RESUMEN
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HRâ=â0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
Asunto(s)
Proteína BRCA2/genética , Neoplasias de la Mama/genética , Cromosomas Humanos Par 6/genética , Estudio de Asociación del Genoma Completo , Adulto , Anciano , Alelos , Proteína BRCA1/genética , Neoplasias de la Mama/patología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Humanos , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
CDKN2A codes for two oncosuppressors by alternative splicing of two first exons: p16INK4a and p14ARF. Germline mutations are found in about 40% of melanoma-prone families, and most of them are missense mutations mainly affecting p16INK4a. A growing number of p16INK4a variants of uncertain significance (VUS) are being identified but, unless their pathogenic role can be demonstrated, they cannot be used for identification of carriers at risk. Predicting the effect of these VUS by either a "standard" in silico approach, or functional tests alone, is rather difficult. Here, we report a protocol for the assessment of any p16INK4a VUS, which combines experimental and computational tools in an integrated approach. We analyzed p16INK4a VUS from melanoma patients as well as variants derived through permutation of conserved p16INK4a amino acids. Variants were expressed in a p16INK4a-null cell line (U2-OS) and tested for their ability to block proliferation. In parallel, these VUS underwent in silico prediction analysis and molecular dynamics simulations. Evaluation of in silico and functional data disclosed a high agreement for 15/16 missense mutations, suggesting that this approach could represent a pilot study for the definition of a protocol applicable to VUS in general, involved in other diseases, as well.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Variación Genética , Melanoma/genética , Secuencias de Aminoácidos , Sustitución de Aminoácidos , Línea Celular Tumoral , Proliferación Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Humanos , Melanoma/diagnóstico , Modelos Moleculares , Mutación Missense , Conformación Proteica , Neoplasias Cutáneas , Melanoma Cutáneo MalignoRESUMEN
CONTEXT: Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. OBJECTIVE: To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. DESIGN, SETTING, AND PARTICIPANTS: A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). MAIN OUTCOME MEASURE: Five-year overall mortality. RESULTS: The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). CONCLUSION: Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.
Asunto(s)
Genes BRCA1 , Genes BRCA2 , Mutación de Línea Germinal , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Análisis de SupervivenciaRESUMEN
Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
Asunto(s)
Artritis/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Sordera/genética , Haplotipos/genética , Policondritis Recurrente/genética , Secuencia de Bases , Simulación por Computador , Femenino , Efecto Fundador , Genotipo , Heterocigoto , Humanos , Judíos/genética , Eliminación de SecuenciaRESUMEN
The CDKN2A locus encodes for two distinct tumor suppressor proteins, p16(INK4A) and p14(ARF), involved in cell cycle regulation. CDKN2A germline mutations have been associated with familial predisposition to melanoma and other tumor types. Besides bona-fide pathogenic mutations, many sequence variants have been identified, but their effect is not well known. We detected the p.Gly23Asp missense mutation in one of the two tested melanoma patients of a family with three melanoma cases. Even though the mutated amino acid is located in a conserved domain that specifically binds to and blocks the function of CDK4/6, its lack of segregation with disease suggested a series of functional assays to discriminate between a pathogenic variant and a neutral polymorphism. The effect of this mutation has been investigated exploiting four p16(INK4A) properties: its ability (i) to bind CDK4, (ii) to inhibit pRb phosphorylation, (iii) to evenly localize in the cell, and (iv) to cause cell cycle arrest. The mutant protein properties were evaluated transfecting three different cell lines (U2-OS and NM-39, both p16-null, and SaOS 2, p53 and pRb-null) with plasmids expressing either p16(wt), p16(23Asp), or the p16(32Pro) pathogenic variant. We found that p16(23Asp) was less efficient than p16(wt) in CDK4 binding, in inhibiting pRb phosphorylation, in inducing G1 cell cycle arrest; moreover, its pattern of distribution throughout the cell was suggestive of protein aggregation, thus assessing a pathogenic role for p16(23Asp) in familial melanoma.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/fisiología , Genes p16 , Melanoma/genética , Mutación Missense , Ciclo Celular , Humanos , Fosforilación , Polimorfismo Genético , Proteínas Salivales Ricas en Prolina/metabolismoRESUMEN
We describe a case of hairy cell leukaemia (HCL) coexistent with non-Hodgkin's lymphoma (NHD). This combination is reported to be extremely rare with no clear demonstration of the clonal relationship between the two conditions. After a previous failure of purine analogue therapy, our patient was successfully treated with rituximab resulting in normalisation of blood cell count cessation of blood transfusion and negative iliac crest biopsy. Unfortunately, the patient developed intense and persistent bone pain during the 1(st) line treatment for HCL. Skeletal X-rays, neck-thorax-abdomen CT scan and repeated bone MRI were unremarkable and bone scintigraphy showed non-specific changes. Laboratory examinations were normal. To better evaluate bone scintigraphy results, we finally performed FDG-PET/CT, which showed multiple foci of intense abnormal radiotracer uptake involving the bone marrow. An FDG-PET/CT guided bone marrow biopsy showed primary bone marrow diffuse large B-cell lymphoma (LBCL). Despite 2(nd) and 3(rd) line treatment, the patient died shortly after for central nervous system involvement by NHD. The role of FDG-PET/CT in identifying bone and bone marrow localization of NHD is reviewed and an earlier use is suggested in poorly understood bone pain.
Asunto(s)
Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Leucemia de Células Pilosas/diagnóstico por imagen , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Neoplasias Primarias Múltiples/diagnóstico por imagen , Radiofármacos , Adulto , Neoplasias de la Médula Ósea/diagnóstico por imagen , Femenino , Humanos , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
The BRCA1 gene is responsible for a high number of hereditary breast and ovarian cancers that cluster in families with a strong genetic predisposition. Despite intense investigation, the accumulating findings on BRCA1 biological functions have not yet been translated into specific therapeutic approaches, also due to the lack of suitable experimental models. The purpose of this study was to establish and characterize cell cultures and xenografts from patients with BRCA1 -/- ovarian cancers. We derived two ovarian cancer cell lines, termed PD-OVCA1 and PD-OVCA2, both from patients previously treated with chemotherapy, that propagate in SCID mice as well as in vitro for a limited number of passages. Both cell lines expressed cytokeratins and the CA125 tumour marker. A detailed molecular characterization highlighted both constitutive and somatic genetic events that abrogate BRCA1 gene function. Both cell lines were shown to lose the wild type BRCA1 allele; intriguingly, these deletions were apparently accompanied by gain of one or more copies of the mutant alleles. Finally, a genomic profile of major chromosomal aberrations was obtained by the Multiplex Ligation-dependent Probe Amplification (MLPA) technique, which disclosed chromosomal imbalances targeting specific genes in each cell line. The PD-OVCA1 and PD-OVCA2 ovarian cancer cell lines will provide a valuable tool for new experimental models for the study of BRCA1-associated tumour biology.
Asunto(s)
Genes BRCA1 , Neoplasias Ováricas/patología , Células Tumorales Cultivadas/patología , Anciano , Animales , Antígeno Ca-125/metabolismo , Técnicas de Cultivo de Célula/métodos , Femenino , Genoma , Genotipo , Humanos , Ratones , Neoplasias Ováricas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante Heterólogo/métodos , Células Tumorales Cultivadas/metabolismoRESUMEN
Germ-line mutations in the breast cancer susceptibility BRCA1 gene account for approximately half of hereditary breast cancer cases and most of breast/ovarian cancer cases. We speculated whether breast hereditary cancers might be differentially sensitive to antitumor agents such as the mitotic spindle poisons Vinca alcaloid vinorelbine (VNR) and the taxoid docetaxel (DOC), which are commonly used in the treatment of breast cancer. We investigated the sensitivity of the BRCA1-mutated HCC1937 (derived from a BRCA1 related hereditary tumor) and BRCA1 competent MCF-7 and MDA-MB468 sporadic breast cancer cell lines to these drugs. We found that HCC1937 cells were significantly more sensitive to VNR as compared to MCF-7 or MDA-MB468 cells. Instead, BRCA1-mutated breast cancer cells exposed to DOC showed similar sensitivity as compared to BRCA1-competent MCF-7 or were less sensitive than MDA-MB468. In order to assess the role of BRCA1 in this specific pattern of chemosensitivity, we transfected the BRCA1-mutated HCC1937 cells with a full-length BRCA1 cDNA and the stable clone (HCC1937/WTBRCA1) was exposed to both drugs. Full-length BRCA1 transfection led to a significant induction of resistance to VNR, whereas only a weak but not significant increase of sensitivity to DOC was detected. Moreover, VNR induced apoptotic cell death and cytoskeletal rearrangements in HCC1937 cells. We further investigated whether a defective targeting of mitotic spindle by the mutated BRCA1 gene product might be involved in the differential sensitivity to VNR. We demonstrated that mutated BRCA1 was indeed capable of co-localizing with alpha-tubulin in the mitotic spindle, suggesting therefore that different mechanisms should account for these effects. In conclusion, our data suggest that BRCA1-mutated tumors might be differentially sensitive to anti-microtubule agents, supporting the rationale for clinical trials to improve the outcome of hereditary breast cancer patients by tailored treatments.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/genética , Genes BRCA1 , Taxoides/farmacología , Vinblastina/análogos & derivados , Vinblastina/farmacología , Apoptosis , Neoplasias de la Mama/patología , Citoesqueleto/patología , Análisis Mutacional de ADN , Docetaxel , Resistencia a Antineoplásicos , Femenino , Mutación de Línea Germinal , Humanos , Microtúbulos/patología , Huso Acromático/patología , Células Tumorales Cultivadas , VinorelbinaRESUMEN
Accurate estimates of breast and ovarian cancer penetrance in BRCA1/2 mutation carriers are crucial in genetic counseling. Estimation is difficult because of the low frequency of mutated alleles and the often-uncertain mechanisms of family ascertainment. We estimated the penetrances of breast and ovarian cancers in carriers of BRCA1/2 mutations by maximizing the retrospective likelihood of the genetic model, given the observed test results, in 568 Italian families screened for germline mutations. The software BRCAPRO was used as a probability calculation tool in a Markov Chain Monte Carlo approach. Breast cancer penetrances were 27% (95% CI 20-34%) at age 50 years and 39% (27-52%) at age 70 in BRCA1 carriers, and 26% (0.18-0.34%) at age 50 and 44% (29-58%) at age 70 in BRCA2 carriers, and ovarian cancer penetrances were 14% (7-22%) at age 50 and 43% (21-66%) at age 70 in BRCA1 carriers and 3% (0-7%) at age 50 and 15% (4-26%) at age 70 in BRCA2 carriers. The new model gave a better fit than the current default in BRCAPRO, the likelihood being 70 log units greater; in addition, the observed numbers of mutations in families stratified by gene and by cancer profile were not significantly different from those expected. Our new penetrance functions are appropriate for predicting breast cancer risk, and for determining the probability of carrying BRCA1/2 mutations, in people who are presently referred to genetic counseling in Italy. Our approach could lead to country-customized versions of the BRCAPRO software by providing appropriate population-specific estimates.
Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutación , Neoplasias Ováricas/genética , Penetrancia , Adulto , Anciano , Neoplasias de la Mama/epidemiología , Mapeo Cromosómico , Simulación por Computador , Femenino , Humanos , Funciones de Verosimilitud , Persona de Mediana Edad , Neoplasias Ováricas/epidemiología , RiesgoRESUMEN
Retroperitoneal fibrosis is a rare disease of uncertain pathogenesis. However, its possible association with several immunopathologic conditions, the possibility of systemic involvement by the fibrous process, the presence of various autoantibodies, and the frequent response to immunosuppressive treatment all support an autoimmune pathogenesis. Riedel's thyroiditis is a rare disease the pathogenesis of which is also thought to be immune-mediated based on its optimal response to steroids; Riedel's thyroiditis is also frequently reported in association with retroperitoneal fibrosis. We describe here two cases of autoimmune thyroid disease associated with retroperitoneal fibrosis, the first with features of primary myxedema, the second of primary thyrotoxicosis. Histology of retroperitoneal fibrosis is documented and it is compatible with an immunopathologic condition. Thus, these two cases add further support to the hypothesis of an autoimmune pathogenesis of retroperitoneal fibrosis and indicate the importance of carefully monitoring for the development of other autoimmune disorders, i.e., of the thyroid gland, in patients with retroperitoneal fibrosis.
Asunto(s)
Enfermedad de Graves/complicaciones , Fibrosis Retroperitoneal/etiología , Tiroiditis Autoinmune/complicaciones , Anciano , Femenino , Humanos , Persona de Mediana Edad , Fibrosis Retroperitoneal/patologíaRESUMEN
PURPOSE: A growing number of sequence changes of unknown clinical significance are being identified in the BRCA1 gene. However, these variants cannot be used for identification and surveillance of at-risk individuals unless their pathogenic role can be demonstrated. The frequency of these variants makes research on this subject a relevant topic in the field of predisposition to breast and ovarian cancers. Herein, we investigate the pathogenicity of the BRCA1 p.Val1688del (c.5181_5183delGTT) variant, which recurs in our population. PATIENTS AND METHODS: Recent studies have drawn attention to different strategies that, if considered singly, do not usually provide sufficient power to firmly state for or against causality, thus forcing to a re-evaluation of the literature on each specific variant. To increase the power of our study, we used a recently described strategy that integrates data from multiple independent evidences. By this approach, we analyzed data from the comprehensive study of 12 breast/ovarian cancer families carrying p.Val1688del. RESULTS: We succeeded in integrating five independent evidences of disease causality including segregation, tumor pathology, and evolutionary and epidemiologic data. Under this model, we obtained a final score of 349,000:1 in favor of disease causality. This result largely matches established cutoffs, and thus is readily translatable into a clear clinical message. CONCLUSION: We show that p.Val1688del is a pathogenic mutation deriving from a common founder. Notably, this study alone increases by 15% the number of BRCA1-positive families in our patients' cohort, thus substantially contributing to explain many of the families wherein prediction of a BRCA1 mutation contrasted with the absence of a molecular recognizable defect.
Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Mutación , Neoplasias Ováricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/epidemiología , Análisis Mutacional de ADN , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Exones , Femenino , Amplificación de Genes , Humanos , Italia/epidemiología , Pérdida de Heterocigocidad , Persona de Mediana Edad , Neoplasias Ováricas/epidemiología , Linaje , Reacción en Cadena de la Polimerasa , Factores de RiesgoRESUMEN
Predisposition to familial cutaneous malignant melanoma has been associated with mutations in the CDKN2A and CDK4 genes. However, only a small subgroup of melanoma pedigrees harbour CDKN2A or CDK4 germline mutations. It is possible that other types of CDKN2A rearrangements, not detectable by routine PCR-based approaches, are involved in a fraction of melanoma cases negative for point sequence changes. In order to gain insights on the possible role of CDKN2A large deletions or duplications in melanoma susceptibility in the Italian population, we screened a series of 124 cutaneous malignant melanoma families referred to five national medical/cancer genetics centres. All probands were negative for point mutations in CDKN2A and CDK4. All samples were tested by MLPA (multiplex ligation-dependent probe amplification), and the results were confirmed by real-time quantitative PCR in a subset of 53 cases. No genomic rearrangements were detected in this series, one of the largest so far investigated. These data suggest that large deletions/duplications in the CDKN2A locus are infrequently involved in the development of familial melanoma in the Italian population. Based on these results, routine search for these rearrangements in CDKN2A- and CDK4-mutation negative melanoma families is not warranted, although it would be reasonable to pursue it in selected cases with very strong family history and/or showing linkage to 9p21.
Asunto(s)
Quinasa 4 Dependiente de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Eliminación de Gen , Predisposición Genética a la Enfermedad , Humanos , Italia , Células Jurkat , Linaje , Mutación Puntual/genéticaRESUMEN
A single-nucleotide polymorphism (SNP) in the promoter of the MDM2 gene, SNP309 (a T-->G change), was recently implicated in the early onset of cancer in individuals with Li-Fraumeni syndrome and of sporadic soft-tissue sarcoma. SNP309 induces an increase in the level of Mdm2 protein, which causes attenuation of the p53 pathway. To investigate the effect of this polymorphism in colorectal cancer pathogenesis, we genotyped 153 colorectal cancer patients who were randomly selected from among 330 consecutive patients stratified according to p53 mutation status and age at diagnosis, for alleles of MDM2-SNP309. Among the 77 patients with p53 wild-type tumors, the median age at colorectal cancer diagnosis was 71.5 years for patients with the T/T genotype and 61.0 years for patients with SNP309 (T/G or G/G genotype) (estimated difference between medians [Hodges-Lehmann method] = 8.0 years, 95% confidence interval = 1.0 to 16.0 years; P = .03 [two-sided Wilcoxon rank sum test]). Our data indicate that MDM2-SNP309 is a modifier of the age at colorectal cancer onset for patients whose tumors have a wild-type p53 gene.
Asunto(s)
Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Genes p53 , Mutación , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-mdm2/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Genotipo , Glicina , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , TreoninaRESUMEN
The presence of genomic rearrangements of the BRCA1 gene in breast and/or ovarian cancer families has been intensively investigated in patients from various countries over the last years. A number of different rearrangements have been reported by several studies that clearly document the involvement of this mutation type in genetic predisposition to breast and ovarian cancer. Population-specific studies are now needed to evaluate the prevalence of genomic rearrangements before deciding whether to include ad hoc screening procedures into standard diagnostic mutation detection approaches. Indeed, the vast majority of the studies have been performed on small, highly selected, sample sets because of the limitations imposed by the laborious technical approaches. Moreover, prevalence figures are likely to differ across different countries according to the ethnic origin of each specific population. Here we analyze a large cohort of 653 Italian probands, negative for BRCA1 and BRCA2 point mutations, gathered from four National Institutions. We report the identification of BRCA1 genomic rearrangements in 12 independent families. Noteworthy, half of the probands carry mutations that recur in more than one Italian family. Considering the whole spectrum of Italian BRCA1 gene rearrangements identified thus far in consecutive patients, we estimate that alterations of this type account for 19% (95% CI: 0.11 < 0.19 < 0.28) of the BRCA1 mutation positive families. We conclude that the search for major genomic rearrangements is essential for an accurate and comprehensive BRCA1 mutation detection strategy in Italy.
Asunto(s)
Neoplasias de la Mama/genética , Reordenamiento Génico/genética , Genes BRCA1 , Genes BRCA2 , Neoplasias Ováricas/genética , Mutación Puntual , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Neoplasias de la Mama/epidemiología , Femenino , Genoma Humano , Humanos , Italia/epidemiología , Persona de Mediana Edad , Datos de Secuencia Molecular , Neoplasias Ováricas/epidemiología , PrevalenciaAsunto(s)
Genes Relacionados con las Neoplasias/genética , Predisposición Genética a la Enfermedad/genética , Melanoma/genética , Mutación/genética , Neoplasias Cutáneas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Familia , Humanos , Italia , Modelos Logísticos , Análisis Multivariante , Neoplasias Primarias Múltiples/genéticaRESUMEN
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is generally associated with Helicobacter pylori infection and, in the great majority of patients, regresses after eradication. H. pylori-negative MALT lymphoma occurs in a small minority of cases in which treatment is based on surgery or chemoradiotherapy. In the search for H. pylori based on histology and the C13 urea breath test, this report describes a case with a series of false-negative results, thus confirming the possibility of a lower detectability of H. pylori in patients with MALT gastric lymphoma and supporting the use of additional tests in evaluating such pathology, including polymerase chain reaction. Additionally, treatment with CD20 monoclonal antibody (rituximab) is suggested as an alternative to surgery or treatment with chemotherapy or radiotherapy in patients with truly H. pylori-negative gastric MALT lymphoma.
Asunto(s)
Infecciones por Helicobacter/diagnóstico , Helicobacter pylori/aislamiento & purificación , Linfoma de Células B de la Zona Marginal/diagnóstico , Neoplasias Gástricas/diagnóstico , Adulto , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Biopsia con Aguja , Femenino , Estudios de Seguimiento , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastroscopía , Infecciones por Helicobacter/complicaciones , Humanos , Inmunohistoquímica , Linfoma de Células B de la Zona Marginal/complicaciones , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Medición de Riesgo , Rituximab , Neoplasias Gástricas/complicaciones , Resultado del TratamientoAsunto(s)
Neoplasias de las Trompas Uterinas/epidemiología , Neoplasias de las Trompas Uterinas/patología , Trompas Uterinas/patología , Neoplasias de las Trompas Uterinas/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Neoplasias de Anexos y Apéndices de Piel/patologíaRESUMEN
The recent identification of major genomic rearrangements in breast and breast/ovarian cancer families has widened the mutational spectrum of the BRCA1 gene, thus increasing the number of informative patients who can benefit from molecular screening. Numerous types of alterations have been identified in different populations with variable frequencies, probably due to both ethnic diversity and the technical approach employed. In fact, although several methods have been successfully used to detect large genomic deletions and insertions, most are laborious, time-consuming, and of variable sensitivity. In order to estimate the contribution of BRCA1 genomic rearrangements to breast/ovarian cancer predisposition in Italian families, we applied, for the first time as a diagnostic tool, the recently described multiplex ligation-dependent probe amplification (MLPA) methodology. Among the 37 hereditary breast/ovarian cancer (HBOC) families selected, all had a high prior probability of BRCA1 mutation, and 15 were previously shown to carry a mutation in either the BRCA2 (five families) or BRCA1 gene (10 families, including one genomic rearrangement). The application of BRCA1-MLPA to the remaining 22 uninformative families allowed the identification of five additional genomic rearrangements. Moreover, we observed that loss of constitutive heterozygosity of polymorphic markers in linkage disequilibrium is predictive of such BRCA1 alterations. By means of this approach, we demonstrate that BRCA1 genomic deletions account for more than one-third (6/15) of the pathogenic BRCA1 mutations in our series. We therefore propose to systematically include MLPA in the BRCA1 mutational analysis of breast/ovarian cancer families.