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Ming Wu Shuho Semba Naohide Oue Nobunao Ikehara Wataru Yasui Hiroshi Yokozaki 《Gastric cancer》2004,7(4):246-253
Background The BRAF and K-ras genes are the most frequently mutated oncogenes in various human malignancies. We examined BRAF and K-ras mutations in human gastric cancer, and investigated their relationship with microsatellite instability (MSI) and the hypermethylation of promoter regions in hMLH1 and O
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-methylguanine DNA methyltransferase (MGMT).Methods Sixteen gastric cancer cell lines and 62 gastric cancer tissue samples were screened for BRAF and K-ras mutations by direct sequencing. We also performed a microsatellite assay and investigated methylation status in the promoter regions of hMLH1 and MGMT.Results mutation was not found in any of the cancer cell lines examined. One (1.6%) cancer tissue sample showed a point mutation in the BRAF gene (GT_G GA_G; V599E). K-ras mutation (GG_T GA_T, G12D) was detected in five (31%) gastric cancer cell lines and in 1 (1.6%) gastric cancer tissue sample. In the gastric cancer tissue samples examined, MSI was detected in 23 (37%) samples. Hypermethylated promoter regions in hMLH1 and MGMT, respectively, were detected in 6 (10%) and 13 (21%) gastric cancer tissue samples. Microsatellite stable (MSS) tumors showed frequent lymphatic invasion (P = 0.050).Conclusion Although BRAF mutation has been reported in a variety of other human cancers, it is a rare event in the carcinogenesis and progression/development of gastric cancer. 相似文献
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Sliwinski T Krupa R Majsterek I Rykala J Kolacinska A Morawiec Z Drzewoski J Zadrozny M Blasiak J 《Breast cancer research and treatment》2005,94(2):105-109
Summary We performed a case-control study (150 cases and 150 controls) to test the association between three polymorphisms in BRCA2 and RAD51 genes and breast cancer risk. Genotypes were determined in DNA from blood cells by PCR–RFLP. Cancer occurrence was strongly
associated with the BRCA2 Met/1915Thr homozygous polymorphic variants, whereas heterozygous variant was associated with significant reduction in breast
cancer risk. Gene-gene interaction between the BRCA2-Met1915Thr Thr/Thr and BRCA2-Met784Val Met/Met homozygous variants increased the risk. Therefore, the Met1915Thr polymorphism in the BRCA2 gene may be considered as an independent marker of breast cancer. 相似文献
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<Emphasis Type="Italic">Abstracts</Emphasis> 总被引:10,自引:0,他引:10
Summary Epidermal growth factor receptor (EGFR) overexpression correlates with both loss of estrogen receptor (ER) and poor prognosis in breast cancer. Interestingly, in normal breast EGFR appears to be expressed more frequently than in malignant tissue, and there may be a different relationship between ER and EGFR. A variety of cellular regulators, such as EGF, TGF, phorbol esters, and steroid hormones, are capable of altering the level of EGFR expression in breast cells. However, much work remains to be done on the mechanistic details of EGFR regulation in this disease. The significance of EGFR as an oncogene in breast cancer is compounded by its potential interactions with other oncogenes such as c-erbB-2 and c-myc. Additionally, several recent studies have placed EGFR prominently in the signal transduction pathway, demonstrating that the EGFR-ligand system may play important roles throughout the course of malignant progression in breast cancer. 相似文献
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Taila Hartley Luca Cavallone Nelly Sabbaghian Rachel Silva-Smith Nancy Hamel Olga Aleynikova Erika Smith Valerie Hastings Pedro Pinto Marc Tischkowitz Eva Tomiak William D Foulkes 《Hereditary cancer in clinical practice》2014,12(1):19
Background
PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient.Methods
The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario.Results
We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del – major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations.Conclusions
PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families. 相似文献6.
Purnomosari D Pals G Wahyono A Aryandono T Manuaba TW Haryono SJ van Diest PJ 《Breast cancer research and treatment》2007,106(2):297-304
Specific mutations in BRCA1 and BRCA2 genes have been identified in specific populations and ethnic groups. However, little is known about the contribution of BRCA1 and BRCA2 mutations to breast cancers in the Indonesian population. One hundred-twenty moderate to high risk breast cancer patients were tested using PCR-DGGE, and any aberrant band was sequenced. Multiplex ligation-dependent probe amplification (MLPA) was performed on all samples to detect large deletions in the two genes. Twenty-three different mutations were detected in 30 individuals, ten were deleterious mutations and 20 were "unclassified variants" with uncertain clinical consequences. Three of seven (c.2784_2875insT, p.Leu1415X and del exon 13-15) and two of four (p.Glu2183X and p.Gln2894X) deleterious mutations that were found in BRCA1 and BRCA2 respectively, are novel. Several novel, pathogenic BRCA1 and BRCA2 germline mutations are found in early onset Indonesian breast cancer patients, these may therefore be specific for the Indonesian population. 相似文献
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Katsumata K Sumi T Tomioka H Aoki T Koyanagi Y 《International journal of clinical oncology / Japan Society of Clinical Oncology》2003,8(6):352-356
Background We investigated the influence of genes on the apoptosis of colorectal tumor cells, based on DNA and mRNA kinetics.Methods In 30 colorectal cancer patients, we examined the mRNA expression of p53, bax, bcl-2, and p21
WAF1
, and we also investigated the development of tumor cell apoptosis, using a terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method.Results TUNEL-positive cells showed a positive correlation with bax (P = 0.010) and a negative correlation with p21 (P = 0.04). We also investigated the relationship between p53 point mutation, p21 immunostaining degree, and apoptosis, based on DNA ladder expression. A remarkable correlation (P = 0.0090) was found between p21 and apoptosis.Conclusions The present study findings suggest that tumor cell apoptosis is (1) strongly inhibited by p21, (2) induced by bax, and (3) influenced by bcl-2, which, presumably, inhibits tumor cell apoptosis. 相似文献
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Syamala VS Sreeja L Syamala V Raveendran PB Balakrishnan R Kuttan R Ankathil R 《Familial cancer》2008,7(3):213-220
Identifying genes associated with familial inheritance of breast cancer continues to be a major goal of current research as the known high penetrance genes could be attributable for only a small percentage of the risk. So, it is hypothesized that the low penetrance genes may also modify the risk for familial breast cancer. In the present case-control study, undertaken to examine the influence of polymorphisms of GSTs in familial and sporadic breast cancer susceptibility, 597 women including 222 sporadic breast cancer patients, 125 familial breast cancer patients and 250 females with no history of cancer as controls were genotyped by PCR based methods. Odds Ratios (ORs) and 95% Confidence Intervals (95%CIs) were calculated by unconditional logistic regression adjusted to age. Interestingly, GSTM1 deletion was found to be significantly associated only with familial breast cancer (OR = 2.0; 95%CI = 1.252-3.128) while GSTT1 was associated only with sporadic breast cancer (OR = 2.3; 95%CI = 1.336-3.970). GSTP1 Ile(105)Val polymorphism was associated neither with sporadic nor familial breast cancer susceptibility (P value > 0.05). The GST genotypes did not have any effect on the survival of both familial and sporadic breast cancer patients. However, familial breast cancer patients with GSTM1 null genotype had a relative risk of 0.42 (95%CI = 0.18-0.97) for an advanced disease stage. The results indicate that, in addition to the known high penetrance genes, certain low penetrance genes may also play a role, in the familial inheritance of breast cancer. It is also noticed that all the polymorphisms associated with sporadic breast cancer are not associated with familial breast cancer. 相似文献
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Slattery ML Sweeney C Wolff R Herrick J Baumgartner K Giuliano A Byers T 《Breast cancer research and treatment》2007,104(2):197-209
Background An insulin-related pathway to breast cancer has been hypothesized.
Methods We examine the 19 CA repeat of the IGF1 gene, the -202 C > A IGFBP3, the G972R IRS, and the G1057D IRS2 polymorphisms among 1,175 non-Hispanic white (NHW) and 576 Hispanic newly diagnosed breast cancer cases and 1,330 NHW and
727 Hispanic controls living in Arizona, Colorado, New Mexico, and Utah.
Results Among post-menopausal women not recently exposed to hormones, not having the 19 CA repeat of IGF1 gene was associated with breast cancer among NHW women [odds ratio (OR) 2.14, 95% confidence interval (CI) 1.21–3.79] and
having an R allele of G972R IRS1 increased breast cancer risk among Hispanic women (OR 2.70, 95% CI 1.13–6.46). Among post-menopausal Hispanic women recently
exposed to hormones the A allele of the -202 C > A IGFBP3 polymorphism increased risk of breast cancer (OR 1.57, 95% CI 1.06–2.33). The IGF1 19 CA repeat polymorphism interacted with hormone replacement therapy (HRT) among NHW post-menopausal women; women who had
the 19/19 IGF1 genotype were at reduced risk of breast cancer (OR 0.64, 95% CI 0.47–0.88) if they did not use HRT. We also observed interaction
between body mass index and IGF1 19 CA repeat (p=0.06) and between weight gain and the -202 C > A IGFBP3 polymorphism (p=0.05) in NHW post-menopausal women not recently exposed to hormones.
Conclusions Our data suggest that associations between insulin-related genes and breast cancer risk among women living in the Southwestern
United States may be dependent on estrogen exposure and may differ by ethnicity. 相似文献
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Slattery ML Sweeney C Herrick J Wolff R Baumgartner K Giuliano A Byers T 《Breast cancer research and treatment》2007,105(3):327-335
Estrogen and androgen are thought to influence breast cancer risk. The actions of estrogens and androgens are mediated through
the respective receptors. In this study we examine the association of the Xb1 polymorphism of estrogen receptor alpha (ESR1) and the CAG repeat of the androgen receptor (AR) gene with risk of breast cancer in women living in the Southwestern United States. Cases (N = 1169 non-Hispanic white (NHW) and 576 Hispanic) with first primary breast cancer were matched to controls (N = 1330 NHW and 725 Hispanic) by location (Arizona, Colorado, New Mexico, or Utah) and 5-year age group. Detailed weight history
was obtained along with other diet and lifestyle information. Neither the ESR1 nor the AR polymorphisms evaluated were associated independently with breast cancer risk in either Hispanic or NHW women. However, among
Hispanic women taking hormone replacement therapy (HRT), there was a 40% reduced risk of breast cancer among women with an
X allele (95% CI 0.39, 0.94). Also Hispanic women with the xx genotype had a significant reduced risk of breast cancer in
the presence of weight gain prior to age 50 if post-menopausal or prior to diagnosis if pre-menopausal (P interaction 0.02 and <0.01 respectively). These results suggest differences in risk factors for NHW and Hispanic women. However,
they provide only minor support for the role of the AR and ESR1 gene in the etiology of breast cancer. 相似文献
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Rashid MU Torres D Zaidi A Rasheed F Sultan F Shakoori AR Amin A Hamann U 《Breast cancer research and treatment》2008,107(1):155-156
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Sillanpää P Heikinheimo L Kataja V Eskelinen M Kosma VM Uusitupa M Vainio H Metsola K Hirvonen A 《Breast cancer research and treatment》2007,104(3):287-297
We investigated the associations between two CYP1A1 polymorphisms (Ile462Val and Thr461Asn) and one CYP1B1 polymorphism (Leu432Val) and breast cancer risk. The study population consisted of 483 breast cancer patients and 482 healthy population controls,
all of homogenous Finnish origin. No statistically significant overall associations were found between the CYP1A1 and CYP1B1 genotypes and breast cancer risk. However, a significant increase in the breast cancer risk was seen for women who had smoked
1–9 cigarettes/day and carried the CYP1B1
432Val allele; the OR was 2.6 (95% CI 1.07–6.46) for women carrying the Leu/Val genotype and 5.1 (95% CI 1.30–19.89, P for trend 0.005) for women with the Val/Val genotype compared to similarly smoking women homozygous for the 432Leu allele. Furthermore, when CYP1B1 genotypes were combined with the previously analyzed N-acetyl transferase (NAT2) genotypes, a significant increase in breast cancer risk was found among women who had at least one CYP1B1
432Val allele together with the NAT2 slow acetylator genotype (OR 1.52; 95% CI 1.03–2.24) compared to women carrying a combination of CYP1B1
Leu/Leu and NAT2 rapid acetylator genotypes. This risk was seen to be confined to ever smokers; the OR was 2.46 (95% CI 1.11–5.45) for ever
smokers carrying at least one CYP1B1
432Val allele together with the NAT2 slow acetylator genotype compared to ever smokers with the CYP1B1
Leu/Leu and NAT2 rapid acetylator genotype combination. Our results suggest that the CYP1B1 polymorphism may be an important modifier of breast cancer risk in Finnish Caucasian women who have been exposed to tobacco
smoke and/or carry the NAT2 slow acetylator genotype. 相似文献
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Scrideli CA Carlotti CG Mata JF Neder L Machado HR Oba-Sinjo SM Rosemberg S Marie SK Tone LG 《Journal of neuro-oncology》2007,83(3):233-239
Overexpression of the EGFR, IGFBP-2 and HIF-2A genes has been observed in high-grade astrocytomas and these genes seem to be functionally related to one another. This study
aimed to define the profile of their expressions, interactions and correlation with clinical features and prognostic significance
in microdissected tumor samples from 84 patients with astrocytomas of different grades and from 6 white matter non-neoplasic
brain tissue sample. EGFR, IGFBP-2 and HIF-2A gene expression levels were analyzed by quantitative real-time PCR and differed significantly between grades I–IV astrocytic
tumors (P < 0.0001, P < 0.0001 and P: 0.0013, respectively) when analyzed by the Kruskal–Wallis test. Grade I astrocytomas presented gene expression levels similar
to those encountered in samples of microdissected white matter of non-neoplastic brain tissue Overexpression of the EGFR, IGFBP-2 and HIF-2A genes was significantly associated with lower 2-year survival (P: 0.009, P: 0.0002 and P: 0.008, respectively). Co-overexpression of these genes was strongly associated with high-grade gliomas and lower survival
in univariate (P < 0.0001) and multivariate (P: 0.009) analysis, suggesting that the co-expression of the EGFR/IGFBP-2/HIF-2A pathway genes may have a more important clinical and biological impact than the expression of each individual gene alone.
These data support the existence of a common pathway involving these genes that could contribute to the design of new target
treatments. 相似文献
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Screening for exonic copy number mutations at <Emphasis Type="Italic">MSH2</Emphasis> and <Emphasis Type="Italic">MLH1</Emphasis> by MAPH 总被引:1,自引:0,他引:1
Akrami SM Dunlop MG Farrington SM Frayling IM MacDonald F Harvey JF Armour JA 《Familial cancer》2005,4(2):145-149
Background: Exonic deletions in MSH2 and MLH1 are significant contributors to the mutation spectrum in HNPCC, and heterozygous changes in exon copy number are not detected by conventional mutation screening methods. Aims: We aimed to develop methods for screening copy number changes in all the exons of the MLH1 and MSH2 genes using a single multiplex amplifiable probe hybridisation (MAPH) assay. Methods: We developed a probe set consisting of probes from the 19 exons of MLH1 and 16 exons of MSH2, and 3 control probes, and applied it to screening for deletions and duplications using fluorescent detection of amplified fragments. Results: We tested 73 DNA samples from controls and 50 from HNPCC patients in whom no point mutations had been found, and detected 10 copy number changes among the patient samples. A deletion of about 1.4 kb including exon 3 of MSH2 was confirmed by amplification of a junction fragment, and was shown to be the result of an unequal recombination between intronic Alu elements. Conclusions: MAPH can detect exonic copy number changes in MLH1 and MSH2 in DNA from HNPCC patients. Since finding an exonic deletion or duplication makes full sequence analysis unnecessary, it may be most cost-effective to pre-screen samples by MAPH or MLPA before screening for point mutations. 相似文献
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A high frequency of skewed X-chromosome inactivation has been reported in peripheral blood lymphocytes from early onset breast
cancer or invasive ovarian cancer patients. Recent findings have shown that breast and ovarian carcinoma cells from BRCA1 mutation carrier women lack the hallmarks of inactive X chromatin structure. These observations suggested that loss of functional
BRCA1 in female cells may perturb the process of X inactivation and have lead us to the hypothesis that analysis of skewing
could be used as a predictive test for BRCA1 germline mutation in lymphocytes from breast cancer patients. In the present study, we have compared the X inactivation pattern
in lymphoblastoid cell lines from 38 females carrying heterozygous BRCA1 mutation to 41 controls. X inactivation analysis was assessed on the polymorphic CAG repeat within the human androgen receptor
gene. Our observations rule out an effect of a monoallelic BRCA1 germline mutation on the choice of inactivated chromosome X and therefore the possibility of using analysis of Xi skewing
as a predictive test for BRCA1 germline mutation carrier status. 相似文献
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The succinate dehydrogenase (SDH) is a mitochondrial enzyme complex with an important role in oxydative phosphorylation and intracellular oxygene sensing and signaling. Mutations in the SDHB (1p35–36) and SDHD subunits (11q23) give rise to the paraganglioma syndromes (PGL), namely PGL 4 and PGL 1, and generate paraganglioma and pheochromocytoma. For both genes mutations have been described that result in a loss of function of the gene products. SDHBmutations were found in five of eight exons and in two introns, SDHD mutations in all four exons and one intron. Phenotypes and rate of malignancy of SDHB and SDHD seem to be different, with a higher frequency of head-and-neck tumors in SDHD and indications of a higher risk of malignancy in SDHB mutations. As routine diagnostic procedure all SDH mutation carriers should have urine catecholamine analysis as well as pelvic, abdominal, thoracic and skull/neck MRI. 相似文献
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Coupier I Cousin PY Hughes D Legoix-Né P Trehin A Sinilnikova OM Stoppa-Lyonnet D 《Familial cancer》2005,4(4):273-277
BAP1 whose protein interacts with BRCA1 was analysed in a series of 47 French familial breast cancer cases negatively tested for
BRCA1/2 mutations. The lack of detection of deleterious mutations suggests that BAP1 is not a high risk breast cancer predisposing gene. However, a common identified variant, rs123602, may be tested in sporadic
cases as candidate for moderate risk. 相似文献
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Monne M Piras G Fancello P Santona MC Uras A Landriscina G Mastio G Gabbas A 《Familial cancer》2007,6(1):73-79
The population of Sardinia is characterized by a relatively low level of genetic heterogeneity: therefore ‘founder mutations’
can be expected to be found. We analysed 17 probands from families with high incidence of breast cancer or breast and ovarian
cancer by sequencing the full-length coding regions of BRCA1 and BRCA2 genes. A novel BRCA2 frameshift mutation, 3951del3insAT, which produces a protein truncated at codon 1258, was observed in six patients with BC from the same village. The mutation
was not found in unaffected females (matched on basis of ethnicity and age) with no family history of cancer. Haplotype analysis
strongly suggests that all affected persons had a common ancestor. The identification of this clinically significant founder
mutation may facilitate screening/testing for inherited risk of breast cancer. 相似文献
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