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Search Results: 1 - 10 of 468528 matches for " Patricia A Prolla "
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TP53 mutation p.R337H in gastric cancer tissues of a 12-year-old male child - evidence for chimerism involving a common mutant founder haplotype: case report
Edaise M da Silva, Maria W Achatz, Ghyslaine Martel-Planche, André L Montagnini, Magali Olivier, Patricia A Prolla, Pierre Hainaut, Fernando A Soares
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-449
Abstract: The patient, diagnosed with metastatic disease, died seven months after surgery. DNA from intra-surgical specimens revealed a TP53 mutation at codon 337 (p.R337H) in samples with neoplastic cells (dysplasia, tumor and metastasis) but not in non-transformed cells (incomplete intestinal metaplasia and non-involved celiac lymph node). In all mutation-positive tissues, p.R337H occurred on the same background, a founder allele identified by a specific haplotype previously described in Brazilian Li-Fraumeni syndrome patients. The same mutant haplotype, corresponding to a founder mutation present in 0.3% of the general population in Southern Brazil, was found in the genome of the father. Presence of this inherited haplotype in the tumor as well as in the father's germline, suggests a rare case of microchimerism in this patient, who may have harbored a small number of mutant cells originating in another individual, perhaps a dizygotic twin that died early in gestation.This case represents one of the earliest ages at diagnosis of gastric cancer ever reported. It shows that cancer inheritance can occur in the absence of an obvious germline mutation, calling for caution in assessing early cancers in populations with common founder mutations such as p.R337H in Southern Brazil.Gastric cancer is the 4th most common cancer in both genders in Brazil, as observed in population-based cancer registries across the country, with incidence rates varying from 22.4 to 53.6 per 100.000 individuals in the States of Goiania and S?o Paulo, respectively [1]. Despite recent reduction in incidence and mortality observed in the country, occurrence of gastric cancer remains amongst the highest worldwide, in contrast with the sharp decline observed in many countries over recent years [2,3]. The reasons for high incidence are still unclear and are likely to involve multiple etiological factors.In recent studies on cancer occurrence in Li-Fraumeni syndrome subjects who are carriers of germline TP53 mu
Increased Oxidative Damage in Carriers of the Germline TP53 p.R337H Mutation
Gabriel S. Macedo, Leonardo Lisb?a da Motta, Juliana Giacomazzi, Cristina B. O. Netto, Vanusa Manfredini, Camila S.Vanzin, Carmen Regla Vargas, Pierre Hainaut, Fábio Klamt, Patricia Ashton-Prolla
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0047010
Abstract: Germline mutations in TP53 are the underlying defect of Li-Fraumeni Syndrome (LFS) and Li-Fraumeni-like (LFL) Syndrome, autosomal dominant disorders characterized by predisposition to multiple early onset cancers. In Brazil, a variant form of LFS/LFL is commonly detected because of the high prevalence of a founder mutation at codon 337 in TP53 (p.R337H). The p53 protein exerts multiple roles in the regulation of oxidative metabolism and cellular anti-oxidant defense systems. Herein, we analyzed the redox parameters in blood samples from p.R337H mutation carriers (C, n = 17) and non-carriers (NC, n = 17). We identified a significant increase in erythrocyte GPx activity and in plasma carbonyl content,an indicator of protein oxidative damage, in mutation carriers compared to non-carriers (P = 0.048 and P = 0.035, respectively). Mutation carriers also showed a four-fold increase in plasma malondialdehyde levels, indicating increased lipid peroxidation (NC = 40.20±0.71, C = 160.5±0.88, P<0.0001). Finally, carriers showed increased total antioxidant status but a decrease in plasma ascorbic acid content. The observed imbalance could be associated with deregulated cell bioenergetics and/or with increased inflammatory stress, two effects that may result from loss of wild-type p53 function. These findings provide the first evidence that oxidative damage occurs in carriers of a germline TP53 mutation, and these may have important implications regarding our understanding of the mechanisms responsible for germline TP53 p.R337H mutation-associated carcinogenesis.
Population prevalence of hereditary breast cancer phenotypes and implementation of a genetic cancer risk assessment program in southern Brazil
Palmero, Edenir I.;Caleffi, Maira;Schüler-Faccini, Lavínia;Roth, Fernanda L.;Kalakun, Luciane;Netto, Cristina Brinkmann Oliveira;Skonieski, Giovana;Giacomazzi, Juliana;Weber, Bernadete;Giugliani, Roberto;Camey, Suzi A.;Ashton-Prolla, Patricia;
Genetics and Molecular Biology , 2009, DOI: 10.1590/S1415-47572009005000058
Abstract: in 2004, a population-based cohort (the núcleo mama porto alegre - nmpoa cohort) was started in porto alegre, southern brazil and within that cohort, a hereditary breast cancer study was initiated, aiming to determine the prevalence of hereditary breast cancer phenotypes and evaluate acceptance of a genetic cancer risk assessment (gcra) program. women from that cohort who reported a positive family history of cancer were referred to gcra. of the 9218 women enrolled, 1286 (13.9%) reported a family history of cancer. of the 902 women who attended gcra, 55 (8%) had an estimated lifetime risk of breast cancer 3 20% and 214 (23.7%) had pedigrees suggestive of a breast cancer predisposition syndrome; an unexpectedly high number of these fulfilled criteria for li-fraumeni-like syndrome (122 families, 66.7%). the overall prevalence of a hereditary breast cancer phenotype was 6.2% (95%ci: 5.67-6.65). these findings identified a problem of significant magnitude in the region and indicate that genetic cancer risk evaluation should be undertaken in a considerable proportion of the women from this community. the large proportion of women who attended gcra (72.3%) indicates that the program was well-accepted by the community, regardless of the potential cultural, economic and social barriers.
Hereditary non-polipomatous colorectal cancer: hereditary predisposition, diagnosis and prevention
Coura, Renata dos Santos;Ashton-Prolla, Patricia;Prolla, Jo?o Carlos;
Arquivos de Gastroenterologia , 2005, DOI: 10.1590/S0004-28032005000200007
Abstract: background: colorectal cancer is the third in frequency and the second in mortality in developed countries. in brazil, it is among the six more common malignant neoplasias. about 20% of colorectal tumors have some hereditary component. aim: this study presents a review of genetic and clinic aspects, as well as diagnosis and prevention of the hereditary non-polipomatous colorectal cancer, that is the more frequent form of hereditary colorectal cancer. this approach is important because, currently there are possibilities of management, prevention and surveillance specific to individuals at-risk for hereditary non-polipomatous colorectal cancer that can lead to a great improvement in patients' survival and their at-risk relatives.
Prevalence of the TP53 p.R337H Mutation in Breast Cancer Patients in Brazil
Juliana Giacomazzi, Marcia S. Graudenz, Cynthia A. B. T. Osorio, Patricia Koehler-Santos, Edenir I. Palmero, Marcelo Zagonel-Oliveira, Rodrigo A. D. Michelli, Cristovam Scapulatempo Neto, Gabriela C. Fernandes, Maria Isabel W. S. Achatz, Ghyslaine Martel-Planche, Fernando A. Soares, Maira Caleffi, José Roberto Goldim, Pierre Hainaut, Suzi A. Camey, Patricia Ashton-Prolla
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099893
Abstract: Germline TP53 mutations predispose individuals to multiple cancers and are associated with Li-Fraumeni/Li-Fraumeni-Like Syndromes (LFS/LFL). The founder mutation TP53 p.R337H is detected in 0.3% of the general population in southern Brazil. This mutation is associated with an increased risk of childhood adrenal cortical carcinoma (ACC) but is also common in Brazilian LFS/LFL families. Breast Cancer (BC) is one of the most common cancers diagnosed in TP53 mutation carriers. We have assessed the prevalence of p.R337H in two groups: (1) 59 BC affected women with a familial history (FH) suggestive of hereditary cancer syndrome but no LFS/LFL features; (2) 815 BC affected women unselected for cancer FH, diagnosed with BC at or before age 45 or at age 55 or older. Among group 1 and group 2 patients, 2/59 (3.4%, CI95%: 0.4%–11.7%) and 70/815 (8.6%, CI95%: 6.8%–10.7%), respectively, were p.R337H carriers in the germline. The prevalence of p.R337H was higher in women diagnosed with BC at or before age 45 (12.1%, CI95%: 9.1%–15.8%) than at age 55 or older (5.1%, CI95%: 3.2%–7.7%), p<0.001). The Brazilian founder p.R337H haplotype was detected in all carriers analysed. These results suggest that inheritance of p.R337H may significantly contribute to the high incidence of BC in Brazil, in addition to its recently demonstrated impact on the risk of childhood ACC.
Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome
Ingrid P Ewald, Patrícia Izetti, Fernando R Vargas, Miguel AM Moreira, Aline S Moreira, Carlos A Moreira-Filho, Danielle R Cunha, Sara Hamaguchi, Suzi A Camey, Aishameriane Schmidt, Maira Caleffi, Patrícia Koehler-Santos, Roberto Giugliani, Patricia Ashton-Prolla
Hereditary Cancer in Clinical Practice , 2011, DOI: 10.1186/1897-4287-9-12
Abstract: Breast cancer is the most common non-cutaneous malignancy in Brazilian women of all ages. In the Southern and Southeastern States of Brazil, the estimated breast cancer incidence rates for 2010 reached 64.54 and 64.30 per 100,000 women, the highest in the country [1]. In spite of continuous efforts to improve early detection and treatment, breast cancer remains the leading cause of deaths by cancer in Brazilian women. Furthermore, mortality rates by this type of cancer are still increasing in the Southern States of the country [2,3].It is estimated that 5-10% of breast cancers are hereditary, arising from highly penetrant germline mutations in cancer predisposition genes [4]. A significant proportion of individuals with hereditary breast cancer have mutations in the tumor suppressor genes BRCA1 (OMIM # 113705) and BRCA2 (OMIM # 600185) [5]. Carriers of such mutations are usually predisposed to breast, ovarian, prostate and other cancers at an early age, a syndrome known as Hereditary Breast and Ovarian Cancer (HBOC) [6].BRCA1 and BRCA2 are similar in their structure and quite large (100 and 70 kb, respectively). Germline mutations in these genes are usually point mutations, and are scattered along their entire coding sequences; mutational hot-spots are uncommon. Deleterious gene rearrangements may also occur in up to 30% of the cases [7]. Therefore, full gene sequencing and rearrangement testing is warranted for accurate diagnosis in most individuals. In a few populations, however, founder mutations have been described and are responsible for a significant proportion of the mutation-positive diagnoses. This is the case for the c.68_69del and c.5266dup mutations in BRCA1 and c.5946del mutation in BRCA2 (until recently referred in the literature as 185delAG, 5382insC and 6174delT, respectively) which are found in 10-12% of Ashkenazi Jewish women diagnosed with breast cancer [8,9]. BRCA gene founder mutations have also been described in other populations, including the
Cheol Koo Lee,Tomas A. Prolla,Richard Weindruch
The Scientific World Journal , 2001, DOI: 10.1100/tsw.2001.117
Polymorphic variation of mononucleotide microsatellites in healthy humans and its implication for microsatellite instability screening
Cossio, Silvia Liliana;Coura, Renata dos Santos;Bortolini, Maria Cátira;Giugliani, Roberto;Ashton-Prolla, Patricia;Prolla, Jo?o Carlos;
Arquivos de Gastroenterologia , 2007, DOI: 10.1590/S0004-28032007000100014
Abstract: background: colorectal cancer is the sixth most common tumor and the fifth in mortality in brazil. molecular markers have been associated with disease prognosis, especially in relation to therapeutic response and overall survival rates. among these, microsatellite instability has been extensively studied. microsatellite stability status is usually determined by comparison of normal and tumoral tissues from the same patient and instability is characterized by the difference in the pcr-amplification profile of these tissues at a given locus. usually, a panel of five markers is used for this purpose. two of them (bat-25 and bat-26) are considered monomorphic in populations of european origin. aim: to analyse the frequency of constitutive polymorphic variation at bat-25 and bat-26 loci in a sample of individuals from southern brazil. methods: two-hundred and sixteen healthy and unrelated individuals were analised to assess the frequency of allelic variation at the bat-25 and bat-26 loci in dna extracted from peripheral blood. analysis was done by polymerase chain reaction - single strand conformation polymorphism (pcr-sscp). results: from the sample of patients studied, 7% and 6% of the patients had possible constitutive allelic variation at the bat-25 and bat-26 loci, respectively. conclusions: these results indicate that significant constitutive allelic variation of these loci does occur in heterogeneous populations such as ours, and reinforce the importance of comparative studies between tumoral and corresponding normal tissue to determine microsatellite stability status and correctly identify microsatellite instability in selected populations.
Genomic rearrangements in BRCA1 and BRCA2: a literature review
Ewald, Ingrid Petroni;Ribeiro, Patricia Lisboa Izetti;Palmero, Edenir Inêz;Cossio, Silvia Liliana;Giugliani, Roberto;Ashton-Prolla, Patricia;
Genetics and Molecular Biology , 2009, DOI: 10.1590/S1415-47572009005000049
Abstract: women with mutations in the breast cancer genes brca1 or brca2 have an increased lifetime risk of developing breast, ovarian and other brca-associated cancers. however, the number of detected germline mutations in families with hereditary breast and ovarian cancer (hboc) syndrome is lower than expected based upon genetic linkage data. undetected deleterious mutations in the brca genes in some high-risk families are due to the presence of intragenic rearrangements such as deletions, duplications or insertions that span whole exons. this article reviews the molecular aspects of brca1 and brca2 rearrangements and their frequency among different populations. an overview of the techniques used to screen for large rearrangements in brca1 and brca2 is also presented. the detection of rearrangements in brca genes, especially brca1, offers a promising outlook for mutation screening in clinical practice, particularly in hboc families that test negative for a germline mutation assessed by traditional methods.
Effect of HFE gene polymorphism on sustained virological response in patients with chronic hepatitis C and elevated serum ferritin
Coelho-Borges, Silvia;Cheinquer, Hugo;Wolff, Fernando Herz;Cheinquer, Nelson;Krug, Luciano;Ashton-Prolla, Patricia;
Arquivos de Gastroenterologia , 2012, DOI: 10.1590/S0004-28032012000100003
Abstract: context: abnormal serum ferritin levels are found in approximately 20%-30% of the patients with chronic hepatitis c and are associated with a lower response rate to interferon therapy. objective: to determine if the presence of hfe gene mutations had any effect on the sustained virological response rate to interferon based therapy in chronic hepatitis c patients with elevated serum ferritin. methods: a total of 44 treatment na?ve patients with histologically demonstrated chronic hepatitis c, all infected with hepatitis c virus genotype non-1 (38 genotype 3; 6 genotype 2) and serum ferritin above 500 ng/ml were treated with interferon (3 mu, 3 times a week) and ribavirin (1.000 mg, daily) for 24 weeks. results: sustained virological response was defined as negative qualitative hcv-rna more than 24 weeks after the end of treatment. serum hcv-rna was measured by qualitative in house polymerase chain reaction with a limit of detection of 200 iu/ml. hfe gene mutation was detected using restriction-enzyme digestion with rsai (c282y mutation analysis) and bcli (h63d mutation analysis) in 16 (37%) patients, all heterozygous (11 h63d, 2 c282y and 3 both). sustained virological response was achieved in 0 of 16 patients with hfe gene mutations and 11 (41%) of 27 patients without hfe gene mutations (p = 0.002; exact fisher test). conclusion: heterozigozity for h63d and/or c282y hfe gene mutation predicts absence of sustained virological response to combination treatment with interferon and ribavirin in patients with chronic hepatitis c, non-1 genotype and serum ferritin levels above 500 ng/ml.
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