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1.
J Investig Med ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32184228

RESUMO

This study aimed to investigate the frequency of the somatic BRAF p.V600E in patients with colorectal cancer (CRC) in Mexico and compare it with those estimated for Latin American and Caribbean populations. One hundred and one patients with CRC with AJCC stages ranging I-IV from Western Mexico were included, out of which 55% were male and 61% had AJCC stage III-IV, with a mean age of 60 years. PCR-Sanger sequencing was used to identify the BRAF p.V600E variant. In addition, a systematic literature search in PubMed/Medline database and Google of the 42 countries in Latin America and the Caribbean led to the collection of information on the BRAF p.V600E variant frequency of 17 population reports. To compare the BRAF variant prevalence among populations, a statistical analysis was performed using GraphPad Prism V.6.0. We found that 4% of patients with CRC were heterozygous for the p.V600E variant. The χ2 test showed no significant difference (p>0.05) in p.V600E detection when comparing with other Latin American and Caribbean CRC populations, except for Chilean patients (p=0.02). Our observational study provides the first evidence on the frequency of BRAF p.V600E in patients with CRC from Western Mexico, which is 4%, but increases to 7.8% for all of Latin America and the Caribbean. The patient mean age and genetic descent on the observed frequencies of the variant in populations could influence the frequency differences.

2.
Cancers (Basel) ; 12(2)2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32050665

RESUMO

The authors wish to make the following corrections to this paper [1]: The authors would like to replace Table 3 in [1]. The corrections are correcting typographical errors when translating our database in BIC format to HGVS nomenclature, and removing four carriers which had zero follow-up time. [...].

3.
Genet Med ; 22(1): 15-25, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31337882

RESUMO

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

4.
5.
Sci Rep ; 9(1): 18555, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31811167

RESUMO

We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. In all, 138 breast cancer (BC) cases, 34 colorectal cancer (CRC) and 19 multiple early-onset cancers were included. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS). Pathogenic or likely pathogenic variants were identified mostly in familial BC individuals (7/9) and were located in 5 genes: ATM (3), BRCA2 (1), CHEK2 (1), MSH6 (1) and MUTYH (1), followed by multiple early-onset (2/9) individuals, affecting the CHEK2 and ATM genes. Eleven of the 87 VUS were tested, and 4/11 were found to have an impact on splicing by using a minigene splicing assay. We here report for the first time the splicing anomalies using this assay for the variants ATM c.3806A > G and BUB1 c.677C > T, whereas CHEK1 c.61G > A did not result in any detectable splicing anomaly. Our study confirms the presence of pathogenic or likely pathogenic variants in genes that are not routinely tested in the context of the above-mentioned clinical phenotypes. Interestingly, more than half of the pathogenic germline variants were found in the moderately penetrant ATM and CHEK2 genes, where only truncating variants from these genes are recommended to be reported in clinical genetic testing practice.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31636762

RESUMO

Background: We previously reported that in pathogenic mismatch repair (path_MMR) variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated. Methods: The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only path_MMR variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis. Results: Ninety-nine path_MMR carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 path_MLH1, 17 path_MSH2, and 2 path_MSH6 carriers. The number of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5-3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively (p < 0.001). Ten-year crude survival when the last colonoscopy had been < 1.5, 1.5-2.5, 2.5-3.5 or > 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively (p = 0.91). Conclusions: In path_MLH1 and path_MSH2 carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of path_MMR variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30858900

RESUMO

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

8.
Cancers (Basel) ; 11(2)2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30678073

RESUMO

Background: We have previously demonstrated that the Norwegian frequent pathogenic BRCA1 (path_BRCA1) variants are caused by genetic drift and recurrent de-novo mutations. We here examined the penetrance of frequent path_BRCA1 variants in fertile ages as a surrogate marker for fitness. Material and methods: We conducted an observational prospective study of penetrance for cancer in Norwegian female carriers of frequent path_BRCA1 variants, and compared our observed results to penetrance of infrequent path_BRCA1 variants and to average penetrance of path_BRCA1 variants reported by others. Results: The cumulative risk for breast cancer at 45 years in carriers of frequent path_BRCA1 variants was 20% (94% confidence interval 10⁻30%), compared to 35% (95% confidence interval 22⁻48%) in carriers of infrequent path_BRCA1 variants (p = 0.02), and to the 35% (confidence interval 32⁻39%) average for path_BRCA1 carriers reported by others (p = 0.0001). Discussion and conclusion: Carriers of the most frequent Norwegian path_BRCA1 variants had low incidence of cancer in fertile ages, indicating a low selective disadvantage. This, together with the variant locations being hotspots for de novo mutations and subject to genetic drift, as previously described, may have caused their high prevalence today. Besides being of theoretical interest to explain the phenomenon that a few path_BRCA1 variants are frequent, the later onset of breast cancer associated with the most frequent path_BRCA1 variants may be of interest for carriers who have to decide if and when to select prophylactic mastectomy.

9.
Mutat Res ; 810: 39-44, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29615272

RESUMO

Hearing and balance disorders are related to the inner ear and are among the major cause of falls in older adults. Hearing loss that commonly occurs with aging (aka presbyacusis) can result from noise exposure, smoking, ototoxic drugs and genetic factors such as mutations in nuclear and mitochondrial genes. Mutations in mitochondrial DNA (mtDNA) have been reported to play an important role in cell function by providing energy, as well as, cell death (apoptosis). This study aims to systematically review mitochondrial mutations associated with presbyacusis and suggests preventive measurements to improve the quality of life in older adults.


Assuntos
DNA Mitocondrial/genética , Orelha Interna/patologia , Perda Auditiva/genética , Mitocôndrias/genética , Equilíbrio Postural/genética , Presbiacusia/genética , Transtornos das Sensações/genética , Humanos
10.
Genes Chromosomes Cancer ; 57(7): 350-358, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29520894

RESUMO

Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not. Nine such MLH1 variants have been identified in South American colorectal cancer (CRC) patients (p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro), and evidence of pathogenicity or neutrality was not available for the majority of these variants. We therefore performed biochemical laboratory testing of the variant proteins and compared the results to protein in silico predictions on structure and conservation. Additionally, we collected all available clinical information of the families to come to a conclusion concerning their pathogenic potential and facilitate clinical diagnosis in the affected families. We provide evidence that four of the alterations are causative for Lynch syndrome, four are likely neutral and one shows compromised activity which can currently not be classified with respect to its pathogenic potential. The work demonstrates that biochemical testing, corroborated by congruent evolutionary and structural information, can serve to reliably classify uncertain variants when other data are insufficient.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença , Proteína 1 Homóloga a MutL/genética , Mutação , Neoplasias Colorretais Hereditárias sem Polipose/etnologia , Simulação por Computador , Células HEK293 , Humanos , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/química , Conformação Proteica , América do Sul
11.
BMC Med Genet ; 19(1): 26, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29458332

RESUMO

BACKGROUND: The genetic mechanisms for families who meet the clinical criteria for Lynch syndrome (LS) but do not carry pathogenic variants in the mismatch repair (MMR) genes are still undetermined. We aimed to study the potential contribution of genes other than MMR genes to the biological and clinical characteristics of Norwegian families fulfilling Amsterdam (AMS) criteria or revised Bethesda guidelines. METHODS: The Hereditary Cancer Biobank of the Norwegian Radium Hospital was interrogated to identify individuals with a high risk of developing colorectal cancer (CRC) for whom no pathogenic variants in MMR genes had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by using our in-house designed TruSeq amplicon-based assay for targeted sequencing. RNA splicing- and protein-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as likely to affect splicing were experimentally analyzed by resorting to minigene assays. RESULTS: We identified a patient who met the revised Bethesda guidelines and carried a likely pathogenic variant in CHEK2 (c.470 T > C, p.I157T). In addition, 25 unique VUS were identified in 18 individuals, of which 2 exonic variants (MAP3K1 c.764A > G and NOTCH3 c.5854G >A) were analyzed in the minigene splicing assay and found not to have an effect on RNA splicing. CONCLUSIONS: Among high-risk CRC patients that fulfill the AMS criteria or revised Bethesda guidelines, targeted gene sequencing identified likely pathogenic variant and VUS in other genes than the MMR genes (CHEK2, NOTCH3 and MAP3K1). Our study suggests that the analysis of genes currently excluded from routine molecular diagnostic screens may confer cancer susceptibility.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Variação Genética , Adulto , Quinase do Ponto de Checagem 2/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Reparo de Erro de Pareamento de DNA , Éxons , Feminino , Predisposição Genética para Doença , Humanos , MAP Quinase Quinase Quinase 1/genética , Masculino , Noruega , Processamento de RNA , Receptor Notch3/genética , Análise de Sequência de DNA
12.
Artigo em Inglês | MEDLINE | ID: mdl-29371908

RESUMO

Background: In kindreds carrying path_BRCA1/2 variants, some women in these families will develop cancer despite testing negative for the family's pathogenic variant. These families may have additional genetic variants, which not only may increase the susceptibility of the families' path_BRCA1/2, but also be capable of causing cancer in the absence of the path_BRCA1/2 variants. We aimed to identify novel genetic variants in prospectively detected breast cancer (BC) or gynecological cancer cases tested negative for their families' pathogenic BRCA1/2 variant (path_BRCA1 or path_BRCA2). Methods: Women with BC or gynecological cancer who had tested negative for path_BRCA1 or path_BRCA2 variants were included. Forty-four cancer susceptibility genes were screened for genetic variation through a targeted amplicon-based sequencing assay. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the ones most likely affecting pre-mRNA splicing were experimentally analyzed in a minigene assay. Results: We identified 48 women who were tested negative for their family's path_BRCA1 (n = 13) or path_BRCA2 (n = 35) variants. Pathogenic variants in the ATM, BRCA2, MSH6 and MUTYH genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from path_BRCA1 and 9% (3/35) from path_BRCA2 families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing (APC c.721G > A, MAP3K1 c.764A > G and MSH2 c.815C > T). However, by using a minigene, assay we here show that APC c.721G > A does not cause a splicing defect, similarly to what has been recently reported for the MAP3K1 c.764A > G. The MSH2 c.815C > T was previously described as causing partial exon skipping and it was identified in this work together with the path_BRCA2 c.9382C > T (p.R3128X). Conclusion: All women in breast or breast/ovarian cancer kindreds would benefit from being offered genetic testing irrespective of which causative genetic variants have been demonstrated in their relatives.

13.
Fam Cancer ; 17(1): 141-153, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28608266

RESUMO

To study the potential contribution of genes other than BRCA1/2, PTEN, and TP53 to the biological and clinical characteristics of multiple early-onset cancers in Norwegian families, including early-onset breast cancer, Cowden-like and Li-Fraumeni-like syndromes (BC, CSL and LFL, respectively). The Hereditary Cancer Biobank from the Norwegian Radium Hospital was used to identify early-onset BC, CSL or LFL for whom no pathogenic variants in BRCA1/2, PTEN, or TP53 had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by our in-house designed TruSeq amplicon-based assay for targeted sequencing. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the more likely to affect splicing were experimentally analyzed by minigene assay. We identified a CSL individual carrying a variant in CHEK2 (c.319+2T>A, IVS2), here considered as likely pathogenic. Out of the five VUS (BRCA2, CDH1, CHEK2, MAP3K1, NOTCH3) tested in the minigene splicing assay, only NOTCH3 c.14090C>T (p.Ser497Leu) showed a significant effect on RNA splicing, notably by inducing partial skipping of exon 9. Among 13 early-onset BC, CSL and LFL patients, gene panel sequencing identified a potentially pathogenic variant in CHEK2 that affects a canonical RNA splicing signal. Our study provides new information on genetic loci that may affect the risk of developing cancer in these patients and their families, demonstrating that genes presently not routinely tested in molecular diagnostic settings may be important for capturing cancer predisposition in these families.


Assuntos
Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Testes Genéticos/métodos , Síndrome do Hamartoma Múltiplo/genética , Síndrome de Li-Fraumeni/genética , Doenças Mitocondriais/genética , Adulto , Idade de Início , Idoso , Neoplasias da Mama/diagnóstico , Éxons/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Síndrome do Hamartoma Múltiplo/diagnóstico , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Noruega , Processamento de RNA/genética , Adulto Jovem
14.
Fam Cancer ; 17(3): 395-402, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29128931

RESUMO

Microsatellite instability (MSI) is a hallmark tool for Lynch syndrome (LS) screening and a prognostic marker for sporadic colorectal cancer (CRC). In regions with limited resources and scarce CRC molecular characterization as South America, the implementation of universal MSI screening is under debate for both its purposes. We sought to estimate the frequency of BAT26 in colorectal adenocarcinomas and to determine associated clinical and histological features. Consecutive patients from a CRC registry were included. BAT26 determination was performed in all cases; if instability was found, immunohistochemistry (IHC) and BRAF mutation analyses were done, as appropriate. Differences were assessed by chi-squared or Fisher's exact test, or by T test or Mann-Whitney. Multiple logistic regression was used to identify factors independently associated with BAT26-unstable tumors. We included 155 patients; mean age was 65.6 (SD 14.4) and 56.1% were male. The frequency of BAT26-unstable tumors was 22% (95% CI 15.7-29.3). Factors independently associated with BAT26-unstable tumors were right colon localization (OR 3.4, 95% CI 1.3-8.7), histological MSI features (OR 5.1, 95% CI 1.9-13.6) and Amsterdam criteria (OR 23.2, 95% CI 1.9-286.7). IHC was altered in 85.3% BAT26-unstable tumors and 70.6% lacked MLH1 expression; 47.8% of these harbored BRAF V600E mutation. We provide evidence to link the frequency of BAT26 to an increased diagnostic yield (up to 1.4-folds) of suspected LS cases in comparison to the revised Bethesda guidelines alone. In regions with limited resources, clinical and histological features associated with BAT26-unstable status could be useful to direct MSI screening in sporadic CRCs and may help guide clinical care and future research.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Marcadores Genéticos/genética , Repetições de Microssatélites/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adulto , Idoso , Argentina , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade
15.
BMC Cancer ; 17(1): 623, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28874130

RESUMO

BACKGROUND: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. METHODS: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. RESULTS: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. CONCLUSION: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Biologia Computacional/métodos , Reparo de Erro de Pareamento de DNA , Feminino , Efeito Fundador , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Variação Genética , Mutação em Linhagem Germinativa , Humanos , América Latina/epidemiologia , Masculino , Pessoa de Meia-Idade , Vigilância da População , Processamento de RNA , Sistema de Registros , Fatores de Risco
17.
Anticancer Res ; 36(9): 4399-405, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27630275

RESUMO

In the past two decades, significant advances have been made in our understanding of colorectal (CRC) tumors with DNA mismatch (MMR) repair deficiency. The knowledge from molecular and genetic alterations in a variety of clinical conditions has refined the disease terminology and classification. Hereditary non-polyposis colorectal cancer (HNPCC) encompasses a spectrum of conditions that have significant phenotypic overlapping that makes clinical diagnosis a challenging task. Distinguishing among the HNPCC disorders is clinically important, as the approach to surveillance for patients and their at-risk family members differs according to risks for colonic and extracolonic cancer associated with each syndrome. Prospective and next-generation studies will provide valuable clinical information regarding the natural history of disease that will help differentiate the Lynch syndrome mimics and guide diagnosis and management for heterogeneous conditions currently grouped under the category of familial CRC. The review is intended to present and discuss the molecular nature of various conditions related to MMR deficiency and discusses the tools and strategies that have been used in detecting these conditions.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/fisiopatologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/fisiopatologia , Pareamento Incorreto de Bases , Biomarcadores Tumorais/genética , Reparo de Erro de Pareamento de DNA , Reparo do DNA , Rearranjo Gênico , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Repetições de Microssatélites , Mutação , Fenótipo , Fatores de Risco
18.
Cancer Res ; 76(18): 5326-36, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27406829

RESUMO

By affecting immunological presentation, the presence of cytomegalovirus in some glioblastomas may impact progression. In this study, we examined a hypothesized role for natural killer (NK) cells in impacting disease progression in this setting. We characterized 108 glioblastoma patients and 454 healthy controls for HLA-A,-B,-C, NK-cell KIR receptors, and CMV-specific antibodies and correlated these metrics with clinical parameters. Exome sequences from a large validation set of glioblastoma patients and control individuals were examined from in silico databases. We demonstrated that the KIR allele KIR2DS4*00101 was independently prognostic of prolonged survival. KIR2DS4*00101 displayed 100% concordance with cognate HLA-C1 ligands in glioblastoma patients, but not controls. In the context of both HLA-C1/C2 ligands for the KIR2DS4 receptor, patient survival was further extended. Notably, all patients carrying KIR2DS4*00101 alleles were CMV seropositive, but not control individuals, and exhibited increased NK-cell subpopulations, which expressed the cytotoxicity receptors CD16, NKG2D, and CD94/NKG2C. Finally, healthy controls exhibited a reduced risk for developing glioblastoma if they carried two KIR2DS4*00101 alleles, where protection was greatest among Caucasian individuals. Our findings suggest that KIR2DS4*00101 may offer a molecular biomarker to identify intrinsically milder forms of glioblastoma. Cancer Res; 76(18); 5326-36. ©2016 AACR.


Assuntos
Biomarcadores Tumorais/imunologia , Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Biomarcadores Tumorais/análise , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/virologia , Criança , Infecções por Citomegalovirus/complicações , Feminino , Citometria de Fluxo , Glioblastoma/mortalidade , Glioblastoma/virologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Modelos de Riscos Proporcionais , Adulto Jovem
19.
BMC Urol ; 16: 15, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-27013479

RESUMO

BACKGROUND: A possible role for prostate cancer in Lynch syndrome has been debated based on observations of mismatch-repair defective tumors and reports of an increased risk of prostate cancer in mutation carriers. Potential inclusion of prostate cancer in the Lynch syndrome tumor spectrum is relevant for family classification, risk estimates and surveillance recommendations in mutation carriers. METHODS: We used the population-based Danish HNPCC-register to identify all prostate cancers that developed in mutation carriers and in their first-degree relatives from 288 Lynch syndrome families. The tumors were evaluated for clinicopathologic features and mismatch-repair status, and the cumulative risk of prostate cancer was determined. RESULTS: In total, 28 prostate cancers developed in 16 mutation carriers and in 12 first-degree relatives at a median age of 63 years. The majority of the tumors were high-grade tumors with Gleason scores 8-10. Prostate cancer was associated with mutations in MSH2, MLH1 and MSH6 with loss of the respective mismatch repair protein in 69 % of the tumors, though a MSI-high phenotype was restricted to 13 % of the tumors. The cumulative risk of prostate cancer at age 70 was 3.7 % (95 % CI: 2.3-4.9). CONCLUSION: We provide evidence to link prostate cancer to Lynch syndrome through demonstration of MMR defective tumors and an increased risk of the disease, which suggests that prostate cancer should be considered in the diagnostic work-up of Lynch syndrome.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adenocarcinoma/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Neoplasias da Próstata/genética , Sistema de Registros , Idoso , Idoso de 80 Anos ou mais , Reparo de Erro de Pareamento de DNA/genética , Dinamarca , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Mutação
20.
Urology ; 86(6): 1212-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26385421

RESUMO

OBJECTIVE: To evaluate the risk of urothelial cancer in the upper urinary tract and the bladder, determine the contribution from the different mismatch-repair genes, and define clinical characteristics of urothelial cancer in Lynch syndrome. MATERIALS AND METHODS: The national hereditary nonpolyposis colorectal cancer registry was used to identify all 288 Lynch syndrome families in Denmark. Urothelial cancers that developed in mutation carriers and in their first-degree relatives were identified, mismatch-repair status was assessed, clinicopathologic variables were defined, and cumulative lifetime risks were determined. RESULTS: In total, 48 cancers of the ureter, 34 cancers of the renal pelvis, and 54 urinary bladder cancers developed at a mean age of 61 (24-89) years. The tumors were typically of high grade, showed loss of mismatch-repair protein expression in 90% of the tumors and microsatellite instability in 23% of the tumors. Mutations in MSH2 were overrepresented (73%), and MSH2 mutation carriers were at a significantly increased risk of developing urinary tract cancer compared with individuals with mutations in MLH1 or MSH6. CONCLUSION: Cancers of the upper urinary tract and the urinary bladder are included in the Lynch syndrome tumor spectrum. Urothelial cancers are predominantly linked to MSH2 mutations, which suggest that surveillance should be targeted at individuals with mutations herein.


Assuntos
Carcinoma de Células de Transição/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias Primárias Múltiplas/genética , Segunda Neoplasia Primária/genética , Neoplasias Urológicas/genética , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Trifosfatases/análise , Adenosina Trifosfatases/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas de Arabidopsis/análise , Proteínas de Arabidopsis/genética , Carcinoma de Células de Transição/epidemiologia , Enzimas Reparadoras do DNA/análise , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/genética , Dinamarca/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/análise , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Primárias Múltiplas/patologia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/patologia , Proteínas Nucleares/análise , Proteínas Nucleares/genética , Linhagem , Fatores de Risco , Neoplasias Urológicas/epidemiologia , Neoplasias Urológicas/patologia
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