Valentina Silvestri - Academia.edu (original) (raw)

Papers by Valentina Silvestri

Biochimica et biophysica acta, Jan 13, 2016

The human lysine methyltransferase Smyd3, a member of the SET and MYND domain containing protein ... more The human lysine methyltransferase Smyd3, a member of the SET and MYND domain containing protein family, harbors methylation activity on both histone and non-histone targets in a tightly regulated manner. The mechanism of how Smyd3 dynamically regulates substrate recognition is still not fully unveiled. Here, we employed molecular dynamics simulations on full length human Smyd3, performed to a total of 1.2μ-second, in the presence (holo) and absence (apo) of the S-Adenosyl methionine (AdoMet) cofactor. The dynamical features of Smyd3 in apo and holo states have been examined and compared via examining geometrical and electrostatic properties. The results show a distinct dynamics of the C-terminal domain (CTD) in the two states. In the apo state, the CTD undergoes a large hinge like motion and samples more opened configurations, thus acting like a loosened clamp and resulting in expanded substrate binding crevice. In the holo state, the CTD exhibits a restricted motion while the over...

European Journal of Cancer, 2015

Increasing evidence indicates that common genetic variants may contribute to the heritable risk o... more Increasing evidence indicates that common genetic variants may contribute to the heritable risk of breast cancer (BC). In this study, we investigated whether single nucleotide polymorphisms (SNPs), within the 8q24.21 multi-cancer susceptibility region and within http://dx.

Human molecular genetics, Jan 30, 2015

Numerous genetic factors that influence breast cancer risk are known. However, approximately two ... more Numerous genetic factors that influence breast cancer risk are known. However, approximately two thirds of the overall familial risk remains unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8,635 familial breast cancer cases and 6,625 controls from different countries yielded an association between the…

European Journal of Cancer, 2014

European Journal of Cancer, 2014

European Journal of Cancer, 2014

European Journal of Cancer Supplements, 2010

95% CI) = 0.51-0.89, P = 0.006). The TGFBR2-875G>A polymorphism frequencies for homozygous GG and... more 95% CI) = 0.51-0.89, P = 0.006). The TGFBR2-875G>A polymorphism frequencies for homozygous GG and GA/AA were 63% and 37% in PC group and 62% and 38% in the control group, respectively. We found lack of statistical significant association of TGFBR2 genetic variants with PC risk (aOR = 1.05, 95% CI = 0.80-1.38, P = 0.731). Conclusions: Our results show a protective effect associated with C allele (TGFB1+869T>C) for PC development. Functional polymorphisms that influence cellular microenvironment may help determine individual higher risk genetic profiles, which can impact PC diagnosis and chemoprevention strategies.

European Journal of Cancer Supplements, 2010

95% CI) = 0.51-0.89, P = 0.006). The TGFBR2-875G>A polymorphism frequencies for homozygous GG and... more 95% CI) = 0.51-0.89, P = 0.006). The TGFBR2-875G>A polymorphism frequencies for homozygous GG and GA/AA were 63% and 37% in PC group and 62% and 38% in the control group, respectively. We found lack of statistical significant association of TGFBR2 genetic variants with PC risk (aOR = 1.05, 95% CI = 0.80-1.38, P = 0.731). Conclusions: Our results show a protective effect associated with C allele (TGFB1+869T>C) for PC development. Functional polymorphisms that influence cellular microenvironment may help determine individual higher risk genetic profiles, which can impact PC diagnosis and chemoprevention strategies.

Breast cancer research and treatment, 2014

Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are... more Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were geno...

Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2013

Male breast cancer (MBC) is a rare disease compared with female BC and our current understanding ... more Male breast cancer (MBC) is a rare disease compared with female BC and our current understanding regarding breast carcinogenesis in men has been largely extrapolated from the female counterpart. We focus on differences between the ethical issues related to male and female BC patients. A systematic literature search by using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), was carried out to provide a synopsis of the current research in the field of MBC genetics, epigenetics and ethics. Original articles and reviews published up to September 2012 were selected by using the following search key words to query the PubMed website: 'male breast cancer', 'male breast cancer and genetic susceptibility', 'male breast cancer and epigenetics', 'male breast cancer and methylation', 'male breast cancer and miRNA', 'male breast cancer and ethics'. As in women, three classes of breast cancer genetic susceptibility (high, moderate, and low penetrance) a...

European Journal of Cancer Supplements, 2008

It has been reported as a result of epidemiological studies that gastric cancer risk increases in... more It has been reported as a result of epidemiological studies that gastric cancer risk increases in atomic-bomb (A-bomb) radiation exposures. We previously found that gene polymorphisms of IL-10, an inflammationrelated cytokine, was one of the genetic factors involved in susceptibility to gastric cancer development (two major haplotype alleles, i.e., GGCG [variant] and ATTA [wild], which included IL-10 promoter regions, were strongly correlated with plasma IL-10 levels). On the other hand, it has been thought that carcinogenic pathways differ between intestinal-and diffuse-type gastric cancers. In this study, we examined risks of both intestinal-and diffuse-type gastric cancers in relation to combinations of radiation exposure dose and IL-10 haplotypes. From the Adult Health Study cohort of the Radiation Effects Research Foundation, we selected 181 cases and 1,576 controls to conduct analysis. Classification into intestinaland diffuse-type gastric cancers was based on local cancer registry data. Written informed consent was obtained from all subjects. This study was approved by the RERF Ethical Committee for Genome Research. As a result, our analysis of relationship between the rates of the two types of cancer and radiation dose among the cases showed that the rate of the diffuse type was higher and that of the intestinal type lower among heavily exposed subjects. A multivariate analysis taking other confounding factors into account also showed that radiation exposure was involved in increased risk of diffuse-type gastric cancer but was not related significantly to risk of intestinal-type cancer. Further, we found that, in the case of the intestinal type, gastric cancer risk of unexposed people differed widely by IL-10 haplotype. We also found, however, that radiation exposure did not greatly affect cancer risks of the respective haplotypes. In contrast, in the case of the diffuse type, there was a large difference between risks by IL-10 haplotype, and radiation exposure also increased the risk especially for ATTA/ATTA. As a result, subjects exposed to high dose radiation and with variant allele GGCG showed the highest risk of gastric cancer, but variation of risk by IL-10 haplotype decreased. As shown above, past radiation exposure was related to diffuse-type gastric cancer risk. On the other hand, no significant relationship was observed for intestinal-type gastric cancer. In addition, strong correlation was found between IL-10 haplotypes and radiation for diffuse-type gastric cancer. In other words, increase in risk due to radiation exposure was marked in subjects with certain haplotypes, suggesting that there is a group of people who are genetically susceptible to radiation-related gastric cancer.

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2015

The influence of DNA repair capacity, plasma nutrients and tobacco smoke exposure on DNA methylat... more The influence of DNA repair capacity, plasma nutrients and tobacco smoke exposure on DNA methylation was investigated in blood cells of twenty-one couples of monozygotic twins with discordant smoking habits. All study subjects had previously been characterized for mutagen sensitivity with challenge assays with ionizing radiation in peripheral blood lymphocytes. Plasma levels of folic acid, vitamin B12 and homocysteine were also available from a previous investigation. In this work DNA methylation in the promoter region of a panel of ten genes involved in cell cycle control, differentiation, apoptosis and DNA repair (p16, FHIT, RAR, CDH1, DAPK1, hTERT, RASSF1A, MGMT, BRCA1 and PALB2) was assessed in the same batches of cells isolated for previous studies, using the methylation-sensitive high-resolution melting technique.

The Application of Clinical Genetics, 2011

Breast cancer is the most common cancer among women, accounting for about 30% of all cancers. In ... more Breast cancer is the most common cancer among women, accounting for about 30% of all cancers. In contrast, breast cancer is a rare disease in men, accounting for less than 1% of all cancers. Up to 10% of all breast cancers are hereditary forms, caused by inherited germ-line mutations in "high-penetrance," "moderate-penetrance," and "low-penetrance" breast cancer susceptibility genes. The remaining 90% of breast cancers are due to acquired somatic genetic and epigenetic alterations. A heterogeneous set of somatic alterations, including mutations and gene amplification, are reported to be involved in the etiology of breast cancer. Promoter hypermethylation of genes involved in DNA repair and hormone-mediated cell signaling, as well as altered expression of micro RNAs predicted to regulate key breast cancer genes, play an equally important role as genetic factors in development of breast cancer. Elucidation of the inherited and acquired genetic and epigenetic alterations involved in breast cancer may not only clarify molecular pathways involved in the development and progression of breast cancer itself, but may also have an important clinical and therapeutic impact on improving the management of patients with the disease.

Oncology, 2014

In this study, we analyzed multiple somatic mutations in 10 genes relevant in melanoma tumorigene... more In this study, we analyzed multiple somatic mutations in 10 genes relevant in melanoma tumorigenesis and targeted therapies. Overall, 45% of the tumors showed mutations and, in particular, 33% had multiple mutations. Based on our results, we conclude that the assessment of mutation status of multiple genes, including CDKN2A, could provide a genetic profile that can be useful as a prognostic and therapeutic marker in melanocytic tumors.

Journal of Cellular and Molecular Medicine, 2013

SULT1A1, a member of sulfotransferase superfamily, is a drug and hormone metabolizing enzyme invo... more SULT1A1, a member of sulfotransferase superfamily, is a drug and hormone metabolizing enzyme involved in the metabolism of a variety of potential mammary carcinogens of endogenous and exogenous origin. Interestingly, the metabolic activity of SULT1A1 can be affected by variations in gene copy number. Male Breast Cancer (MBC) is a rare disease and less investigated disease compared to female BC (FBC). As in FBC, the concurrent effects of genetic risk factors, particularly BRCA2 mutations, increased exposure to estrogens and environmental carcinogens play a relevant role in MBC. By quantitative real-time PCR with TaqMan probes, we investigated the presence of SULT1A1 gene copy number variations (CNVs) in a series of 72 MBCs. SULT1A1 gene deletion was observed in 10 of the 72 MBCs (13.9%). In a multivariate analysis association between BRCA2 mutation and SULT1A1 gene deletion emerged (p = 0.0005). Based on the evidence that the level of SULT1A1 enzyme activity is correlated with CNV, our data suggest that in male breast tumors SULT1A1 activity may be decreased. Thus, it can be hypothesized that in a proportion of MBCs, particularly in BRCA2-associated MBCs, the level of estrogens and environmental carcinogens exposure might be increased suggesting a link between gene and environmental exposure in the pathogenesis of MBC.

European Journal of Cancer, 2012

European Journal of Cancer, 2012

DNA and Cell Biology, 2014

Psoriasis is caused by a combination of genetic, immunologic, and environmental factors. The vita... more Psoriasis is caused by a combination of genetic, immunologic, and environmental factors. The vitamin D receptor (VDR) is involved in antiproliferative and prodifferentiation pathways in keratinocytes and exerts immunosuppressive effects. We aimed to investigate possible associations between VDR polymorphisms and psoriasis susceptibility and to evaluate functional effects of potential psoriasis-associated polymorphisms. We genotyped 108 patients with psoriasis and 268 healthy controls at 5 VDR polymorphisms (A-1012G, FokI, BsmI, ApaI, and TaqI) by TaqMan allelic-discrimination real-time polymerase chain reaction. We found a significant increased overall risk of psoriasis for the VDR A-1012G promoter polymorphism (odds ratio [OR]=2.43, 95% confidence interval [CI]: 1.15-5.13; p=0.05). A significant higher frequency (p=0.035) of the A allele was found in psoriatic cases compared with controls. In a case-case analysis, a statistically significant association between A-1012G and family history emerged (p=0.033). Furthermore, a significant association of A-1012G risk genotypes with a lower expression of VDR mRNA emerged (p=0.0028). Our data show that VDR promoter A-1012G polymorphism is associated with psoriasis risk and suggest that this polymorphism may modulate psoriasis risk by affecting VDR expression.

Current Women's Health Reviews, 2012

ABSTRACT Male breast cancer (MBC) is a rare disease compared with female breast cancer (FBC), but... more ABSTRACT Male breast cancer (MBC) is a rare disease compared with female breast cancer (FBC), but its incidence is increasing. Because of its rarity, MBC is often compared with FBC and our current understanding regarding MBC biology, natural history and treatment strategies has been largely extrapolated from the female counterpart. Based on age-frequency distribution, age-specific incidence rate patterns and prognostic factors profiles, MBC is considered similar to late-onset post-menopausal estrogen/progesterone receptors (ER/PR)-positive FBC. This suggests that common BC risk factors may affect both genders. Indeed, similar to BC in women, MBC is likely to be caused by the concurrent effects of different risk factors, including hormonal, environmental and genetic risk factors. However, clinical and pathological characteristics of MBC do not exactly overlap FBC. Compared with women, BC occurs in men later in life, is mostly represented by invasive ductal carcinoma with higher stage, lower grade and ER/PR expression. Although rare, MBC remains a substantial cause for morbidity and mortality in men, probably because of its occurrence in advanced age and delayed diagnosis. MBC treatment generally follows the same indications as post-menopausal FBC. BC mortality and survival rates have improved significantly over time for both male and female BC, but the improvement for male is smaller if compared to female patients, thus suggesting a delay or non-appropriate utilization of adjuvant therapy. Overall, much still needs to be learned about MBC and, because of its rarity, the main effort is to develop national and international consortia for moving forward in our understanding of MBC.

Breast Cancer: Targets and Therapy, 2010

Although rare, male breast cancer (MBC) remains a substantial cause for morbidity and mortality i... more Although rare, male breast cancer (MBC) remains a substantial cause for morbidity and mortality in men. Based on age frequency distribution, age-specific incidence rate pattern, and prognostic factor profiles, MBC is considered similar to postmenopausal breast cancer (BC). Compared with female BC (FBC), MBC cases are more often hormonal receptor (estrogen receptor/progesterone receptor [ER/PR]) positive and human epidermal growth factor receptor 2 (HER2) negative. Treatment of MBC patients follows the same indications as female postmenopausal with surgery, systemic therapy, and radiotherapy. To date, ER/PR and HER2 status provides baseline predictive information used in selecting optimal adjuvant/neoadjuvant therapy and in the selection of therapy for recurrent or metastatic disease. HER2 represents a very interesting molecular target and a number of compounds (trastuzumab [Herceptin ® ; F. Hoffmann-La Roche, Basel, Switzerland] and lapatinib [Tykerb ® , GlaxoSmithKline, London, UK]) are currently under clinical evaluation. Particularly, trastuzumab, a monoclonal antibody which selectively binds the extracellular domain of HER2, has become an important therapeutic agent for women with HER2-positive (HER2+) BC. Currently, data regarding the use of trastuzumab in MBC patients is limited and only few case reports exist. In all cases, MBC patients received trastuzumab concomitantly with other drugs and no severe toxicity above grade 3 was observed. However, MBC patients that would be candidate for trastuzumab therapy (ie, HER2+/ER+ or HER2+/ER− MBCs) represent only a very small percentage of MBC cases. This is noteworthy, when taking into account that trastuzumab is an important and expensive component of systemic BC therapy. Since there is no data supporting the fact that response to therapy is different for men or women, we concluded that systemic therapy in MBC should be considered on the same basis as for FBC. Particularly in male patients, trastuzumab should be considered exclusively for advanced disease or high-risk HER2+ early BCs. On the other hand, lapatinib (Tykerb), a novel oral dual tyrosine kinase inhibitor that targets both HER2 and epidermal growth factor receptor, may represent an interesting and promising therapeutic agent for trastuzumab-resistant MBC patients.

Biochimica et biophysica acta, Jan 13, 2016

The human lysine methyltransferase Smyd3, a member of the SET and MYND domain containing protein ... more The human lysine methyltransferase Smyd3, a member of the SET and MYND domain containing protein family, harbors methylation activity on both histone and non-histone targets in a tightly regulated manner. The mechanism of how Smyd3 dynamically regulates substrate recognition is still not fully unveiled. Here, we employed molecular dynamics simulations on full length human Smyd3, performed to a total of 1.2μ-second, in the presence (holo) and absence (apo) of the S-Adenosyl methionine (AdoMet) cofactor. The dynamical features of Smyd3 in apo and holo states have been examined and compared via examining geometrical and electrostatic properties. The results show a distinct dynamics of the C-terminal domain (CTD) in the two states. In the apo state, the CTD undergoes a large hinge like motion and samples more opened configurations, thus acting like a loosened clamp and resulting in expanded substrate binding crevice. In the holo state, the CTD exhibits a restricted motion while the over...

European Journal of Cancer, 2015

Increasing evidence indicates that common genetic variants may contribute to the heritable risk o... more Increasing evidence indicates that common genetic variants may contribute to the heritable risk of breast cancer (BC). In this study, we investigated whether single nucleotide polymorphisms (SNPs), within the 8q24.21 multi-cancer susceptibility region and within http://dx.

Human molecular genetics, Jan 30, 2015

Numerous genetic factors that influence breast cancer risk are known. However, approximately two ... more Numerous genetic factors that influence breast cancer risk are known. However, approximately two thirds of the overall familial risk remains unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8,635 familial breast cancer cases and 6,625 controls from different countries yielded an association between the…

European Journal of Cancer, 2014

European Journal of Cancer, 2014

European Journal of Cancer, 2014

European Journal of Cancer Supplements, 2010

95% CI) = 0.51-0.89, P = 0.006). The TGFBR2-875G>A polymorphism frequencies for homozygous GG and... more 95% CI) = 0.51-0.89, P = 0.006). The TGFBR2-875G>A polymorphism frequencies for homozygous GG and GA/AA were 63% and 37% in PC group and 62% and 38% in the control group, respectively. We found lack of statistical significant association of TGFBR2 genetic variants with PC risk (aOR = 1.05, 95% CI = 0.80-1.38, P = 0.731). Conclusions: Our results show a protective effect associated with C allele (TGFB1+869T>C) for PC development. Functional polymorphisms that influence cellular microenvironment may help determine individual higher risk genetic profiles, which can impact PC diagnosis and chemoprevention strategies.

European Journal of Cancer Supplements, 2010

95% CI) = 0.51-0.89, P = 0.006). The TGFBR2-875G>A polymorphism frequencies for homozygous GG and... more 95% CI) = 0.51-0.89, P = 0.006). The TGFBR2-875G>A polymorphism frequencies for homozygous GG and GA/AA were 63% and 37% in PC group and 62% and 38% in the control group, respectively. We found lack of statistical significant association of TGFBR2 genetic variants with PC risk (aOR = 1.05, 95% CI = 0.80-1.38, P = 0.731). Conclusions: Our results show a protective effect associated with C allele (TGFB1+869T>C) for PC development. Functional polymorphisms that influence cellular microenvironment may help determine individual higher risk genetic profiles, which can impact PC diagnosis and chemoprevention strategies.

Breast cancer research and treatment, 2014

Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are... more Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were geno...

Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2013

Male breast cancer (MBC) is a rare disease compared with female BC and our current understanding ... more Male breast cancer (MBC) is a rare disease compared with female BC and our current understanding regarding breast carcinogenesis in men has been largely extrapolated from the female counterpart. We focus on differences between the ethical issues related to male and female BC patients. A systematic literature search by using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), was carried out to provide a synopsis of the current research in the field of MBC genetics, epigenetics and ethics. Original articles and reviews published up to September 2012 were selected by using the following search key words to query the PubMed website: 'male breast cancer', 'male breast cancer and genetic susceptibility', 'male breast cancer and epigenetics', 'male breast cancer and methylation', 'male breast cancer and miRNA', 'male breast cancer and ethics'. As in women, three classes of breast cancer genetic susceptibility (high, moderate, and low penetrance) a...

European Journal of Cancer Supplements, 2008

It has been reported as a result of epidemiological studies that gastric cancer risk increases in... more It has been reported as a result of epidemiological studies that gastric cancer risk increases in atomic-bomb (A-bomb) radiation exposures. We previously found that gene polymorphisms of IL-10, an inflammationrelated cytokine, was one of the genetic factors involved in susceptibility to gastric cancer development (two major haplotype alleles, i.e., GGCG [variant] and ATTA [wild], which included IL-10 promoter regions, were strongly correlated with plasma IL-10 levels). On the other hand, it has been thought that carcinogenic pathways differ between intestinal-and diffuse-type gastric cancers. In this study, we examined risks of both intestinal-and diffuse-type gastric cancers in relation to combinations of radiation exposure dose and IL-10 haplotypes. From the Adult Health Study cohort of the Radiation Effects Research Foundation, we selected 181 cases and 1,576 controls to conduct analysis. Classification into intestinaland diffuse-type gastric cancers was based on local cancer registry data. Written informed consent was obtained from all subjects. This study was approved by the RERF Ethical Committee for Genome Research. As a result, our analysis of relationship between the rates of the two types of cancer and radiation dose among the cases showed that the rate of the diffuse type was higher and that of the intestinal type lower among heavily exposed subjects. A multivariate analysis taking other confounding factors into account also showed that radiation exposure was involved in increased risk of diffuse-type gastric cancer but was not related significantly to risk of intestinal-type cancer. Further, we found that, in the case of the intestinal type, gastric cancer risk of unexposed people differed widely by IL-10 haplotype. We also found, however, that radiation exposure did not greatly affect cancer risks of the respective haplotypes. In contrast, in the case of the diffuse type, there was a large difference between risks by IL-10 haplotype, and radiation exposure also increased the risk especially for ATTA/ATTA. As a result, subjects exposed to high dose radiation and with variant allele GGCG showed the highest risk of gastric cancer, but variation of risk by IL-10 haplotype decreased. As shown above, past radiation exposure was related to diffuse-type gastric cancer risk. On the other hand, no significant relationship was observed for intestinal-type gastric cancer. In addition, strong correlation was found between IL-10 haplotypes and radiation for diffuse-type gastric cancer. In other words, increase in risk due to radiation exposure was marked in subjects with certain haplotypes, suggesting that there is a group of people who are genetically susceptible to radiation-related gastric cancer.

Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2015

The influence of DNA repair capacity, plasma nutrients and tobacco smoke exposure on DNA methylat... more The influence of DNA repair capacity, plasma nutrients and tobacco smoke exposure on DNA methylation was investigated in blood cells of twenty-one couples of monozygotic twins with discordant smoking habits. All study subjects had previously been characterized for mutagen sensitivity with challenge assays with ionizing radiation in peripheral blood lymphocytes. Plasma levels of folic acid, vitamin B12 and homocysteine were also available from a previous investigation. In this work DNA methylation in the promoter region of a panel of ten genes involved in cell cycle control, differentiation, apoptosis and DNA repair (p16, FHIT, RAR, CDH1, DAPK1, hTERT, RASSF1A, MGMT, BRCA1 and PALB2) was assessed in the same batches of cells isolated for previous studies, using the methylation-sensitive high-resolution melting technique.

The Application of Clinical Genetics, 2011

Breast cancer is the most common cancer among women, accounting for about 30% of all cancers. In ... more Breast cancer is the most common cancer among women, accounting for about 30% of all cancers. In contrast, breast cancer is a rare disease in men, accounting for less than 1% of all cancers. Up to 10% of all breast cancers are hereditary forms, caused by inherited germ-line mutations in "high-penetrance," "moderate-penetrance," and "low-penetrance" breast cancer susceptibility genes. The remaining 90% of breast cancers are due to acquired somatic genetic and epigenetic alterations. A heterogeneous set of somatic alterations, including mutations and gene amplification, are reported to be involved in the etiology of breast cancer. Promoter hypermethylation of genes involved in DNA repair and hormone-mediated cell signaling, as well as altered expression of micro RNAs predicted to regulate key breast cancer genes, play an equally important role as genetic factors in development of breast cancer. Elucidation of the inherited and acquired genetic and epigenetic alterations involved in breast cancer may not only clarify molecular pathways involved in the development and progression of breast cancer itself, but may also have an important clinical and therapeutic impact on improving the management of patients with the disease.

Oncology, 2014

In this study, we analyzed multiple somatic mutations in 10 genes relevant in melanoma tumorigene... more In this study, we analyzed multiple somatic mutations in 10 genes relevant in melanoma tumorigenesis and targeted therapies. Overall, 45% of the tumors showed mutations and, in particular, 33% had multiple mutations. Based on our results, we conclude that the assessment of mutation status of multiple genes, including CDKN2A, could provide a genetic profile that can be useful as a prognostic and therapeutic marker in melanocytic tumors.

Journal of Cellular and Molecular Medicine, 2013

SULT1A1, a member of sulfotransferase superfamily, is a drug and hormone metabolizing enzyme invo... more SULT1A1, a member of sulfotransferase superfamily, is a drug and hormone metabolizing enzyme involved in the metabolism of a variety of potential mammary carcinogens of endogenous and exogenous origin. Interestingly, the metabolic activity of SULT1A1 can be affected by variations in gene copy number. Male Breast Cancer (MBC) is a rare disease and less investigated disease compared to female BC (FBC). As in FBC, the concurrent effects of genetic risk factors, particularly BRCA2 mutations, increased exposure to estrogens and environmental carcinogens play a relevant role in MBC. By quantitative real-time PCR with TaqMan probes, we investigated the presence of SULT1A1 gene copy number variations (CNVs) in a series of 72 MBCs. SULT1A1 gene deletion was observed in 10 of the 72 MBCs (13.9%). In a multivariate analysis association between BRCA2 mutation and SULT1A1 gene deletion emerged (p = 0.0005). Based on the evidence that the level of SULT1A1 enzyme activity is correlated with CNV, our data suggest that in male breast tumors SULT1A1 activity may be decreased. Thus, it can be hypothesized that in a proportion of MBCs, particularly in BRCA2-associated MBCs, the level of estrogens and environmental carcinogens exposure might be increased suggesting a link between gene and environmental exposure in the pathogenesis of MBC.

European Journal of Cancer, 2012

European Journal of Cancer, 2012

DNA and Cell Biology, 2014

Psoriasis is caused by a combination of genetic, immunologic, and environmental factors. The vita... more Psoriasis is caused by a combination of genetic, immunologic, and environmental factors. The vitamin D receptor (VDR) is involved in antiproliferative and prodifferentiation pathways in keratinocytes and exerts immunosuppressive effects. We aimed to investigate possible associations between VDR polymorphisms and psoriasis susceptibility and to evaluate functional effects of potential psoriasis-associated polymorphisms. We genotyped 108 patients with psoriasis and 268 healthy controls at 5 VDR polymorphisms (A-1012G, FokI, BsmI, ApaI, and TaqI) by TaqMan allelic-discrimination real-time polymerase chain reaction. We found a significant increased overall risk of psoriasis for the VDR A-1012G promoter polymorphism (odds ratio [OR]=2.43, 95% confidence interval [CI]: 1.15-5.13; p=0.05). A significant higher frequency (p=0.035) of the A allele was found in psoriatic cases compared with controls. In a case-case analysis, a statistically significant association between A-1012G and family history emerged (p=0.033). Furthermore, a significant association of A-1012G risk genotypes with a lower expression of VDR mRNA emerged (p=0.0028). Our data show that VDR promoter A-1012G polymorphism is associated with psoriasis risk and suggest that this polymorphism may modulate psoriasis risk by affecting VDR expression.

Current Women's Health Reviews, 2012

ABSTRACT Male breast cancer (MBC) is a rare disease compared with female breast cancer (FBC), but... more ABSTRACT Male breast cancer (MBC) is a rare disease compared with female breast cancer (FBC), but its incidence is increasing. Because of its rarity, MBC is often compared with FBC and our current understanding regarding MBC biology, natural history and treatment strategies has been largely extrapolated from the female counterpart. Based on age-frequency distribution, age-specific incidence rate patterns and prognostic factors profiles, MBC is considered similar to late-onset post-menopausal estrogen/progesterone receptors (ER/PR)-positive FBC. This suggests that common BC risk factors may affect both genders. Indeed, similar to BC in women, MBC is likely to be caused by the concurrent effects of different risk factors, including hormonal, environmental and genetic risk factors. However, clinical and pathological characteristics of MBC do not exactly overlap FBC. Compared with women, BC occurs in men later in life, is mostly represented by invasive ductal carcinoma with higher stage, lower grade and ER/PR expression. Although rare, MBC remains a substantial cause for morbidity and mortality in men, probably because of its occurrence in advanced age and delayed diagnosis. MBC treatment generally follows the same indications as post-menopausal FBC. BC mortality and survival rates have improved significantly over time for both male and female BC, but the improvement for male is smaller if compared to female patients, thus suggesting a delay or non-appropriate utilization of adjuvant therapy. Overall, much still needs to be learned about MBC and, because of its rarity, the main effort is to develop national and international consortia for moving forward in our understanding of MBC.

Breast Cancer: Targets and Therapy, 2010

Although rare, male breast cancer (MBC) remains a substantial cause for morbidity and mortality i... more Although rare, male breast cancer (MBC) remains a substantial cause for morbidity and mortality in men. Based on age frequency distribution, age-specific incidence rate pattern, and prognostic factor profiles, MBC is considered similar to postmenopausal breast cancer (BC). Compared with female BC (FBC), MBC cases are more often hormonal receptor (estrogen receptor/progesterone receptor [ER/PR]) positive and human epidermal growth factor receptor 2 (HER2) negative. Treatment of MBC patients follows the same indications as female postmenopausal with surgery, systemic therapy, and radiotherapy. To date, ER/PR and HER2 status provides baseline predictive information used in selecting optimal adjuvant/neoadjuvant therapy and in the selection of therapy for recurrent or metastatic disease. HER2 represents a very interesting molecular target and a number of compounds (trastuzumab [Herceptin ® ; F. Hoffmann-La Roche, Basel, Switzerland] and lapatinib [Tykerb ® , GlaxoSmithKline, London, UK]) are currently under clinical evaluation. Particularly, trastuzumab, a monoclonal antibody which selectively binds the extracellular domain of HER2, has become an important therapeutic agent for women with HER2-positive (HER2+) BC. Currently, data regarding the use of trastuzumab in MBC patients is limited and only few case reports exist. In all cases, MBC patients received trastuzumab concomitantly with other drugs and no severe toxicity above grade 3 was observed. However, MBC patients that would be candidate for trastuzumab therapy (ie, HER2+/ER+ or HER2+/ER− MBCs) represent only a very small percentage of MBC cases. This is noteworthy, when taking into account that trastuzumab is an important and expensive component of systemic BC therapy. Since there is no data supporting the fact that response to therapy is different for men or women, we concluded that systemic therapy in MBC should be considered on the same basis as for FBC. Particularly in male patients, trastuzumab should be considered exclusively for advanced disease or high-risk HER2+ early BCs. On the other hand, lapatinib (Tykerb), a novel oral dual tyrosine kinase inhibitor that targets both HER2 and epidermal growth factor receptor, may represent an interesting and promising therapeutic agent for trastuzumab-resistant MBC patients.