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1.
Endocr Connect ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31336362

RESUMO

Breast cancer in men is a rare and still poorly characterized disease. Inherited mutations in BRCA1, BRCA2 and PALB2 genes, as well as common polymorphisms, play a role in male breast cancer genetic predisposition. Male breast cancer is considered a hormone-dependent tumor specifically related to hyperestrogenism. Polymorphisms in genes involved in estrogen biosynthesis and metabolism pathways, such as CYP17A1 and CYP1B1, have been associated with breast cancer risk. Here, we aimed to investigate the role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk. A series of 597 male breast cancer cases and 1022 male controls, recruited within the Italian Multicenter Study on male breast cancer, was genotyped for CYP17A1 rs743572, CYP1B1 rs1056836 and rs1800440 polymorphisms by allelic discrimination real-time PCR with TaqMan probes. Associations with male breast cancer risk were estimated using logistic regression. No statistically significant associations between male breast cancer risk and the three analyzed polymorphisms emerged. Similar results were obtained also when BRCA1/2 mutational status was considered. No significant differences in the distribution of the genotypes according to estrogen receptor status emerged. In conclusion, our study, based on a large series of male breast cancer cases, is likely to exclude a relevant role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer predisposition. Overall, these results add new data to the increasing evidence that polymorphisms in these genes may not be associated with breast cancer risk.

2.
Clin Epigenetics ; 11(1): 100, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288858

RESUMO

BACKGROUND: Clustered protocadherins (PCDHs) map in tandem at human chromosome 5q31 and comprise three multi-genes clusters: α-, ß- and γ-PCDH. The expression of this cluster consists of a complex mechanism involving DNA hub formation through DNA-CCTC binding factor (CTCF) interaction. Methylation alterations can affect this interaction, leading to transcriptional dysregulation. In cancer, clustered PCDHs undergo a mechanism of long-range epigenetic silencing by hypermethylation. RESULTS: In this study, we detected frequent methylation alterations at CpG islands associated to these clustered PCDHs in all the solid tumours analysed (colorectal, gastric and biliary tract cancers, pilocytic astrocytoma), but not hematologic neoplasms such as chronic lymphocytic leukemia. Importantly, several altered CpG islands were associated with CTCF binding sites. Interestingly, our analysis revealed a hypomethylation event in pilocytic astrocytoma, suggesting that in neuronal tissue, where PCDHs are highly expressed, these genes become hypomethylated in this type of cancer. On the other hand, in tissues where PCDHs are lowly expressed, these CpG islands are targeted by DNA methylation. In fact, PCDH-associated CpG islands resulted hypermethylated in gastrointestinal tumours. CONCLUSIONS: Our study highlighted a strong alteration of the clustered PCDHs methylation pattern in the analysed solid cancers and suggested these methylation aberrations in the CpG islands associated with PCDH genes as powerful diagnostic biomarkers.

3.
Crit Rev Oncol Hematol ; 140: 67-72, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31176273

RESUMO

The current availability of new Poly(ADP-ribose) Polymerase (PARP)-inhibitors for the treatment of ovarian cancer patients independently of the presence of a BRCA pathogenic variant, together with the validation of somatic test for the analysis of BRCA1/2 genes, involves the need to optimise the guidelines for BRCA testing. The AIOM-SIGU-SIBIOC-SIAPEC-IAP Italian Scientific Societies, in this position paper, recommend the implementation of BRCA testing with 2 main objectives: the first is the identification of ovarian cancer patients with higher probability of benefit from specific anticancer treatments (test for response to therapy); the second goal, through BRCA testing in the family members of ovarian cancer patients, is the identification of carriers of pathogenic variant, who have inheredited predisposition to cancer development (test for cancer risk). These individuals with increased risk of cancer, should be encouraged to participate in dedicated high-risk surveillance clinics and specific risk-reducing measures (primary and/or secondary prevention programs).


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Testes Genéticos/normas , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Sociedades Médicas , Bioquímica , Feminino , Genética , Humanos , Itália , Oncologia , Neoplasias Ovarianas/diagnóstico
4.
Eur J Cancer Care (Engl) ; 28(5): e13083, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31056822

RESUMO

OBJECTIVE: In the era of cancer panel testing, new models of genetic counselling providing effective decision-making support are needed. As little is known about Southern European patients' and families' needs and experiences in this regard, we explored Italian women's experiences of clinical BRCA1/2 counselling and testing. METHODS: We interviewed 19 Italian women with a strong family history but no personal history of cancer who had had clinical BRCA1/2 testing. Interviews were recorded and transcribed, and qualitative data were organised into themes. RESULTS: Most respondents had decided to pursue testing before pre-test counselling. Although half the sample reported having reached the decision without thinking through its implications, most participants qualified their choice as unequivocally "the right one." CONCLUSION: A subset of Italian women may arrive at their first cancer genetic consultation having already made a firm decision about testing. To empower women's decision-making, new models of cancer genetic counselling could usefully take into account differences in how they approach the testing process. This includes understanding decision-making from different cultural perspectives. In familistic countries like Italy, for example, decisional support may involve exploring widely shared assumptions regarding responsibilities towards family members and the prioritisation of family over self.

5.
Patient Educ Couns ; 102(6): 1210-1216, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30718092

RESUMO

BACKGROUND: Mutations in the BRCA 1/2 genes increase the risk of developing breast and/or ovarian cancer compared with the general population. However, the risk is low at age 30, and for women younger than 25, no preventive or screening options are available. Scientists wonder whether genetic predictive BRCA testing is appropriate at a very young age. Furthermore, although young women have positive attitudes toward testing, their understanding of genetic information seems scarce. OBJECTIVE: To assess how young (18-24) versus adult (30-45) women at general population- level risk understand information about BRCA testing. METHODS: 302 women read an informative pamphlet and answered an ad-hoc questionnaire assessing usefulness of the information for decision making, intention to undergo predictive testing, and comprehension (perceived, general, and risk comprehension; open-ended questions). RESULTS: Younger women had a lower comprehension of important BRCA information; it was more difficult for young women to identify the risk figures of cancer, and they showed errors when answering open-ended questions. LIMITATIONS: Results are limited by the study's hypothetical nature. CONCLUSIONS: Young women seem to have particular difficulty understanding BRCA information. PRACTICE IMPLICATIONS: Counsellors should be aware of the difficulties young women have in understanding information about BRCA predictive testing.

6.
Int J Cancer ; 145(2): 390-400, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30613976

RESUMO

Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.


Assuntos
Neoplasias da Mama Masculina/genética , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Mutação , Análise de Sequência de DNA/métodos , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , DNA Glicosilases/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
PLoS One ; 13(5): e0197522, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29782524

RESUMO

BACKGROUND: Telomere length in peripheral blood leukocytes (PBL-TL) was proposed as a biomarker of cancer risk. Recent scientific evidence suggested PBL-TL plays a diverse role in different cancers. Inconsistent results were obtained on PBL-TL in relation to breast cancer risk and specifically to the presence of BRCA1 and BRCA2 mutations. The aim of the present case-control study was to analyse the correlation between family history of breast cancer or presence of a BRCA mutation and PBL-TL in the hypothesis that TL is a modifier of cancer risk. METHODS: PBL-TL was measured using the real-time quantitative PCR method in DNA for 142 cases and 239 controls. All the women enrolled were characterized for cancer family history. A subgroup of 48 women were classified for the presence of a BRCA mutation. PBL-TL were summarized as means and standard deviations, and compared by standard analysis of variance. A multivariable Generalised Linear Model was fitted to the data with PBL-TL as the dependent variable, case/control status and presence of a BRCA/VUS mutation as factors, and age in 4 strata as a covariate. RESULTS: Age was significantly associated with decreasing PBL-TL in controls (p = 0.01), but not in BC cases. The telomere length is shorter in cases than in controls after adjusting for age. No effect on PBL-TL of BMI, smoke nor of the most common risk factors for breast cancer was observed. No association between PBL-TL and family history was detected both in BC cases and controls. In the multivariate model, no association was observed between BRCA mutation and decreased PBL-TL. A statistically significant interaction (p = 0.031) between case-control status and a BRCA-mutation/VUS was observed, but no effect was detected for the interaction of cancer status and BRCA or VUS. CONCLUSION: Our study fails to provide support to the hypothesis that PBL-TL is associated with the risk of hereditary BC, or that is a marker of inherited mutations in BRCA genes.

9.
Int J Cancer ; 143(4): 907-920, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29542109

RESUMO

Colorectal cancer (CRC) develops through the accumulation of both genetic and epigenetic alterations. However, while the former are already used as prognostic and predictive biomarkers, the latter are less well characterized. Here, performing global methylation analysis on both CRCs and adenomas by Illumina Infinium HumanMethylation450 Bead Chips, we identified a panel of 74 altered CpG islands, demonstrating that the earliest methylation alterations affect genes coding for proteins involved in the crosstalk between cell and surrounding environment. The panel discriminates CRCs and adenomas from peritumoral and normal mucosa with very high specificity (100%) and sensitivity (99.9%). Interestingly, over 70% of the hypermethylated islands resulted in downregulation of gene expression. To establish the possible usefulness of these non-invasive markers for detection of colon cancer, we selected three biomarkers and identified the presence of altered methylation in stool DNA and plasma cell-free circulating DNA from CRC patients.

10.
Hum Mutat ; 39(5): 729-741, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29460995

RESUMO

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.

11.
Breast ; 38: 92-97, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29287190

RESUMO

INTRODUCTION: Breast cancer (BC) in men is a rare disease, whose etiology appears to be associated with genetic factors. Inherited mutations in BRCA1/2 genes account for about 10-15% of all cases. FANCM, functionally linked to BRCA1/2, has been suggested as a novel BC susceptibility gene. Our aim was to test if FANCM germline mutations could further explain male BC (MBC) susceptibility. METHODS: We screened the entire coding region of FANCM in 286 MBCs by a multi-gene panel analysis, and compared these data with available whole exome sequencing data from 415 men used as population controls. Moreover, we genotyped the two most frequent FANCM mutations (c.5101C>T and c.5791C>T) in 506 MBCs and 854 healthy male controls. RESULTS: Two FANCM truncating mutations, the c.1432C>T (p.Arg478Ter) and c.1972C>T (p.Arg658Ter), were identified in two MBC cases (0.7%). When specifically considering cases at increased genetic risk for BC, FANCM mutation frequency raises up to 1%. One mutation, the c.2201_2202delCT (p.Ser734Terfs), was found among controls (0.24%). Mutation frequency in cases was higher than in controls, however this difference was not statistically significant. FANCM c.5101C>T was not present in any of the cases and controls analyzed, whereas FANCM c.5791C>T was found in two controls (0.23%). CONCLUSION: Rare FANCM truncating mutations, other than c.5101C>T and c.5791C>T, may have a role in MBC susceptibility. The inclusion of FANCM in gene panels for research purpose would allow for the identification of a higher number of mutation carriers, thus helping estimate BC risk associated with FANCM mutations.


Assuntos
Neoplasias da Mama Masculina/genética , DNA Helicases/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Genótipo , Mutação em Linhagem Germinativa , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sequenciamento Completo do Genoma , Adulto Jovem
12.
Genes Chromosomes Cancer ; 56(12): 846-854, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28791770

RESUMO

Familial adenomatous polyposis is a Mendelian syndrome in which germline loss-of-function mutations of APC are associated with multiple adenomatous polyps of the large bowel, a multiplicity of extracolonic features, and a high lifetime risk of colorectal cancer. Different APC germline mutations have been identified, including sequence changes, genomic rearrangements, and expression defects. Recently, very rare families have been associated with constitutive large deletions encompassing the APC-5' regulatory region, while leaving the remaining gene sequence intact; the regulatory region contains a proximal and a distal promoter, called 1A and 1B, respectively. We identified a novel deletion encompassing promoter 1B in a large Italian family that manifested polyposis in three of the six branches descending from a founding couple married in 1797. By combining different molecular approaches on both DNA and RNA, we precisely mapped this deletion (6858 bp in length) that proved to be associated with APC allele silencing. The finding of the same deletion in two additional polyposis families pointed to a founder mutation in Italy. Deletion carriers from the three families all showed a "classical" polyposis phenotype. To explore the molecular mechanisms underlying promoter deletions, we performed an in silico analysis of the breakpoints of 1A and 1B rearrangements so far reported in the literature; moreover, to decipher genotype-phenotype correlations, we critically reviewed current knowledge on deletions versus point mutations in the APC-5' regulatory region.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Efeito Fundador , Deleção de Genes , Polipose Adenomatosa do Colo/patologia , Adolescente , Adulto , Feminino , Mutação em Linhagem Germinativa , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Regiões Promotoras Genéticas
13.
J Genet Couns ; 26(5): 1144-1152, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28337671

RESUMO

The aim of this study was to assess attitudes toward ovarian cancer risk management options for BRCA mutation carriers in healthy Italian women, and to identify predictors of the preference for risk reducing salpingo-oophorectomy (RRSO) over surveillance. One hundred eighty-one women aged 30-45 completed a questionnaire about preferences, knowledge, risk perception, and socio-demographic information. Participants were randomly presented with a pamphlet about BRCA1 or BRCA2 mutation-specific testing, consequences of testing and preventive options for carriers, and they were stratified by having children or not and by age group. Surveillance was the preferred option (64.6%), followed by RRSO (24.3%). Although RRSO is the only effective strategy available to BRCA carriers, most healthy women faced for the first time with this option may not consider it as their preferred choice. Predictors associated with a higher likelihood to prefer surgery over surveillance were: knowing that life expectancy is longer with surgery, perceived comprehension of the consequences of testing, previous knowledge about BRCA testing, anticipated worry about developing cancer, and feelings of risk. Childbearing intentions and the effect of childbearing intentions on choice were associated with a lower preference for surgery. Further research is needed to confirm the role of the factors identified in this study in order to promote informed decision-making about RRSO.


Assuntos
Genes BRCA1 , Genes BRCA2 , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Salpingo-Ooforectomia/estatística & dados numéricos , Adulto , Feminino , Heterozigoto , Humanos , Itália , Pessoa de Meia-Idade , Mutação , Fatores de Risco , Comportamento de Redução do Risco , Salpingectomia
14.
J Hum Genet ; 62(2): 309-315, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27829682

RESUMO

To determine prevalence, spectrum and genotype-phenotype correlations of MUTYH variants in Italian patients with suspected MAP (MUTYH-associated polyposis), a retrospective analysis was conducted to identify patients who had undergone MUTYH genetic testing from September 2002 to February 2014. Results of genetic testing and patient clinical characteristics were collected (gender, number of polyps, age at polyp diagnosis, presence of colorectal cancer (CRC) and/or other cancers, family data). The presence of large rearrangements of the MUTYH gene was evaluated by Multiplex Ligation-dependent Probe Amplification analysis. In all, 299 patients with colorectal neoplasia were evaluated: 61.2% were males, the median age at polyps or cancer diagnosis was 50 years (16-80 years), 65.2% had <100 polyps and 51.8% had CRC. A total of 36 different MUTYH variants were identified: 13 (36.1%) were classified as pathogenetic, whereas 23 (63.9%) were variants of unknown significance (VUS). Two pathogenetic variants were observed in 78 patients (26.1%). A large homozygous deletion of exon 15 was found in one patient (<1.0%). MAP patients were younger than those with negative MUTYH testing at polyps diagnosis (P<0.0001) and at first cancer diagnosis (P=0.007). MAP patients carrying the p.Glu480del variant presented with a younger age at polyp diagnosis as compared to patients carrying p.Gly396Asp and p.Tyr179Cys variants. A high heterogeneity of MUTYH variants and a high rate of VUS were identified in a cohort of Italian patients with suspected MAP. Genotype-phenotype analysis suggests that the p.Glu480del variant is associated with a severe phenotype.


Assuntos
Pólipos do Colo/genética , DNA Glicosilases/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pólipos do Colo/patologia , Neoplasias Colorretais/genética , Feminino , Testes Genéticos , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Mutação , Fenótipo , Estudos Retrospectivos , Adulto Jovem
16.
Breast Cancer Res Treat ; 157(2): 319-327, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27117159

RESUMO

Female BRCA1/BRCA2 mutation carriers are at substantially increased risk for developing breast and/or ovarian cancer, and are offered enhanced surveillance including screening from a young age and risk-reducing surgery (RRS)-mastectomy (RRM) and/or salpingo-oophorectomy (RRSO). While there are established guidelines for early detection of breast cancer in high-risk women who have not undergone RRM, there are less developed guidelines after RRM. We evaluated the schemes offered before and after RRS in internationally diverse high-risk clinics. An e-mailed survey was distributed to high-risk clinics affiliated with CIMBA. Overall, 22 centers from 16 countries responded. Pre RRS surveillance schemes overwhelmingly included breast imaging (primarily MRI) from 18 to 30 years and clinical breast exam (CBE) at 6-12 month intervals. For ovarian cancer, all but 6 centers offered semiannual/annual gynecological exam, transvaginal ultrasound, and CA 125 measurements. Post RRM, most centers offered only annual CBE while 4 centers offered annual MRI, primarily for substantial residual breast tissue. After RRSO only 4 centers offered specific gynecological surveillance. Existing guidelines for breast/ovarian cancer detection in BRCA carriers are being applied pre RRS but are not globally harmonized, and most centers offer no specific surveillance post RRS. From this comprehensive multinational study it is clear that evidence-based, long-term prospective data on the most effective scheme for BRCA carriers post RRS is needed.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/prevenção & controle , Mutação , Neoplasias Ovarianas/prevenção & controle , Procedimentos Cirúrgicos Profiláticos/métodos , Adulto , Neoplasias da Mama/genética , Medicina Baseada em Evidências , Feminino , Humanos , Imagem por Ressonância Magnética , Neoplasias Ovarianas/genética , Guias de Prática Clínica como Assunto , Mastectomia Profilática , Estudos Prospectivos , Inquéritos e Questionários , Adulto Jovem
17.
Minerva Ginecol ; 68(5): 579-86, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26930387

RESUMO

Early diagnosis and proper management of gynecologic malignancies represent a challenge in modern oncology. A growing interest has arisen around the gynecological manifestations of hereditary cancer syndromes. In particular, the discovery of the BRCA1 and BRCA2 genes in ovarian cancer and the mismatch repair genes (MMR) in endometrial carcinoma has revolutionized our approach to the diagnosis and screening of women for ovarian and uterine cancers. The clinical, genetic and pathological features of hereditary cancer syndromes with gynecological manifestations are reviewed focusing on Lynch Syndrome, also known as hereditary nonpolyposis colorectal carcinoma (HNPCC), Peutz-Jeghers Syndrome (PJS), Cowden Syndrome or multiple hamartoma syndrome, Gorlin Syndrome or nevoid basal-cell carcinoma syndrome (NBCCS) and Reed's Syndrome or hereditary leiomyomatosis and renal cell cancer (HLRCC).


Assuntos
Neoplasias do Endométrio/terapia , Neoplasias Ovarianas/terapia , Neoplasias Uterinas/terapia , Reparo de Erro de Pareamento de DNA/genética , Detecção Precoce de Câncer , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética
18.
Eur J Cancer ; 51(16): 2289-95, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26248686

RESUMO

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 BC-associated loci widespread in the genome, may influence the risk of BC in men, and whether they may be associated with specific clinical-pathologic characteristics of male BC (MBC). In the frame of the ongoing Italian Multicenter Study on MBC, we performed a case-control study on 386 MBC cases, including 50 BRCA1/2 mutation carriers, and 1105 healthy male controls, including 197 unaffected BRCA1/2 mutation carriers. All 1491 subjects were genotyped by Sequenom iPLEX technology for a total of 29 susceptibility SNPs. By logistic regression models, we found a significant association with MBC risk for five SNPs: rs1562430 (p=0.002) and rs445114 (p=0.026) both within the 8q24.21 region; rs1011970/9p21.3 (p=0.011), rs614367/11q13.3 (p=0.016) and rs1314913/14q24.1 (p<0.0001). Differences in the distribution of rs614367/11q13.3 genotypes according to oestrogen receptor (ER) status (p=0.006), and of rs1011970/9p21.3 genotypes according to human epidermal growth factor receptor 2 (HER2) status (p=0.002) emerged. Association of rs1011970/9p21.3 risk genotype with HER2+MBC was confirmed by a multivariate analysis. rs1314913/14q24.1 was associated with increased MBC risk in analyses restricted to male BRCA1/2 mutation carriers (p=0.041). In conclusion, we provided the first evidence that the 8q24.21 region is associated with MBC risk. Furthermore, we showed that the SNPs rs1562430/8q24.21 and rs1314913/14q24.1 strongly influence BC risk in men and suggested that the SNP rs1314913/14q24.1 may act as a risk modifier locus in male BRCA1/2 mutation carriers.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama Masculina/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 8 , Cromossomos Humanos Par 9 , Polimorfismo de Nucleotídeo Único , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/patologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Frequência do Gene , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Itália , Modelos Lineares , Modelos Logísticos , Masculino , Análise Multivariada , Mutação , Razão de Chances , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco
19.
Public Health Genomics ; 18(4): 225-32, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26111740

RESUMO

BACKGROUND/AIMS: Nearly 15% of all ovarian cancer patients carry a germline BRCA mutation. A pilot project was started at IRCCS AOU San Martino--IST, Genoa, to assess the feasibility and consequences of offering genetic counselling to all ovarian cancer patients during routine oncology appointments. We present early results of this project. METHODS: Patients who attended an oncology visit at the Medical Oncology Unit 1 between November 2012 and December 2013 were identified. Medical records were reviewed for clinical data, genetic counselling and testing outcomes. RESULTS: Out of 104 women diagnosed with ovarian cancer undergoing an oncology visit, 94 had not had genetic counselling in the past. Twenty-nine patients (29/94, 31%) were referred to the Unit of Hereditary Cancer; of these, 14/26 (54%) were referred at the first visit and 15/68 (22%) at the follow-up visit (p = 0.003). Most referred women attended genetic counselling (22/29, 76%) and had BRCA genetic testing (21/22, 95%). Four BRCA1 mutations were detected (4/21, 19%). CONCLUSIONS: Oncologists discuss genetic counselling with a minority of ovarian cancer patients. Mainstreaming such practice is important to optimize the management of these patients and their families. Efforts are needed to identify new models for introducing ovarian cancer genetic risk assessment in oncology practice.


Assuntos
Genes BRCA1 , Aconselhamento Genético , Testes Genéticos , Necessidades e Demandas de Serviços de Saúde , Oncologia/métodos , Neoplasias Ovarianas/genética , Encaminhamento e Consulta , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Predisposição Genética para Doença/genética , Necessidades e Demandas de Serviços de Saúde/tendências , Humanos , Itália , Pessoa de Meia-Idade , Projetos Piloto , Medição de Risco
20.
Breast Cancer Res ; 17: 61, 2015 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-25925750

RESUMO

INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.


Assuntos
Neoplasias da Mama/genética , Genes BRCA2 , Genes Mitocondriais , Heterozigoto , Mutação , Proteína BRCA1/genética , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Filogenia , Risco
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