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PubMed1998

Characterization of ten novel and 13 recurring BRCA1 and BRCA2 germline mutations in Italian breast and/or ovarian carcinoma patients. Mutations in brief no. 178. Online.

Germline mutations in the BRCA1 and BRCA2 genes are associated with approximately 80% of families with a high incidence of breast and/or ovarian cancers (OMIM database reference numbers: 113705, 600185). Furthermore, constitutional mutations in the these genes have been reported in women with early-onset breast carcinoma and without family history of cancer. We analyzed by protein truncation test (PTT) and single strand conformation polymorphism (SSCP) followed by sequence analysis, BRCA1 exons 11 and 20 and BRCA2 exons 10 and 11 in 142 Italian cancer patients. These included six male breast cancer cases, 61 women with breast carcinoma diagnosed before 36 years old and selected independently of family history of breast cancer and 75 familial breast and/or ovarian cancer patients. In a previous report, we described 11 different BRCA1 mutations in a subset of 70 cases. Here, we report the characterization of 23 additional mutations, 14 in BRCA1 and 9 in BRCA2, subsequently identified. Ten mutations were not previously described, while the other 13 were recurrent. Of the 61 women with early-onset breast cancer, 11 carried a germline mutation in BRCA1 (18.0%) and four in BRCA2 (6.6%). These frequencies indicate that BRCA1/BRCA2 genetic tests should be advised to women with breast cancer diagnosed at early age, independently of family history of cancer.

BRCA1 Protein↗
PubMed1992

Origin heterogeneity of Hb Lepore-Boston gene in Italy.

Forty-three hybrid delta-beta-globin genes were characterized by DNA sequence analysis and associated RFLP haplotypes in 40 families from Abruzzo and Campania, which are on the east and west coast of Italy, respectively. All the genes had the delta-globin sequence up to the exon 2 codon 87 and had the beta-globin sequence from IVS-2-8; between these two ends, they had 58 bp in common with the delta- and beta-globin genes. Thus, they were all of the Lepore-Boston type. A chromosomal background heterogeneity was present among the mutant genes. In fact, they were all associated with (+ - - - -) 5' subhaplotype, but 23/31 from Campania were associated with (+ +) 3' subhaplotype, whereas 12/12 genes from Abruzzo and 8/31 from Campania were associated with (+ -). DNA sequencing of homozygous subjects showed that (+ +) 3' subhaplotype was associated, at IVS-2-74, with G, while (+ -) was associated with T; that is they were associated with the beta-globin gene sequence of frameworks 1 and 2, respectively. The molecular characteristics of this heterogeneity, as well as its geographical patterns in the eastern and western regions of Italy, represent strong evidence for the recurrent and multicentric origins of the mutation.

Base Sequence↗
PubMed2005

Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence.

Thrombophilia is the term now used to describe predisposition to increased risk of venous and occasionally arterial thromboembolism due to hematological abnormalities. It can be a multifactorial disorder where congenital defects of anticoagulant or procoagulant factors may be combined with acquired hematological abnormalities. It should be considered in patients with a documented unexplained thrombotic episode or a positive family history. The aim of this document is to provide guidelines for investigation and management of patients with thrombophilia in the presence or absence of venous thromboembolism (VTE).

Activated Protein C Resistance↗
PubMed1997

[Multigenic thrombophilia: genetic anomaly of factor II and mutation of factor V Leiden. Study in a French family].

BACKGROUND: A genetic variation of the prothrombin (factor II) gene, a G to A transition at nucleotide position 20210, was recently found in patients with familial thrombophilia (predisposition to venous thrombosis). It seems to be frequent in patients with the factor V Leiden mutation. We report a family with the factor V Leiden and/or the genetic variation of prothrombin in 3 members. CASE REPORT: The patient had repeated episodes of deep vein thromboses starting at the age of 30 during the 4th pregnancy. She is a heterozygous carrier of both the factor V Leiden nutation and the prothrombin mutation 20210 A. She has 4 asymptomatic children, aged 28 to 32 and 3 of them have been explored: one son has the prothrombin mutation, one daughter the factor V Leiden and one has none of them. DISCUSSION: This case report illustrates the polygenic nature of thrombophilia which may explain the heterogeneity of clinical expression observed in isolated congenital abnormalities, especially in factor V Leiden mutation.

Chromosome Aberrations↗
PubMed1997

[Genetic susceptibility to pancreatitis].

Pancreatitis is a complicated polyetiological disease rather frequently met with. Inflammatory degenerative changes in the pancreas are the underlying cause of the condition which in acute cases may give rise to irreversible pancreonecrosis, and in chronic ones--to fibrosis development and severe pain syndrome. Of utmost importance is the patient's genetic susceptibility to pancreatitis. The purpose of the study is to assay the role of genetic factors involved in the etiopathogenesis of pancreatitis. The interest focused on alpha1 antitrypsin (alpha 1 AT) arises from the fact that its mutant forms are implicated in the destructive processes within the organism. The reduced inhibitory activity of alpha 1 AT enhances the action exerted by the proteolytic enzymes--trypsin and chymotrypsin [correction of hemotrypsin]. Impairment of the balance between proteases and their inhibitors plays certain role in pancreatitis development. Seventy patients, 44 men and 26 women, are covered by the study, with 42 of them presenting acute pancreatitis, and 28--chronic relapsing form. A high rate of alpha 1 AT mutant genes carrier state is established--14.28 per cent, exceeding statistically significantly the incidence of alpha 1 AT variants in the Bulgarian population--4.95 per cent (p < 0.01). In acute pancreatitis patients the incidence of alpha 1 AT variants is 2.38 per cent, and in chronic forms--32.14 per cent. In pancreatitis patients alpha 1 AT deficit brings about genetic predisposition to serious complications, e.g. chronification of the process. Individual therapeutic approach is mandatory, with Kontrikal used in chronic relapsing pancreatitis in the form of substitutive medication, and in acute pancreatitis--according to judgement depending on the clinical picture and laboratory findings.

Acute Disease↗
PubMed2005

A simple and fast method for the simultaneous detection of nine fibroblast growth factor receptor 3 mutations in bladder cancer and voided urine.

PURPOSE: Mutations in the fibroblast growth factor receptor 3 (FGFR3) occur in 50% of primary bladder tumors. An FGFR3 mutation is associated with good prognosis, illustrated by significantly lower percentage of patients with progression and disease-specific mortality. FGFR3 mutations are especially prevalent in low grade/stage tumors, with pTa tumors harboring mutations in 85% of the cases. These tumors recur in 70% of patients. Efficient FGFR3 mutation detection for prognostic purposes and for detection of recurrences in urine is an important clinical issue. In this paper, we describe a simple assay for the simultaneous detection of nine different FGFR3 mutations. EXPERIMENTAL DESIGN: The assay consists of one multiplex PCR, followed by extension of primers for each mutation with a labeled dideoxynucleotide. The extended primers are separated by capillary electrophoresis, and the identity of the incorporated nucleotide indicates the presence or absence of a mutation. RESULTS: The assay was found to be more sensitive than single-strand conformation polymorphism analysis. Mutations could still be detected with an input of only 1 ng of genomic DNA and in a 20-fold excess of wild-type DNA. Moreover, in urine samples from patients with a mutant tumor, the sensitivity of mutation detection was 62%. CONCLUSIONS: We have developed a fast, easy to use assay for the simultaneous detection of FGFR3 mutations, which can be of assistance in clinical decision-making and as an alternative for the follow-up of patients by invasive cystoscopy for the detection of recurrences in urine.

DNA↗
PubMed2003

Analysis of the three most common MEFV mutations in 412 patients with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever is an autosomal recessive disease characterized by recurrent attacks of fever and serositis. The disease is caused by mutations in the MEFV gene, presumed to act as a down-regulator of inflammation within the polymorphonuclear cells. OBJECTIVES: To present the results of 412 FMF patients genotyped for three MEFV mutations, M694V, V726A and E148Q. RESULTS: The most frequent mutation, M694V, was detected in 47% of the carrier chromosomes. This mutation, especially common among North African Jewish FMF patients, was not found in any of the Ashkenazi (East European origin) patients. Overall, one of the three mutations was detected in 70% of the carrier chromosomes. M694V/M694V was the most common genotype (27%), followed by M694V/V726A (16%). The full genotype could be assessed in 57% of the patients, and one disease-causing mutation in an additional 26%. Only one patient with the E148Q/E148Q genotype was detected despite a high carrier rate for this mutation in the Jewish population, a finding consistent with a low penetrance of this genotype. The M694V/M694V genotype was observed in 15 patients with amyloidosis compared to 4 amyloidosis patients with other genotypes (P < 0.0001). CONCLUSIONS: Because of low penetrance and as yet other undetermined reasons, mutation analysis of the most common MEFV mutations supports a clinical diagnosis in only about 60% of patients with definite FMF.

Amyloidosis↗
PubMedDate not supplied

Persistence of K-ras mutations in plasma after colorectal tumor resection.

Free DNA in the circulation is increased five-to ten-fold in patients with solid tumours compared to healthy controls. A range of tumor-specific mutated DNA has been shown to be readily extractable and possible to analyse from plasma and serum in these patients. K-ras oncogene mutations are an early event in a subset of colorectal tumors and have been found in 30-60% of patients with colorectal carcinoma (CRC). The presence of tumor-derived k-ras gene mutations in the circulation has previously been described before surgery. The aim of this study was to characterize the presence of mutant k-ras in plasma in the short-term postoperative period after radical surgery of CRC patients, and further to characterize this in relation to relapse of the disease. Tumors and corresponding plasma pre- and postoperatively on day three after surgery were collected from 25 patients with CRC (Dukes' stage A-D). Biopsies for DNA extraction from the tumors were collected from the most invasive parts microscopically. After PCR amplification of the k-ras gene (codon 12 and 13), the presence of mutations was analysed by TGGE (temperature gradient gel electrophoresis). Twenty four/25 patients underwent putatively curative resections. Sixteen of the 25 patients (64%) expressed k-ras mutations in their tumor. Of these, 9 patients (56%) also had detectable k-ras mutations in preoperative plasma samples. On day three postoperatively, 8 of these patients persistently were found to have mutant k-ras in the plasma. This was not correlated with tumor stage. None of the 9 tumor mutation-negative cases expressed mutated k-ras in their plasma pre- or postoperatively. The results indicate that plasma mutant k-ras can be detected pre- and early postoperatively in all stages of colorectal neoplasia. No correlation between short-term postoperative persistence of mutant plasma-DNA and disease recurrence at follow-up was found. However, the use of k-ras as a marker during postoperative follow-up and as a possible tool for early detection of recurrent disease must be further characterized.

Aged↗
PubMed2001

Mutations of the cystic fibrosis gene in patients with chronic pancreatitis.

OBJECTIVE: Several studies have reported an increased frequency of cystic fibrosis gene mutations in idiopathic but not in alcoholic chronic pancreatitis. The impact of cystic fibrosis gene mutations on the long-term course of chronic pancreatitis has not been analyzed. The aim of our study was to determine the frequency of cystic fibrosis gene mutations in patients with chronic pancreatitis with long-term follow-up and to see whether patients with mutations have a clinically different natural course compared to those without mutations. METHODS: Eighty two patients with chronic pancreatitis and 11 patients with recurrent acute pancreatitis of our well defined pancreatitis cohort were screened for the 31 most common cystic fibrosis gene mutations. The impact of cystic fibrosis gene mutations on the long-term course of chronic pancreatitis was assessed. RESULTS: A cystic fibrosis gene mutation was detected in five of 49 patients with alcoholic chronic pancreatitis (10.2%; 2.3 times the expected frequency) and in three of 14 patients with idiopathic-juvenile chronic pancreatitis (21.4%; 4.8 times the expected frequency). No mutations were found in the remaining patients with chronic pancreatitis of rare causes, hereditary pancreatitis, and recurrent acute pancreatitis. The frequency of pancreatic calcifications was significantly higher in patients with alcoholic chronic pancreatitis without mutations. This result was not confirmed in patients with idiopathic-juvenile chronic pancreatitis. The duration of pain and the frequency of exocrine and endocrine insufficiency was comparable in both subgroups irrespective of the mutation status. CONCLUSION: Our data indicate a significantly increased frequency of cystic fibrosis gene mutations both in patients with alcoholic and idiopathic-juvenile chronic pancreatitis. The natural course was similar in patients with mutations compared to those without mutations.

Adult↗
PubMed2001

Familial breast cancer: an investigation into the outcome of treatment for early stage disease.

The purpose of this study was to retrospectively compare the outcomes of treatment in 304 women with familial and sporadic breast cancer to clarify the options for the primary management of familial breast cancer. The majority of women were consecutively ascertained on the basis of either breast cancer diagnosed at age < 40 years or bilateral breast cancer. In addition, known BRCA1 mutation carriers were identified through the genetics services in participating centres. These patients were subdivided into those with a significant family history of breast cancer or known BRCA1 mutation (FH+) and those with no significant family history (FH-). There were no significant differences in age, surgical treatment or adjuvant treatment between the two groups, but there were significantly more women whose nodal status was unknown in the FH+ group. Ipsilateral recurrence occurred in 22.2% of FH+ patients compared with 24.1% of FH- patients (p = 0.774) who underwent breast conserving surgery. There was a striking excess of contralateral breast cancers in the FH+ group (35.9% v 16%, p = 0.0007), with a cumulative risk of contralateral cancer of 36% at 10 years. This was reflected in a non-significant trend toward worse relapse free survival in the FH+ group (p = 0.0563), but no difference was observed in overall survival between the two patient groups (p = 0.142). Similarly, for patients with known BRCA1 mutations, contralateral recurrence occurred more frequently, but other outcomes were not significantly different from the FH- group. Breast conserving treatment is not associated with an increased risk of local recurrence in women with familial breast cancer and the prognosis of these women appears to be similar to that of young women with apparently sporadic breast cancer. However, the risk of contralateral breast cancer is significant in the FH+ group and should be considered in planning primary treatment and follow up.

Adult↗
PubMed2005

Approach to genetic analysis in the diagnosis of hereditary autoinflammatory syndromes.

OBJECTIVE: Hereditary autoinflammatory syndromes are characterized by recurrent episodes of fever and inflammation. Seven subtypes have been described, caused by mutations in four different genes. Apart from a common phenotype of lifelong recurrent inflammatory attacks, all subtypes have distinct features and specific therapeutic options, which emphasizes the need for a specific diagnosis in each case. Our aim was to examine whether genetic screening would allow classification of previously unclassified patients, and whether individual patients suffering from an autoinflammatory syndrome carry additional mutations in one of the other autoinflammatory genes. METHODS: We included 60 patients with an unclassified autoinflammatory syndrome, 87 patients diagnosed with either hyper-IgD syndrome, familial Mediterranean fever (FMF) or tumour necrosis factor (TNF)-receptor-associated periodic syndrome and 50 healthy controls. Deoxyribonucleic acid samples were screened for the most prevalent mutations in the MEFV, TNFRSF1A, MVK and CIAS1 genes. RESULTS: We found only one possible diagnosis of FMF in the 60 previously unclassified patients. Two low-penetrance mutations were found in equal numbers in the groups of patients and controls. CONCLUSIONS: Screening of highly prevalent mutations in known genes involved in these disorders does not yield additional relevant information. Differential diagnosis of hereditary autoinflammatory syndromes can be made by thorough clinical examination followed by targeted genetic analysis of the one or two most likely syndromes. High-prevalence low-penetrant mutations from autoinflammatory genes do not occur more frequently in patients with hereditary autoinflammatory syndromes compared with the general population.

Adolescent↗
PubMed2001

Androgen receptor alterations in prostate cancer relapsed during a combined androgen blockade by orchiectomy and bicalutamide.

Mechanisms of prostate cancer (CaP) recurrence during a combined androgen blockade (CAB) are poorly understood. Previously, the role of androgen receptor (AR) gene mutations underlying the CAB therapy relapse has been raised. To investigate the hypothesis that AR gene aberrations are involved in CAB relapse, 11 locally recurrent CaP samples from patients treated with orchiectomy and bicalutamide were analyzed for copy number changes and DNA sequence alterations of the AR gene by fluorescence in situ hybridization and single-strand conformation polymorphism, respectively. Altogether, base changes were detected in four tumors (36%). Three of them were missense mutations (G166S, W741C, M749I) and two were silent polymorphisms. Interestingly, none of the tumors had AR amplification. These data suggest that different AR variants are developed and selected for during various types of hormonal treatments, and also, that CAB achieved by orchiectomy and bicalutamide does not act as a selective force for AR amplification.

Androgen Antagonists↗
PubMed2006

Wide clinical spectrum in a family with hereditary lymphedema type I due to a novel missense mutation in VEGFR3.

Hereditary lymphedema type I (HL-I), also known as Milroy disease, is an autosomal dominant disorder characterized by typical phenotype of infantile onset lower-limb lymphedema accompanied by variable expression of recurrent episodes of cellulites, toenail changes, and papillomatosis. Mutations in the vascular endothelial growth factor receptor 3 (VEGFR3), also known as FLT4 gene, which encodes a lymphatic endothelial-specific tyrosine kinase receptor, have been identified as a genetic cause of HL-I. We report a large Muslim Arab family residing in northern Israel with 14 individuals presenting clinical features of HL-I. Genetic analysis revealed novel missense mutation E1106K in the tyrosine kinase domain II of VEGFR3 that cosegregates with the disorder in the family. Most affected individuals presented with bilateral congenital lower-limb lymphedema. Wide intrafamilial phenotypic variability included two asymptomatic individuals, a case of prenatal hydrothorax evolving to hydrops fetalis, and a late-onset complication, yet unreported, of chronic degenerative joint disease of the knees. This report broadens the known "classic" phenotype of HL-I.

Adolescent↗
PubMed1997

P16 deletion and mutation analysis in human brain tumors.

We screened human primary and recurrent malignant glioma, juvenile pilocytic astrocytoma, medulloblastoma, and meningioma tissue specimens for alterations in p16 gene structure. Single strand conformation polymorphism (SSCP) analysis was used to screen for point mutations, and a quantitative polymerase chain reaction-based assay was used to screen for homozygous gene deletions. In malignant glioma specimens, homozygous p16 gene deletions were significantly more common in high-grade tumors than in low-grade gliomas. Point mutations causing alteration in predicted protein structure were not detected. Medulloblastomas showed rare homozygous deletions and no point mutations. No mutations were detected in meningiomas.

Carrier Proteins↗
PubMed2006

Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers.

INTRODUCTION: BRCA1 and BRCA2 mutation carriers are at increased risk for developing both breast and ovarian cancer. It has been suggested that carriers of BRCA1/2 mutations may also be at increased risk of having recurrent (three or more) miscarriages. Several reproductive factors have been shown to influence the risk of breast cancer in mutation carriers, but the effects of spontaneous and therapeutic abortions on the risk of hereditary breast cancer risk have not been well studied to date. METHODS: In a matched case-control study, the frequencies of spontaneous abortions were compared among 1,878 BRCA1 mutation carriers, 950 BRCA2 mutation carriers and 657 related non-carrier controls. The rates of spontaneous and therapeutic abortions were compared for carriers with and without breast cancer. RESULTS: There was no difference in the rate of spontaneous abortions between carriers of BRCA1 or BRCA2 mutations and non-carriers. The number of spontaneous abortions was not associated with breast cancer risk among BRCA1 or BRCA2 mutation carriers. However, BRCA2 carriers who had two or more therapeutic abortions faced a 64% decrease in the risk of breast cancer (odds ratio = 0.36; 95% confidence interval 0.16-0.83; p = 0.02). CONCLUSION: Carrying a BRCA1 or BRCA2 mutation is not a risk factor for spontaneous abortions and spontaneous abortions do not appear to influence the risk of breast cancer in carriers of BRCA1 or BRCA2 mutations. However, having two or more therapeutic abortions may be associated with a lowered risk of breast cancer among BRCA2 carriers.

Abortion, Spontaneous↗