Introduction: The aim of this study was to analyze and describe the incidence and mortality trend... more Introduction: The aim of this study was to analyze and describe the incidence and mortality trends of ovarian cancer in North Sardinia, Italy, in the period 1992-2010. Materials and methods: Data were obtained from the tumor registry of Sassari province which makes part of a wider registry web, coordinated today by the Italian Association for Tumor Registries. Results: The overall number of ovarian cancer cases registered in the period under investigation was 600. The mean age of the patients was 62 years. The standardized incidence and mortality rates were 11.2/100,000 and 5.1/100,000 respectively. A substantially stable trend in incidence and mortality of ovarian cancer was evidenced. Relative survival at five years from diagnosis was 44.2%. Conclusions: The incidence and mortality trends of ovarian cancer in North Sardinia remained relatively stable in the last decades, while prognosis remains relatively poor.
Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat ... more Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat despite recent advances in targeted and immune therapies. About 50% of advanced melanoma do not benefit of such therapies, and novel treatments are requested. Curcumin and its analogs have shown good anticancer properties and are being considered for use in combination with or sequence to recent therapies to improve patient outcomes. Our group previously published the synthesis and anticancer activity characterization of a novel curcumin-related compound against melanoma and neuroblastoma cells (D6). Here, two hydroxylated biphenyl compounds—namely, compounds 11 and 12—were selected among a small collection of previously screened C2-symmetric hydroxylated biphenyls structurally related to D6 and curcumin, showing the best antitumor potentiality against melanoma cells (IC50 values of 1.7 ± 0.5 μM for 11 and 2.0 ± 0.7 μM for 12) and no toxicity of normal fibroblasts up to 32 µM. Their anti...
Background Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. T... more Background Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. The aim of this study was to evaluate the global survival in a real-life cohort of patients with LAC harboring driver genetic alterations. Methods A series of 1282 consecutive Sardinian LAC patients who underwent genetic testing from January 2011 through July 2016 was collected. Molecular tests were based on the clinical needs of each single case (EGFR-exon18/19/21, ALK, and, more recently, BRAF-exon15), and the availability of tissue (KRAS, MET, and presence of low-frequency EGFR-T790M mutated alleles at baseline). Results The mean follow-up time of the patients was 46 months. EGFR, KRAS, and BRAF mutations were detected in 13.7%, 21.3%, and 3% of tested cases, respectively; ALK rearrangements and MET amplifications were found respectively in 4.7% and 2% of tested cases. As expected, cases with mutations in exons 18–21 of EGFR, sensitizing to anti-EGFR tyrosine kinase inhibitors (TKIs) a...
Background: Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. ... more Background: Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. The aim of this study was to evaluate the global survival in a real-life cohort of patients with LAC harboring driver genetic alterations. Methods: A series of 1282 consecutive Sardinian LAC patients who underwent genetic testing from January 2011 through July 2016 was collected. Molecular tests were based on the clinical needs of each single case (EGFR-exon18/19/21, ALK, and, more recently, BRAF-exon15), and the availability of tissue (KRAS, MET, and presence of lowfrequency EGFR-T790M mutated alleles at baseline). Results: The mean follow-up time of the patients was 46 months. EGFR, KRAS, and BRAF mutations were detected in 13.7%, 21.3%, and 3% of tested cases, respectively; ALK rearrangements and MET amplifications were found respectively in 4.7% and 2% of tested cases. As expected, cases with mutations in exons 18-21 of EGFR, sensitizing to anti-EGFR tyrosine kinase inhibitors (TKIs)...
Background and Objectives: The respiratory apparatus, generally affected by highly aggressive tum... more Background and Objectives: The respiratory apparatus, generally affected by highly aggressive tumors like lung cancer and mesothelioma, is rarely affected by primary malignant melanoma. The aim of this review was to identify cases of primary malignant melanoma of the lung (PMML) published in the modern scientific literature, and to describe their main clinical, pathological and therapeutic features. Materials and Methods: A systematic search of publications in the electronic database PubMed has been performed using keywords, and the references of the selected articles were checked to identify additional missing studies. Results: Globally 52 papers reporting on 76 cases were identified. Among them there were 47 reports of a single case, three papers reporting on two cases each, and two larger case series published in 1997 and 2005 including eight and 15 cases, respectively. Conclusions: PMML was generally diagnosed in middle-aged males, without any apparent correlation with cigarette...
BACKGROUND Chromosome 10q25-q26 has been strongly correlated to endometrial tumorigenesis. A nove... more BACKGROUND Chromosome 10q25-q26 has been strongly correlated to endometrial tumorigenesis. A novel human gene, CASC2, has previously been identified at chromosome 10q26. One out of the three alternative transcripted forms, CASC2a, has been demonstrated to be mutated at a low frequency in endometrial cancer (EC). In this study, the role of the CASC2a gene in cancer has been further defined. MATERIALS AND METHODS Tumour and corresponding normal tissues were analysed for CASC2a mRNA expression by real-time RT-PCR and mutation status by PCR-based approaches. RESULTS A significantly decreased level of CASC2a transcripts was observed in 13/17 (76%) EC tissues, as well as in 6/9 (67%) colorectal cancers. Exogenous expression of CASC2a in undifferentiated AN3CA endometrial cancer cells inhibited cellular growth in anchorage-independent growth assays. Finally, infrequent CASC2a mutations were able to impair the gene function. CONCLUSION Altogether, our findings strongly suggest that CASC2a m...
BackgroundDespite progress in identifying genes associated with breast cancer, many more risk loc... more BackgroundDespite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles.MethodsWe performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs.ResultsOverall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 10−6 level. Twenty of these regions contained defined genes, including one ...
Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation status plays a predom... more Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation status plays a predominant role in the management of MM patients. The aim of this study was to compare BRAF mutational testing performed by conventional nucleotide sequencing approaches with either real-time polymerase chain reaction (rtPCR) or next-generation sequencing (NGS) assays in a real-life, hospital-based series of advanced MM patients. Consecutive patients with AJCC (American Joint Committee on Cancer) stage IIIC and IV MM from Sardinia, Italy, who were referred for molecular testing, were enrolled into the study. Initial screening was performed to assess the mutational status of the BRAF and NRAS genes, using the conventional methodologies recognized by the nationwide guidelines, at the time of the molecular classification, required by clinicians: at the beginning, Sanger-based sequencing (SS) and, after, pyrosequencing. The present study was then focused on BRAF mutation detecting approaches only...
The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since t... more The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience o...
Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or e... more Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that β-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the β-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found ...
The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since t... more The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience o...
Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profiling has e... more Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profiling has enriched our understanding of cancer initiation and progression and has become fundamental to provide guidance on treatment with targeted therapies. Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. Numerous studies performed with traditional sequencing methods have investigated the occurrence of such mutations in lung cancer, and new insights regarding their frequency and clinical significance are continuously provided with the use of last generation sequencing technologies. In this review, we discuss the molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer, namely EGFR, KRAS, BRAF, MET, and HER2 mutations or amplification, as well as ALK and ROS1 fusions. Furthermore, we investigated the predictive impact of these alterations on the outcomes o...
Abstract: Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profi... more Abstract: Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profiling has enriched our understanding of cancer initiation and progression and has become fundamental to provide guidance on treatment with targeted therapies. Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. Numerous studies performed with traditional sequencing methods have investigated the occurrence of such mutations in lung cancer, and new insights regarding their frequency and clinical significance are continuously provided with the use of last generation sequencing technologies. In this review, we discuss the molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer, namely EGFR, KRAS, BRAF, MET, and HER2 mutations or amplification, as well as ALK and ROS1 fusions. Furthermore, we investigated the predictive impact of these alterations on the ...
Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation status plays a predom... more Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation status plays a predominant role in the management of MM patients. The aim of this study was to compare BRAF mutational testing performed by conventional nucleotide sequencing approaches with either real-time polymerase chain reaction (rtPCR) or next-generation sequencing (NGS) assays in a real-life, hospital-based series of advanced MM patients. Consecutive patients with AJCC (American Joint Committee on Cancer) stage IIIC and IV MM from Sardinia, Italy, who were referred for molecular testing, were enrolled into the study. Initial screening was performed to assess the mutational status of the BRAF and NRAS genes, using the conventional methodologies recognized by the nationwide guidelines, at the time of the molecular classification, required by clinicians: at the beginning, Sanger-based sequencing (SS) and, after, pyrosequencing. The present study was then focused on BRAF mutation detecting approaches only...
Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because of this, ... more Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because of this, we currently have a limited understanding of its genetic and molecular constitution. The incidence among SNMs of somatic mutations in the genes involved in the main molecular pathways, which have been largely associated with cutaneous melanoma, is not yet fully understood. Through a next-generation sequencing (NGS) approach using a panel of 25 genes involved in melanoma pathogenesis customized by our group, we performed a mutation analysis in a cohort of 25 SNM patients. Results showed that pathogenic mutations were found in more than 60% of SNM cases at a somatic level, with strikingly 32% of them carrying deleterious mutations in the BRAF gene. The identified mutations mostly lack the typical UV signature associated with cutaneous melanomas and showed no significant association with any histopathological parameter. Oncogenic activation of the BRAF-depending pathway, which may induce im...
Abstract: Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because... more Abstract: Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because of this, we currently have a limited understanding of its genetic and molecular constitution. The incidence among SNMs of somatic mutations in the genes involved in the main molecular pathways, which have been largely associated with cutaneous melanoma, is not yet fully understood. Through a next generation sequencing (NGS) approach using a panel of 25 genes involved in melanoma pathogenesis customized by our group, we performed a mutation analysis in a cohort of 25 SNM patients. Results showed that pathogenic mutations were found in more than 60% of SNM cases at a somatic level, with strikingly 32% of them carrying deleterious mutations in the BRAF gene. The identified mutations mostly lack the typical UV signature associated with cutaneous melanomas and showed no significant association with any histopathological parameter. Oncogenic activation of the BRAF-depending pathway, which may...
Background: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. ... more Background: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. Limited information is available in the current scientific literature on the concordance of genetic alterations between primary and metastatic CMM. In the present study, we performed next-generation sequencing (NGS) analysis of the main genes participating in melanoma pathogenesis and progression, among paired primary and metastatic lesions of CMM patients, with the aim to evaluate levels of discrepancies in mutational patterns. Methods: Paraffin-embedded tumor tissues of the paired lesions were retrieved from the archives of the institutions participating in the study. NGS was performed using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup (IMI) to explore the mutational status of selected regions (343 amplicons; amplicon range: 125-175 bp; coverage 100%) within the main 25 genes involved in CMM pathogenesis; sequencing was performed with the Ion Torrent PG...
Introduction: The aim of this study was to analyze and describe the incidence and mortality trend... more Introduction: The aim of this study was to analyze and describe the incidence and mortality trends of ovarian cancer in North Sardinia, Italy, in the period 1992-2010. Materials and methods: Data were obtained from the tumor registry of Sassari province which makes part of a wider registry web, coordinated today by the Italian Association for Tumor Registries. Results: The overall number of ovarian cancer cases registered in the period under investigation was 600. The mean age of the patients was 62 years. The standardized incidence and mortality rates were 11.2/100,000 and 5.1/100,000 respectively. A substantially stable trend in incidence and mortality of ovarian cancer was evidenced. Relative survival at five years from diagnosis was 44.2%. Conclusions: The incidence and mortality trends of ovarian cancer in North Sardinia remained relatively stable in the last decades, while prognosis remains relatively poor.
Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat ... more Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat despite recent advances in targeted and immune therapies. About 50% of advanced melanoma do not benefit of such therapies, and novel treatments are requested. Curcumin and its analogs have shown good anticancer properties and are being considered for use in combination with or sequence to recent therapies to improve patient outcomes. Our group previously published the synthesis and anticancer activity characterization of a novel curcumin-related compound against melanoma and neuroblastoma cells (D6). Here, two hydroxylated biphenyl compounds—namely, compounds 11 and 12—were selected among a small collection of previously screened C2-symmetric hydroxylated biphenyls structurally related to D6 and curcumin, showing the best antitumor potentiality against melanoma cells (IC50 values of 1.7 ± 0.5 μM for 11 and 2.0 ± 0.7 μM for 12) and no toxicity of normal fibroblasts up to 32 µM. Their anti...
Background Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. T... more Background Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. The aim of this study was to evaluate the global survival in a real-life cohort of patients with LAC harboring driver genetic alterations. Methods A series of 1282 consecutive Sardinian LAC patients who underwent genetic testing from January 2011 through July 2016 was collected. Molecular tests were based on the clinical needs of each single case (EGFR-exon18/19/21, ALK, and, more recently, BRAF-exon15), and the availability of tissue (KRAS, MET, and presence of low-frequency EGFR-T790M mutated alleles at baseline). Results The mean follow-up time of the patients was 46 months. EGFR, KRAS, and BRAF mutations were detected in 13.7%, 21.3%, and 3% of tested cases, respectively; ALK rearrangements and MET amplifications were found respectively in 4.7% and 2% of tested cases. As expected, cases with mutations in exons 18–21 of EGFR, sensitizing to anti-EGFR tyrosine kinase inhibitors (TKIs) a...
Background: Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. ... more Background: Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. The aim of this study was to evaluate the global survival in a real-life cohort of patients with LAC harboring driver genetic alterations. Methods: A series of 1282 consecutive Sardinian LAC patients who underwent genetic testing from January 2011 through July 2016 was collected. Molecular tests were based on the clinical needs of each single case (EGFR-exon18/19/21, ALK, and, more recently, BRAF-exon15), and the availability of tissue (KRAS, MET, and presence of lowfrequency EGFR-T790M mutated alleles at baseline). Results: The mean follow-up time of the patients was 46 months. EGFR, KRAS, and BRAF mutations were detected in 13.7%, 21.3%, and 3% of tested cases, respectively; ALK rearrangements and MET amplifications were found respectively in 4.7% and 2% of tested cases. As expected, cases with mutations in exons 18-21 of EGFR, sensitizing to anti-EGFR tyrosine kinase inhibitors (TKIs)...
Background and Objectives: The respiratory apparatus, generally affected by highly aggressive tum... more Background and Objectives: The respiratory apparatus, generally affected by highly aggressive tumors like lung cancer and mesothelioma, is rarely affected by primary malignant melanoma. The aim of this review was to identify cases of primary malignant melanoma of the lung (PMML) published in the modern scientific literature, and to describe their main clinical, pathological and therapeutic features. Materials and Methods: A systematic search of publications in the electronic database PubMed has been performed using keywords, and the references of the selected articles were checked to identify additional missing studies. Results: Globally 52 papers reporting on 76 cases were identified. Among them there were 47 reports of a single case, three papers reporting on two cases each, and two larger case series published in 1997 and 2005 including eight and 15 cases, respectively. Conclusions: PMML was generally diagnosed in middle-aged males, without any apparent correlation with cigarette...
BACKGROUND Chromosome 10q25-q26 has been strongly correlated to endometrial tumorigenesis. A nove... more BACKGROUND Chromosome 10q25-q26 has been strongly correlated to endometrial tumorigenesis. A novel human gene, CASC2, has previously been identified at chromosome 10q26. One out of the three alternative transcripted forms, CASC2a, has been demonstrated to be mutated at a low frequency in endometrial cancer (EC). In this study, the role of the CASC2a gene in cancer has been further defined. MATERIALS AND METHODS Tumour and corresponding normal tissues were analysed for CASC2a mRNA expression by real-time RT-PCR and mutation status by PCR-based approaches. RESULTS A significantly decreased level of CASC2a transcripts was observed in 13/17 (76%) EC tissues, as well as in 6/9 (67%) colorectal cancers. Exogenous expression of CASC2a in undifferentiated AN3CA endometrial cancer cells inhibited cellular growth in anchorage-independent growth assays. Finally, infrequent CASC2a mutations were able to impair the gene function. CONCLUSION Altogether, our findings strongly suggest that CASC2a m...
BackgroundDespite progress in identifying genes associated with breast cancer, many more risk loc... more BackgroundDespite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles.MethodsWe performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs.ResultsOverall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 10−6 level. Twenty of these regions contained defined genes, including one ...
Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation status plays a predom... more Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation status plays a predominant role in the management of MM patients. The aim of this study was to compare BRAF mutational testing performed by conventional nucleotide sequencing approaches with either real-time polymerase chain reaction (rtPCR) or next-generation sequencing (NGS) assays in a real-life, hospital-based series of advanced MM patients. Consecutive patients with AJCC (American Joint Committee on Cancer) stage IIIC and IV MM from Sardinia, Italy, who were referred for molecular testing, were enrolled into the study. Initial screening was performed to assess the mutational status of the BRAF and NRAS genes, using the conventional methodologies recognized by the nationwide guidelines, at the time of the molecular classification, required by clinicians: at the beginning, Sanger-based sequencing (SS) and, after, pyrosequencing. The present study was then focused on BRAF mutation detecting approaches only...
The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since t... more The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience o...
Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or e... more Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that β-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the β-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found ...
The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since t... more The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience o...
Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profiling has e... more Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profiling has enriched our understanding of cancer initiation and progression and has become fundamental to provide guidance on treatment with targeted therapies. Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. Numerous studies performed with traditional sequencing methods have investigated the occurrence of such mutations in lung cancer, and new insights regarding their frequency and clinical significance are continuously provided with the use of last generation sequencing technologies. In this review, we discuss the molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer, namely EGFR, KRAS, BRAF, MET, and HER2 mutations or amplification, as well as ALK and ROS1 fusions. Furthermore, we investigated the predictive impact of these alterations on the outcomes o...
Abstract: Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profi... more Abstract: Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profiling has enriched our understanding of cancer initiation and progression and has become fundamental to provide guidance on treatment with targeted therapies. Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. Numerous studies performed with traditional sequencing methods have investigated the occurrence of such mutations in lung cancer, and new insights regarding their frequency and clinical significance are continuously provided with the use of last generation sequencing technologies. In this review, we discuss the molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer, namely EGFR, KRAS, BRAF, MET, and HER2 mutations or amplification, as well as ALK and ROS1 fusions. Furthermore, we investigated the predictive impact of these alterations on the ...
Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation status plays a predom... more Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation status plays a predominant role in the management of MM patients. The aim of this study was to compare BRAF mutational testing performed by conventional nucleotide sequencing approaches with either real-time polymerase chain reaction (rtPCR) or next-generation sequencing (NGS) assays in a real-life, hospital-based series of advanced MM patients. Consecutive patients with AJCC (American Joint Committee on Cancer) stage IIIC and IV MM from Sardinia, Italy, who were referred for molecular testing, were enrolled into the study. Initial screening was performed to assess the mutational status of the BRAF and NRAS genes, using the conventional methodologies recognized by the nationwide guidelines, at the time of the molecular classification, required by clinicians: at the beginning, Sanger-based sequencing (SS) and, after, pyrosequencing. The present study was then focused on BRAF mutation detecting approaches only...
Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because of this, ... more Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because of this, we currently have a limited understanding of its genetic and molecular constitution. The incidence among SNMs of somatic mutations in the genes involved in the main molecular pathways, which have been largely associated with cutaneous melanoma, is not yet fully understood. Through a next-generation sequencing (NGS) approach using a panel of 25 genes involved in melanoma pathogenesis customized by our group, we performed a mutation analysis in a cohort of 25 SNM patients. Results showed that pathogenic mutations were found in more than 60% of SNM cases at a somatic level, with strikingly 32% of them carrying deleterious mutations in the BRAF gene. The identified mutations mostly lack the typical UV signature associated with cutaneous melanomas and showed no significant association with any histopathological parameter. Oncogenic activation of the BRAF-depending pathway, which may induce im...
Abstract: Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because... more Abstract: Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because of this, we currently have a limited understanding of its genetic and molecular constitution. The incidence among SNMs of somatic mutations in the genes involved in the main molecular pathways, which have been largely associated with cutaneous melanoma, is not yet fully understood. Through a next generation sequencing (NGS) approach using a panel of 25 genes involved in melanoma pathogenesis customized by our group, we performed a mutation analysis in a cohort of 25 SNM patients. Results showed that pathogenic mutations were found in more than 60% of SNM cases at a somatic level, with strikingly 32% of them carrying deleterious mutations in the BRAF gene. The identified mutations mostly lack the typical UV signature associated with cutaneous melanomas and showed no significant association with any histopathological parameter. Oncogenic activation of the BRAF-depending pathway, which may...
Background: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. ... more Background: Cutaneous malignant melanoma (CMM) is one of the most common skin cancers worldwide. Limited information is available in the current scientific literature on the concordance of genetic alterations between primary and metastatic CMM. In the present study, we performed next-generation sequencing (NGS) analysis of the main genes participating in melanoma pathogenesis and progression, among paired primary and metastatic lesions of CMM patients, with the aim to evaluate levels of discrepancies in mutational patterns. Methods: Paraffin-embedded tumor tissues of the paired lesions were retrieved from the archives of the institutions participating in the study. NGS was performed using a specific multiple-gene panel constructed by the Italian Melanoma Intergroup (IMI) to explore the mutational status of selected regions (343 amplicons; amplicon range: 125-175 bp; coverage 100%) within the main 25 genes involved in CMM pathogenesis; sequencing was performed with the Ion Torrent PG...
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Papers by Giuseppe Palmieri