RESUMO
Multiple genotyping techniques were developed on the basis of real-time PCR. In this article, we present a genotyping technique extending the induced Förster resonance energy transfer (iFRET) mechanism in conjunction with simultaneous mutation scanning. Rapid, asymmetric PCR was performed with SYTO9, polymerase lacking 5 â 3 exonuclease activity, two primers, and a probe labeled with 6-Carboxy-X-rhodamine. Six primers and probe sets were designed to detect germline mutations in BRCA1, a singular polymorphism in CCND1 and somatic mutations in KRAS and BRAF genes. The validation set consisted of 140 archival DNA samples from patients with previously confirmed BRCA1 mutation and 42 archival formalin-fixed and paraffin-embedded tissues from patients with colorectal cancer or malignant melanoma. BRCA1 and CCND1 genotyping by iFRET probe showed 100% agreement with Sanger sequencing and other validated methods. A combination of iFRET and high-resolution melting analysis (HRMA) detected a spectrum of six different mutations in the KRAS gene and three different mutations in the BRAF gene. Due to anallele enrichment effect, the sensitivity of mutation detection of iFRETHRMA genotyping and sequencing of iFRETHRMA PCR products was significant, increasing from 1.5% to 6.2%, respectively. The technique presented in this article is a useful and cost-effective method for the detection of both germline and somatic mutations.
Assuntos
Transferência Ressonante de Energia de Fluorescência , Técnicas de Genotipagem , Alelos , Sequência de Bases , Ciclina D1/genética , Análise Mutacional de DNA , Genes ras , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-raf/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Temperatura de TransiçãoRESUMO
The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial ovarian cancer and 321 women with borderline epithelial ovarian tumors was carried out to test the association between tag single-nucleotide polymorphisms (tSNPs) (n=58) in this pathway and risk of ovarian cancer. We found no association between variation in IGF1, IGFBP1 or IGFBP3 and risk of invasive disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at P<0.05 and followed-up one of the associated SNPs. We conducted genotyping in 3216 additional non-Hispanic white cases and 5382 additional controls and were able to independently replicate our initial findings. In the combined set of studies, rs4320932 was associated with a 13% decreased risk of ovarian cancer per copy of the minor allele carried (95% confidence interval 0.81-0.93, P-trend=7.4 × 10(-5)). No heterogeneity of effect across study centers was observed (p(het)=0.25). IGF2 is emerging as an important gene for ovarian cancer; additional genotyping is warranted to further confirm these associations with IGF2 and to narrow down the region harboring the causal SNP.
Assuntos
Fator de Crescimento Insulin-Like II/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Carcinoma Epitelial do Ovário , Estudos de Casos e Controles , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença , Genótipo , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Fatores de Risco , População Branca/genéticaRESUMO
Among many alterations within the TP53 gene the rs1042522 (C72G, p.Pro72Arg) has been associated with numerous cancers , however the results differ between populations for opposite Pro or Arg alleles. Similar thus inconclusive results are observed in ovarian cancer, which may suggest that the rs1042522 does not influence ovarian carcinogenesis directly, but might be linked to another pathogenic alteration. WRAP53 which overlaps the TP53 is required to maintain normal levels of p53 upon DNA damage, but also when altered may independently increase the risk of cancer. To evaluate the association between three SNPs located in WRAP53-TP53 region: rs1042522, rs2287497, rs2287498 and ovarian cancer risk in Polish population we genotyped 626 cases and 1,045 healthy controls. Our results provide the evidence for an association between studied SNPs and a risk of invasive ovarian cancer in Poland. We found that CC homozygotes in rs1042522 were more frequent in cancers when compared to controls (OR = 1.46, p = 0.03). Similarly in WRAP53 both TT homozygotes in rs2287497 (OR = 1.95, p = 0.03) and AA homozygotes in rs2287498 (OR = 2.65, p = 0,01) were more frequent among cases than healthy individuals. There is also a suggestive evidence that specific homozygosity of studied SNPs in TP53-WRAP53 region is significantly overrepresented in ovarian cancer patients. In conclusion SNPs in WRAP53 (rs2287497 and rs2287498) have stronger association with an ovarian cancer risk than rs1042522 in TP53.
Assuntos
Estudos de Associação Genética , Variação Genética , Neoplasias Ovarianas/genética , Telomerase/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Chaperonas Moleculares , Razão de Chances , Polônia , Risco , Proteína Supressora de Tumor p53/genéticaRESUMO
Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15-1.74) and the HomOR = 1.63 (1.10-1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80-1.17), HomOR = 0.74 (0.58-0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.
Assuntos
Predisposição Genética para Doença/genética , Neoplasias Epiteliais e Glandulares/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Alelos , Proteínas de Ciclo Celular , Feminino , Humanos , Perda de Heterozigosidade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Hereby we present a case of a pregnancy in which careful dysmorphology of the fetus in subsequent sonographic evaluation resulted in detection of a very rare anomaly. It allowed explanation of the fetal phenotype, compared then with that of the newborn and estimation of genetic risk for the next pregnancies in this family.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Nascido Vivo , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Gravidez , Doenças Raras , Ultrassonografia Pré-NatalRESUMO
The aim of the study is to verify the hypothesis that genetic polymorphisms are associated with the predisposition to all malignancies. Using as a model breast cancers from the homogenous Polish population (West Pomeranian region) after stratification of 977 patients by age at diagnosis (under 51 years and above 50 years) and by tumour pathology (ductal cancers--low and high grade, lobular cancers, ER-positive/negative) we tested this hypothesis. Altogether 20 different groups of breast cancer cases have been analyzed. The results were compared to a group of unaffected controls that were matched by age, sex, ethnicity and geographical location and originated from families without cancers of any site among relatives. Molecular alterations selected for analyses included those which have been previously recognized as being associated with breast cancer predisposition. Statistically significant differences between the breast cancer cases and controls were observed in 19 of the 20 analyzed groups. Genetic changes were present in more than 90% of the breast cancer patients in 18 of 20 groups. The highest proportion of cases with constitutional changes-99.3% (139/140) was observed for lobular cancers. The number and type of genetic marker and/or the level of their association with the specific cancer predisposition was different between groups. Markers associated with majority of groups included: BRCA1, CHEK2, p53, TNRnTT, FGFRnAA, XPD CC/AA and XPD GG. Some markers appeared to be group specific and included polymorphisms in CDKN2A, CYP1B1, M3K nAA, and RS67.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fatores Etários , Biomarcadores Tumorais/análise , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Polônia , Polimorfismo GenéticoRESUMO
UNLABELLED: In the following paper we have presented the results of non-invasive and invasive prenatal diagnostic tests performed on 2285 pregnant women from the Western-Pomeranian Region between 2005 and 2006. MATERIAL AND METHODS: Retrospective analysis of screening tests on 2285 pregnant women. Medical history, including age, weight, familial data pedigrees up to third degree relatives, accompanying diseases, gestational complications in the family, type, dosage and period of any drugs intake, was obtained. Sonographic screening and evaluation of maternal serum PAPP-A and betaHCG levels. RESULTS: Screening tests identified 4.5% high-risk pregnancies in this group. 69% of the patients consented to invasive diagnosis. As a result, genetic anomalies were detected in 43.7% of cases. Significant differences in betaHCG levels correlated with oral gestagens intake and place of residence (coastal areas). CONCLUSION: Broad use of certified non-invasive methods of prenatal screening allow substantial reduction of invasive procedures with high levels of positive prediction. Medical drugs intake as well as place of inhabitation may influence on free betaHCG levels.
Assuntos
Programas de Rastreamento/estatística & dados numéricos , Anamnese/estatística & dados numéricos , Complicações na Gravidez/epidemiologia , Diagnóstico Pré-Natal/estatística & dados numéricos , Anormalidades Múltiplas/diagnóstico , Adulto , Gonadotropina Coriônica Humana Subunidade beta/sangue , Feminino , Aconselhamento Genético/estatística & dados numéricos , Humanos , Polônia/epidemiologia , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/prevenção & controle , Gravidez de Alto Risco/sangue , Proteína Plasmática A Associada à Gravidez/metabolismo , Cuidado Pré-Natal/estatística & dados numéricos , Estudos Retrospectivos , Saúde da Mulher , Adulto JovemRESUMO
OBJECTIVE: There is an increasing evidence that genetic factors play a role in the etiology of malignant tumors. Mutations of BRCA1 and BRCA2 genes are responsible for an increased risk of ovarian cancer. The role of mutations in NOD2 gene in this type of neoplasm is still under investigation. THE AIM: The aim of this study was to determine: 1. incidence of NOD 2 3020insC constitutional mutation in a group of consecutive women with ovarian cancer, 2. risk of developing ovarian cancer in patients with NOD2 gene mutation, 3. clinical and pathological features of ovarian cancer in NOD2 gene mutation carriers. PATIENTS AND METHODS: Clinical and pathological data were collected from 257 non-selected patients with primary epithelial ovarian cancer. The researches identified NOD2 3020insC gene mutation. On the basis of patient source documentation we obtained the data concerning the age of patients at diagnosis, histopathological recognition, FIGO stage and morphological grade G. RESULTS: 19 out of 257 women were identified with germ-line 3020insC mutation of NOD2 gene (7.39%). An increased risk of ovarian cancer in NOD2 mutation carriers was not revealed (OR=1.01; p=0.928; 95% Cl=0.61-1.66). The mean age at diagnosis of patients with NOD2 mutation was 54.8 (SD=9.9), while for non-carriers it was 53.2 (SD=10.2). The difference between these frequencies was statistically irrelevant (p=0.550). Clinical and pathological profile of ovarian cancer was made. We assessed the following features: age at disease onset, histopathology, FIGO stage and morphological grade G. For NOD2 mutation carriers no statistically significant features of ovarian cancer were revealed. CONCLUSION: 1. Despite high frequency of constitutional mutations occurrence in NOD2 gene in women with ovarian cancer, genetic testing seem not to be justified in all women diagnosed with this disease. 2. Due to a lack of increased risk of ovarian cancer in NOD2 gene mutation carriers, proceedings for them may not differ from recommendations for general population. 3. It is difficult to determine characteristic clinical and pathological features of ovarian cancer for NOD2 gene mutation carriers.
Assuntos
Genes BRCA1 , Genes BRCA2 , Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Epiteliais e Glandulares/genética , Proteína Adaptadora de Sinalização NOD2 , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Adulto , Alelos , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos/estatística & dados numéricos , Humanos , Incidência , Pessoa de Meia-Idade , Polônia/epidemiologiaRESUMO
In 1999 it has been recognized that 3 BRCA1 abnormalities - 5382insC, C61G and 4153delA - constitute almost 90% of all germline mutations of this gene in Poland. Due to the above findings we started performing the cheap and quick large scale testing for BRCA1 mutations and, these days, we have almost 4,000 carriers diagnosed and under direct or indirect supervision what is probably the largest number in the world. Additionally, the above results pushed us to hypothesize that genetic homogeneity will be seen in Poland in studies of other genes. Actually, the next studies allowed us to identify genes / changes associated with moderate / low breast cancer risk and showed, similarly to BRCA1, high level of genetic homogeneity. This series included BRCA2, C5972T, CHEK2 del5395; 1100delC, I157T or IVS2 + 1G > A, CDKN2A (p16) A148T, XPD Asp312Asn and Lys751Gln, CYP1B1 R48G, A119S and L43V. The results of the above studies led us in 2004 already to hypothesize that >90% of all cancers have genetic (constitutional) background. Two years later we were able to show a panel of markers covering 92% of consecutive breast cancers in Poland, and we formulated the hypothesis that all cancers have a genetic background. These days we are demonstrating for the first time that genetic components to malignancy play a role in all cancers. We are presenting it on examples of late-onset breast cancers from Poland, but it seems to be justified to expect that similar results can be achieved from other malignancies.
Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/genética , Hidrocarboneto de Aril Hidroxilases , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Quinase do Ponto de Checagem 2 , Citocromo P-450 CYP1B1 , Sistema Enzimático do Citocromo P-450/genética , Feminino , Efeito Fundador , Genes BRCA1 , Genes BRCA2 , Genes p16 , Predisposição Genética para Doença , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Mutação , Razão de Chances , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Polônia/epidemiologia , Proteínas Serina-Treonina Quinases/genética , Medição de Risco , Fatores de Risco , Proteína Grupo D do Xeroderma Pigmentoso/genéticaRESUMO
In this study we determined in what proportion of consecutive malignant melanoma (MM) cases the 657del5 mutation of exon 6 of the NBS1 gene can be detected and whether it is associated with the occurrence of MM. Two groups of patients were studied: a series of 80 consecutive patients with histologically confirmed MM of the skin diagnosed in the city of Szczecin, Poland, and a series of 530 consecutive individuals selected at random by family doctors from the city of Szczecin. Molecular examination included an allele-specific polymerase chain reaction assay for the NBS1 founder mutation (657del5), genomic sequencing, loss of heterozygosity analysis using CA-repeat microsatellite markers, and haplotype analysis. The NBS1 founder mutation was detected in two of the 80 (2.5%) MM cases and in three of the 530 individuals (0.6%) from the general population. The difference was not statistically significant. However, examination of tumorous DNA from the patients with MM and NBS1 mutation revealed loss of heterozygosity in both cases. Haplotype analysis revealed that allellic loss affects wild-type alleles. Breast cancer was found in second-degree relatives of both MM probands with NBS1 mutations. One of these probands was simultaneously affected with breast cancer. It seems that the 657del5 mutation of exon 6 of NBS1 gene may be responsible for the occurrence of a small proportion of MM patients, characterized by the occurrence of breast cancer among their relatives.
Assuntos
Proteínas de Ciclo Celular/genética , DNA de Neoplasias/análise , DNA de Neoplasias/genética , Mutação em Linhagem Germinativa/genética , Melanoma/genética , Proteínas Nucleares/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Comorbidade , Feminino , Efeito Fundador , Genética Populacional , Haplótipos/genética , Humanos , Perda de Heterozigosidade/genética , Masculino , Melanoma/epidemiologia , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Polônia/epidemiologia , Prevalência , Distribuição Aleatória , Análise de Sequência de DNA , Neoplasias Cutâneas/epidemiologiaRESUMO
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10â»4 and P = 6 × 10â»4, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10â»9 and P = 4 × 10⻹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cromossomos Humanos Par 19/genética , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Neoplasias Ovarianas/genética , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Perfilação da Expressão Gênica , Genótipo , Humanos , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Ovário/patologia , Polimorfismo de Nucleotídeo Único/genética , Células Tumorais CultivadasRESUMO
Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and approximately 2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10(-8)). The most significant SNP (rs3814113; P = 2.5 x 10(-17)) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79-0.86, P(trend) = 5.1 x 10(-19)). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73-0.81, P(trend) = 4.1 x 10(-21)).
Assuntos
Cromossomos Humanos Par 9 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Ovarianas/genética , Alelos , Austrália , Sequência de Bases , Estudos de Casos e Controles , Mapeamento Cromossômico , Intervalos de Confiança , Europa (Continente) , Feminino , Frequência do Gene , Genótipo , Haplótipos , Heterozigoto , Homozigoto , Humanos , Desequilíbrio de Ligação , Dados de Sequência Molecular , Razão de Chances , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Estados Unidos , População Branca/genética , População Branca/estatística & dados numéricosRESUMO
Several genome-wide searches for common cancers have lead to the identification of a small number of loci that harbor low-risk cancer susceptibility markers. One marker, rs6983267 on chromosome 8q24, has been linked to both colon and prostate cancer, and is therefore a good candidate for a multicancer susceptibility marker. To determine the range of cancer sites associated with rs6983267, we genotyped 7,665 cases of cancer, representing 11 common cancer sites, and 1,910 controls. A significant odds ratio (OR) was observed for prostate cancer for carriers of genotype GG [OR, 1.77; 95% confidence interval (CI), 1.47-2.13]. The homozygote OR was higher for tumors with Gleason score 8 to 10 (OR, 1.94; 95% CI, 1.18-3.20) than for tumors with Gleason score 7 and below (OR, 1.65; 95% CI, 1.31-2.08). Significantly elevated (homozygote) ORs were observed for 4 other cancer sites, including colon (OR, 1.36; 95% CI, 1.08-1.72), kidney (OR, 1.52; 95% CI, 1.12-2.05), thyroid (OR, 1.37; 95% CI, 1.02-1.82), and larynx (OR, 1.39; 95% CI, 1.02-1.90). Information was available on family histories of cancer for eight sites. For six of the eight sites (prostate, breast, bladder, larynx, lung, and kidney), the homozygote ORs were higher for cases with a positive family history (at least one first-degree with any cancer) than for cases with unaffected first-degree relatives. Our results suggest that the range of cancers associated with the rs6983267 marker might be larger than previously thought.
Assuntos
Cromossomos Humanos Par 8 , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Marcadores Genéticos/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
We sought to examine the association between MC1R variants and the risk of melanoma and breast cancer in Polish population. We also determined the prevalence of compound heterozygous carriers of MC1R and CDKN2A (A148T) variants. We examined 500 unselected melanoma cases, 511 consecutive invasive breast cancer patients, 800 newborns, 421 healthy adults matched for sex and age with the melanoma cases and 511 healthy women matched for sex and age with the breast cancer cases. A statistically significant association of all 4 MC1R variants with the melanoma risk was found. For the R151C variant p value was 0.000008 and odds ratio 2.9; for the V60L variant p value was 0.007 and OR 1.78; for the R160C p was 0.006 and OR 1.76; for the R163Q p was 0.015 and odds ratio 2.1. None of the compound heterozygotes were significantly over-represented among any of the melanoma cases, the highest OR (4.2) observed in patients harbouring the A148T variant in CDKN2A and the R151C variant in MC1R. Positive association was found between carrying any of the MC1R variants and (i) increased occurrence of melanoma among I degree relatives of the carriers; (ii) increased occurrence of melanoma on UV-non-exposed skin areas. We also observed a tendency of increased risk of multiple melanomas among carriers of MC1R variants. The haplotype analysis demonstrates that MC1R variants do not co-occur in cis, compound carriers have both alleles affected. We found no association with the MC1R variants and breast cancer risk. In conclusion, the results of this population-based study show herein that MC1R variants are associated with increased melanoma risk in the Polish population. The risk of disease seems to be increased additively for patients harbouring also the CDKN2A common variant A148T.
Assuntos
Neoplasias da Mama/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Melanoma/genética , Receptor Tipo 1 de Melanocortina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Estudos de Casos e Controles , Primers do DNA , Feminino , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-IdadeRESUMO
The population frequencies of the CDKN2A common variants remain undetermined. In Poland, there is a common variant of the CDKN2A: an alanine to threonine substitution (A148T), which has been detected in other populations. We have recently showed that it is significantly overrepresented among Polish melanoma patients when compared to general population. Herein, we ascertained the prevalence of the A148T variant in 3,583 unselected cancer cases and 3,000 random control subjects from the same Polish population. We evaluated eleven different malignancies, representing the majority of all common cancer sites. Positive association with A148T variant was observed for lung cancer (OR, 2.0; p = 0.0052). A similar trend, although nonsignificant after the Bonferroni correction, was observed for colorectal cancer (OR, 1.5; p = 0.5499). These results suggest that A148T variant may be associated with a multi-organ cancer risk in the Polish population.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Genes p16 , Neoplasias/epidemiologia , Neoplasias/genética , Adulto , Idoso , Alanina , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Feminino , Variação Genética , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polônia/epidemiologia , Prevalência , Medição de Risco , Fatores de Risco , TreoninaRESUMO
Ovarian carcinoma is the fourth most common cause of cancer death in women. The cause and pathogenesis of this disease has remained obscure. Galactose, the hydrolyzing product of the milk sugar lactose, has been hypothesized to be toxic to ovarian epithelial cells and consumption of dairy products and lactase persistence has been suggested to be a risk factor for ovarian carcinoma. In adults, downregulation of lactase depends on a variant C/T-13910 at the 5' end of the lactase gene. To explore whether lactase persistence is related to the risk of ovarian carcinoma we determined the C/T-13910 genotype in a cohort of 782 women with ovarian carcinoma. The C/T-13910 genotype was defined by solid phase minisequencing from 327 Finnish, 303 Polish, 152 Swedish patients and 938 Finnish, 296 Polish and 97 Swedish healthy individuals served as controls. Lactase persistence did not associate significantly with increased risk for ovarian carcinoma in the Finnish (odds ratio [OR]=0.77, 95% confidence interval [CI]=0.57-1.05, p=0.097), in the Polish (OR=0.95, 95% CI=0.68-1.33, p=0.75), or in the Swedish populations (OR=1.63, 95% CI=0.65-4.08, p=0.29). Our results do not support the hypothesis that lactase persistence increases the ovarian carcinoma risk. On the contrary, lactase persistence may decrease the ovarian carcinoma risk at least in the Finnish population.
Assuntos
Adenocarcinoma Mucinoso/genética , Carcinoma Endometrioide/genética , Cistadenocarcinoma Seroso/genética , Predisposição Genética para Doença , Lactase/genética , Neoplasias Ovarianas/genética , Adenocarcinoma Mucinoso/enzimologia , Adenocarcinoma Mucinoso/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/enzimologia , Carcinoma Endometrioide/epidemiologia , Estudos de Coortes , Cistadenocarcinoma Seroso/enzimologia , Cistadenocarcinoma Seroso/epidemiologia , Feminino , Finlândia/epidemiologia , Genótipo , Humanos , Lactase/deficiência , Lactase/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/enzimologia , Neoplasias Epiteliais e Glandulares/epidemiologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/epidemiologia , Polônia/epidemiologia , Reação em Cadeia da Polimerase , Fatores de Risco , Suécia/epidemiologiaRESUMO
The NOD2 gene has been associated with susceptibility to Crohn's disease and individuals with Crohn's disease are at increased risk for cancer at a number of organ sites. We studied the association between the 3020insC allele of the NOD2 gene and cancer among 2604 cancer patients and 1910 controls from Poland. Patients were diagnosed with one of twelve types of cancer in the Szczecin region between 1994 and 2004. Significant associations were found for colon cancer (OR = 1.8; 95% CI 1.2 to 2.6), for lung cancer (OR = 1.7; 95% CI = 1.1 to 2.5) and for ovarian cancer (OR = 1.6; 95% CI 1.1 to 2.3). In addition, a significant association was found for early-onset laryngeal cancer (OR = 2.9; 95% CI 1.4 to 6.2) and for breast cancer in the presence of DCIS (OR = 2.1 95% CI = 1.2 to 3.6). The NOD2 3020insC allele is relatively common (in Poland 7.3% of individuals) and may be responsible for an important fraction of cancer cases. We estimate that the lifetime cancer risk among carriers of this allele is 30% higher than that of individuals with two wild-type alleles.
RESUMO
In this report the proportion of consecutive and familial breast cancer cases harboring the 657del5 of exon 6 of the NBS1 gene was determined to assess whether it is associated with the increased risk of breast cancer development. The study consisted of 3 groups of patients: a series of consecutive 150 patients with histologically confirmed breast cancer, diagnosed under the age of 50 in the city of Szczecin; a series of 80 breast cancer patients with a family history of breast cancer in their first-degree relatives; and a series of 530 consecutive individuals without the diagnosis of breast cancer selected at random by family doctors from the city of Szczecin. Molecular examination included allele-specific PCR assay for the common Slavic NBS1 mutation (657del5), LOH analysis using denucleotide CA repeat microsatellite markers, haplotype analysis and sequencing. The NBS1 founder mutation was detected in 2 of 150 (1.3%) consecutive breast cancer cases diagnosed under the age of 50 years; in 3 of 80 familial breast cancer cases (3.7%); and in 3 of 530 individuals (0.6%) from the general population. Examination of tumor DNA from patients with the NBS1 mutation (groups A and B) revealed loss of heterozygosity (LOH) in all cases. Additional haplotype analysis revealed that allelic loss affects specifically wild-type alleles. The majority of probands with breast cancer and the NBS1 mutation had a positive family history of breast cancer in their first-degree relatives. It appears that the 657del5 mutation in exon 6 of the NBS1 gene is responsible for the occurrence of a small but significant proportion of familial breast cancer patients.