disclosed a high agreement for 15/16 missense mutations, suggesting that this approach could represent a pilot study for the definition of a protocol applicable to VUS in general, involved in other diseases, as well.
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http://dx.doi.org/10.1002/humu.22550DOI Listing
July 2014

Dried blood spot sampling for detection of monoclonal immunoglobulin gene rearrangement.

Leuk Res 2013 Oct 13;37(10):1265-70. Epub 2013 Aug 13.

Department of Surgery, Oncology and Gastroenterology, Section of Immunology and Oncology, AIDS Reference Center, University of Padova, Padova, Italy.

Molecular methods are important tools for diagnosis and monitoring of many lymphoproliferative disorders. The reliability of lymphoma diagnoses is strikingly different between developed and developing countries, partly due to lack of access to these advanced molecular analyses. To overcome these problems, we propose a new application of dried blood spots (DBS) for detecting clonal B-cell populations in peripheral blood (PB). We ensured that the DBS contained sufficient lymphocytes to perform a PCR-based clonality assay without producing false positives. Using the Namalwa B-cell line, we established that the assay is sensitive enough to detect 200 clonal cells in the analyzed sample. Very similar clonal results were obtained between DNA from DBS and fresh whole blood from patients with B-cell chronic lymphocytic leukemia. B-cell clonality can also be detected in DBS from African children with EBV-associated diseases. This is the first study demonstrating that clonality testing can be performed on DBS samples, thus improving the diagnostic and monitoring options for lymphoproliferative diseases in resource-limited settings.
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http://dx.doi.org/10.1016/j.leukres.2013.08.003DOI Listing
October 2013

Survivin expression impacts prognostically on NSCLC but not SCLC.

Lung Cancer 2013 Feb 4;79(2):180-6. Epub 2012 Dec 4.

Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.

Survivin is expressed in lung cancer and in most cancer tissues and has a significant impact on prognosis. This work aimed to comparatively assess survivin expression and significance in Non-Small (NSCLC) and Small Cell Lung Cancers (SCLC). Sixty-five NSCLC and 35 SCLC samples were analyzed by semi-quantitative real-time RT-PCR. Survivin mRNA levels were significantly higher in tumors than in normal tissue, and in SCLC than in NSCLC samples. Immunohistochemistry and FISH analyses were performed in 59 and 26 tumor specimens, respectively. In SCLC survivin was only present in cytoplasm, while in some NSCLC cases it also showed nuclear or mixed patterns. FISH analysis did not disclose survivin gene amplification, except for one NSCLC case. Finally, 90 samples were genotyped for the -31G/C SNP of survivin promoter by direct sequencing; the -31G/C SNP genotype status showed a significant association only with nodal NSCLC metastasis, but not with survivin expression in any tumor group. A better prognosis was correlated to higher levels of survivin mRNA and to the presence of at least one G allele at -31 SNP in NSCLC, while these parameters did not correlate with overall survival in SCLC. Moreover, this SNP would appear to have no effect on the risk of lung cancer in our samples. The different prognostic role played by survivin in NSCLC and SCLC highlights the biological differences between these lung tumor histotypes and stresses the need to clarify the molecular pathways leading to their neoplastic transformation.
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http://dx.doi.org/10.1016/j.lungcan.2012.11.004DOI Listing
February 2013

The p53 codon 72 Pro/Pro genotype identifies poor-prognosis neuroblastoma patients: correlation with reduced apoptosis and enhanced senescence by the p53-72P isoform.

Neoplasia 2012 Jul;14(7):634-43

Department of Medical Sciences, University of Modena and Reggio Emilia, Modena, Italy.

The p53 gene is rarely mutated in neuroblastoma, but codon 72 polymorphism that modulates its proapoptotic activity might influence cancer risk and clinical outcome. We investigated whether this polymorphism affects neuroblastoma risk and disease outcome and assessed the biologic effects of the p53-72R and p53-72P isoforms in p53-null cells. Comparison of 288 healthy subjects and 286 neuroblastoma patients revealed that the p53-72 polymorphism had no significant impact on the risk of developing neuroblastoma; however, patients with the Pro/Pro genotype had a shorter survival than those with the Arg/Arg or the Arg/Pro genotypes even in the stage 3 and 4 subgroup without MYCN amplification. By Cox regression analysis, the p53 Pro/Pro genotype seems to be an independent marker of poor prognosis (hazard ratio = 2.74; 95% confidence interval = 1.14-6.55, P = .014) together with clinical stage, MYCN status, and age at diagnosis. In vitro, p53-72P was less effective than p53-72R in inducing apoptosis and inhibiting survival of p53-null LAN-1 cells treated with etoposide, topotecan, or ionizing radiation but not taxol. By contrast, p53-72P was more effective in promoting p21-dependent accelerated senescence, alone or in the presence of etoposide. Thus, the p53-72 Pro/Pro genotype might be a marker of poor outcome independent of MYCN amplification, possibly improving risk stratification. Moreover, the lower apoptosis and the enhanced accelerated senescence by the p53-72P isoform in response to DNA damage suggest that patients with neuroblastoma with the p53-72 Pro/Pro genotype may benefit from therapeutic protocols that do not rely only on cytotoxic drugs that function, in part, through p53 activation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421959PMC
http://dx.doi.org/10.1593/neo.12594DOI Listing
July 2012

Functional impairment of p16(INK4A) due to CDKN2A p.Gly23Asp missense mutation.

Mutat Res 2009 Dec 25;671(1-2):26-32. Epub 2009 Aug 25.

Section of Oncology, Department of Oncology and Surgical Sciences, University of Padova, via Gattamelata, 64, I-35128 Padova, Italy.

The CDKN2A locus encodes for two distinct tumor suppressor proteins, p16(INK4A) and p14(ARF), involved in cell cycle regulation. CDKN2A germline mutations have been associated with familial predisposition to melanoma and other tumor types. Besides bona-fide pathogenic mutations, many sequence variants have been identified, but their effect is not well known. We detected the p.Gly23Asp missense mutation in one of the two tested melanoma patients of a family with three melanoma cases. Even though the mutated amino acid is located in a conserved domain that specifically binds to and blocks the function of CDK4/6, its lack of segregation with disease suggested a series of functional assays to discriminate between a pathogenic variant and a neutral polymorphism. The effect of this mutation has been investigated exploiting four p16(INK4A) properties: its ability (i) to bind CDK4, (ii) to inhibit pRb phosphorylation, (iii) to evenly localize in the cell, and (iv) to cause cell cycle arrest. The mutant protein properties were evaluated transfecting three different cell lines (U2-OS and NM-39, both p16-null, and SaOS 2, p53 and pRb-null) with plasmids expressing either p16(wt), p16(23Asp), or the p16(32Pro) pathogenic variant. We found that p16(23Asp) was less efficient than p16(wt) in CDK4 binding, in inhibiting pRb phosphorylation, in inducing G1 cell cycle arrest; moreover, its pattern of distribution throughout the cell was suggestive of protein aggregation, thus assessing a pathogenic role for p16(23Asp) in familial melanoma.
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http://dx.doi.org/10.1016/j.mrfmmm.2009.08.007DOI Listing
December 2009

Clinical genetic testing for familial melanoma in Italy: a cooperative study.

J Am Acad Dermatol 2009 Nov 4;61(5):775-82. Epub 2009 Jun 4.

Department of Oncology, Biology, and Genetics, University of Genoa, Genoa, Italy.

Background: The Italian Society of Human Genetics' (SIGU) recommendations on genetic counseling and testing for hereditary melanoma state that clinical genetic testing can be offered to Italian melanoma families with at least two affected members.

Objective: In the framework of a cooperative study, we sought to establish the frequency of cyclin-dependent kinase inhibitor 2A mutations in melanoma families that underwent clinical genetic counseling and testing in accordance with the SIGU recommendations at 9 centers in different Italian regions.

Methods: Cyclin-dependent kinase inhibitor 2A testing was conducted by direct sequencing and multiplex ligation-dependent probe amplification analysis in melanoma families with at least two affected members.

Results: A total of 33% (68/204) of the families harbored cyclin-dependent kinase inhibitor 2A mutations. In the 145 families with two affected members the mutation frequency was 25%. Three novel mutations, L94P, A86T, and c.407dupG, were identified among the cases and not in 200 controls.

Limitations: We were unable to perform separate analyses for individual centers, as in some cases the number of families was too small.

Conclusions: The availability of clinical genetic testing for melanoma to families with just two affected members in the same branch is justified in Italy in terms of the likelihood of identifying a mutation.
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http://dx.doi.org/10.1016/j.jaad.2009.03.039DOI Listing
November 2009

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene.

Proc Natl Acad Sci U S A 2009 Jun 4;106(25):10236-41. Epub 2009 Jun 4.

The Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom.

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1-4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant.
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http://dx.doi.org/10.1073/pnas.0901298106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700939PMC
June 2009
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