ABSTRACT
BACKGROUND: Sarcomas in adults can be associated with hereditary cancer syndromes characterized by early-onset predisposition to numerous types of cancer. Because of variability in familial presentation and the largely unexplained genetic basis of sarcomas, ascertainment of patients for whom a genetics evaluation is most indicated poses challenges. We assessed the utility of a Sarcoma Clinic Genetic Screening (scgs) questionnaire in facilitating that task. METHODS: Between 2008 and 2012, 169 patients (median age: 53 years; range: 17-88 years) completed a self-administered scgs questionnaire. A retrospective chart review was completed for all respondents, and descriptive statistics were reported. Probands were divided into two groups depending on whether they did or did not report a family history of Li-Fraumeni syndrome-type cancers. RESULTS: A family history of cancer (as far as 3rd-degree relatives) was reported in 113 of 163 sarcoma patients (69%). Eeles Li-Fraumeni-like (lfl) criteria were fulfilled in 46 probands (28%), Chompret lfl in 21 (13%), Birch lfl in 8 (5%), and classic Li-Fraumeni in none. In the 10 probands tested for TP53 mutations, 1 pathogenic mutation was found. Further investigation of selected families led to the discovery of germline mutations in MLH1, MSH2, and APC genes in 3 individuals. CONCLUSIONS: The scgs questionnaire was useful for ascertaining probands with sarcoma who could benefit from a genetic assessment. The tool allowed us to identify high-risk families fitting the criteria for lfl and, surprisingly, other hereditary cancer syndromes. Similar questionnaires could be used in other cancer-specific clinics to increase awareness of the genetic component of these cancers.
ABSTRACT
We identified an MSH6 mutation (c.10C>T, p.Gln4*) causing Lynch syndrome (LS) in 11 French Canadian (FC) families from the Canadian province of Quebec. We aimed to investigate the molecular and clinical implications of this mutation among FC carriers and to assess its putative founder origin. We studied 11 probands and 27 family members. Additionally 6433 newborns, 187 colorectal cancer (CRC) cases, 381 endometrial cancer (EC) cases and 179 additional controls, all of them from Quebec, were used. Found in approximately 1 of 400 newborns, the mutation is one of the most common LS mutations described. We have found that this mutation confers a greater risk for EC than for CRC, both in the 11 studied families and in the unselected cases: EC [odds ratio (OR) = 7.5, p < 0.0001] and CRC (OR = 2.2, p = 0.46). Haplotype analyses showed that the mutation arose in a common ancestor, probably around 430-656 years ago, coinciding with the arrival of the first French settlers. Application of the results of this study could significantly improve the molecular testing and clinical management of LS families in Quebec.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA-Binding Proteins/genetics , Ethnicity/genetics , Founder Effect , Mutation , Adolescent , Adult , Aged , Canada/epidemiology , Child , Child, Preschool , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/genetics , Family , Female , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Heterozygote , Humans , Loss of Heterozygosity , Male , Middle Aged , Quebec , Risk , Young AdultABSTRACT
Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3-5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Founder Effect , Mutation/genetics , Neoplasm Proteins/genetics , Adaptor Proteins, Signal Transducing , Adult , Carrier Proteins , Evolution, Molecular , Haplotypes/genetics , Humans , Immunohistochemistry , Italy/ethnology , Microsatellite Repeats/genetics , Middle Aged , MutL Protein Homolog 1 , Nuclear Proteins , Pedigree , Quebec , Sequence Analysis, DNASubject(s)
Carcinoma, Medullary/genetics , Cornea/innervation , Drosophila Proteins , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Thyroid Neoplasms/genetics , Alleles , Carcinoma, Medullary/pathology , Cornea/pathology , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Family Health , Female , Germ-Line Mutation , Humans , Male , Middle Aged , Mutation, Missense , Pedigree , Proto-Oncogene Proteins c-ret , Thyroid Neoplasms/pathologyABSTRACT
We describe a French Canadian hereditary non-polyposis colorectal cancer (HNPCC) kindred which carries a novel truncating mutation in hMLH1. Interestingly, the I1307K APC polymorphism, associated with an increased risk of colorectal cancer, is also present in this family. The I1307K polymorphism has previously only been identified in individuals of self-reported Ashkenazi Jewish origins. In addition, in this family, there appears to be no relationship between the I1307K polymorphism and the presence or absence of cancer.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Cytoskeletal Proteins/genetics , DNA-Binding Proteins , Neoplasm Proteins/genetics , Adaptor Proteins, Signal Transducing , Adenomatous Polyposis Coli Protein , Amino Acid Substitution , Carrier Proteins , DNA Mutational Analysis , Family , Female , Humans , Male , MutL Protein Homolog 1 , MutS Homolog 2 Protein , Mutation , Nuclear Proteins , Pedigree , Polymorphism, Genetic , Proto-Oncogene Proteins/geneticsABSTRACT
We have studied two brothers with submicroscopic 22q11 deletion. One brother had findings suggestive of DiGeorge syndrome, while the other had milder anomalies, including polydactyly. Fluorescence in situ hybridization (FISH) showed a minor cell line with deletion 22q11 in the mother. To our knowledge, this is the first report of a deletion of 22q11 in two sibs with different phenotypes and apparent maternal mosaicism detected with FISH. This family illustrates the variability of the syndrome and further demonstrates the possibility of gonadal mosaicism for a microdeletion. Prenatal diagnosis may be offered after the birth of a child with a 22q11 deletion, even in the absence of parental chromosomal anomalies.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 22/genetics , Child , Child, Preschool , Chromosome Banding , DiGeorge Syndrome/genetics , Genetic Markers , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Mosaicism/genetics , PhenotypeABSTRACT
Benign thyroid disease is a risk factor for nonmedullary thyroid carcinoma [Houlston and Stratton: Q J Med 88:685-693, 1995]. We report on a family with 7 members with benign and/or malignant thyroid neoplasia; one affected female died of a paravertebral alveolar rhabdomyosarcoma at age 20. The occurrence of thyroid nodular hyperplasia, nonmedullary thyroid cancer, and rhabdomyosarcoma in the same family may be due to chance, common environmental factors, or, most likely, genetic predisposition.
Subject(s)
Graves Disease , Muscle Neoplasms , Thyroid Neoplasms , Adolescent , Child , Female , Goiter/genetics , Graves Disease/genetics , Humans , Male , Muscle Neoplasms/genetics , Pedigree , Rhabdomyosarcoma, Alveolar/genetics , Risk Factors , Thymoma/genetics , Thyroid Diseases/genetics , Thyroid Neoplasms/geneticsABSTRACT
A 7-year-old boy with deficient activity of methylmalonyl coenzyme A mutase (mut-methylmalonic acidemia) was seen in severe metabolic crisis. After hemodialysis and clearance of toxic metabolites, severe lactic acidosis persisted with multiorgan failure. Glutathione deficiency was noted and high-dose ascorbate therapy (120 mg/kg) commenced. Glutathione deficiency may contribute to the lactic acidosis observed during decompensation in patients with methylmalonic acidemia.
Subject(s)
Amino Acid Metabolism, Inborn Errors/complications , Ascorbic Acid/administration & dosage , Glutathione/deficiency , Methylmalonic Acid/blood , Acidosis, Lactic/etiology , Acidosis, Lactic/therapy , Acute Disease , Amino Acid Metabolism, Inborn Errors/therapy , Child , Humans , Male , Renal DialysisABSTRACT
Intercellular gap junction channels are thought to form when oligomers of connexins from one cell (connexons) register and pair with connexons from a neighboring cell en route to forming tightly packed arrays (plaques). In the current study we used the rat mammary BICR-M1Rk tumor cell line to examine the trafficking, maturation, and kinetics of connexin43 (Cx43). Cx43 was conclusively shown to reside in the Golgi apparatus in addition to sites of cell-cell apposition in these cells and in normal rat kidney cells. Brefeldin A (BFA) blocked Cx43 trafficking to the surface of the mammary cells and also prevented phosphorylation of the 42-kD form of Cx43 to 44- and 46-kD species. However, phosphorylation of Cx43 occurred in the presence of BFA while it was still a resident of the ER or Golgi apparatus yielding a 43-kD form of Cx43. Moreover, the 42- and 43-kD forms of Cx43 trapped in the ER/Golgi compartment were available for gap junction assembly upon the removal of BFA. Mammary cells treated with BFA for 6 h lost preexisting gap junction "plaques," as well as the 44- and 46-kD forms of Cx43 and functional coupling. These events were reversible 1 h after the removal of BFA and not dependent on protein synthesis. In summary, we provide strong evidence that in BICR-M1Rk tumor cells: (a) Cx43 is transiently phosphorylated in the ER/Golgi apparatus, (b) Cx43 trapped in the ER/Golgi compartment is not subject to rapid degradation and is available for the assembly of new gap junction channels upon the removal of BFA, (c) the rapid turnover of gap junction plaques is correlated with the loss of the 44- and 46-kD forms of Cx43.
Subject(s)
Connexin 43/metabolism , Endoplasmic Reticulum/metabolism , Gap Junctions/metabolism , Receptors, Cell Surface , Animals , Antifungal Agents/pharmacology , Brefeldin A , Cell Line , Connexin 43/antagonists & inhibitors , Cycloheximide/pharmacology , Cyclopentanes/pharmacology , Gap Junctions/drug effects , Golgi Apparatus/metabolism , Isomerases/metabolism , Kinetics , Mammary Neoplasms, Animal , Phosphorylation , Protein Biosynthesis , Protein Disulfide-Isomerases , Protein Synthesis Inhibitors/pharmacology , Rats , Receptors, Fibroblast Growth Factor , Sialoglycoproteins/metabolism , Tumor Cells, Cultured , Uncoupling Agents/pharmacologyABSTRACT
Peptide analogues of Sch 37137 the antifungal antibiotic have been synthesized and evaluated in vitro against Candida sp. Di- and tripeptides containing methionine, leucine, norvaline, lysine, glutamic acid and N3-(trans-epoxysuccinamoyl)-L-2,3-diaminopropanoic acid, (EADP) were obtained. Peptides containing (D)-, and (L)-trans-epoxysuccinamic acid were also prepared. All of the analogues examined displayed in general higher anticandidal activity than a mixture of diastereomers of Sch 37137.
Subject(s)
Antifungal Agents/pharmacology , Candida/drug effects , Amino Acids, Diamino/chemistry , Amino Acids, Diamino/pharmacology , Antifungal Agents/chemistry , Magnetic Resonance Spectroscopy , Structure-Activity RelationshipABSTRACT
The binding of several anticandidal peptides containing N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP) to serum proteins was studied using equilibrium dialysis. The affinity of these FMDP-peptides for serum albumin was low and well correlated with their biological activity against Candica albicans ATCC 26278 in serum albumin solution. This binding did not affect the biological activity of FMDP-peptides. On the other hand, substantial raising of MIC values was observed when anticandidal activity of FMDP peptides was assayed in the presence of complete serum proteins. This effect was likely to be a result of interaction with non-albumin components of serum proteins. Preliminary evidence points to the possibility of non-specific interaction with components containing sulfhydryl groups. In this study Nva-FMDP-Nva peptide was shown to be the most active compound in the serum protein solution. Moreover Nva-FMDP-Nva was most resistant to inactivation by serum components in comparison to other FMDP-peptides.
Subject(s)
Antifungal Agents/pharmacology , Blood Proteins/pharmacology , Fumarates/pharmacology , Peptides/pharmacology , beta-Alanine/analogs & derivatives , Animals , Antifungal Agents/metabolism , Blood Proteins/metabolism , Candida albicans/drug effects , Cattle , Dipeptides/pharmacology , Drug Interactions , Fumarates/metabolism , Humans , Kinetics , Microbial Sensitivity Tests , Peptides/metabolism , Serum Albumin, Bovine/metabolism , Serum Albumin, Bovine/pharmacology , beta-Alanine/metabolism , beta-Alanine/pharmacologyABSTRACT
The mechanism of anticandidal action of novel synthetic dipeptides containing N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP) residues was shown to be consistent with the "warhead delivery" concept. FMDP dipeptides were shown to be transported into Candida albicans cells by the di-tripeptide permease and subsequently hydrolyzed by intracellular peptidases, especially aminopeptidase. The anticandidal activity of the particular FMDP dipeptide was influenced by the rate of its transport and, to a lower extent, by the intracellular cleavage rate. A high transport rate accompanied by a high cleavage rate resulted in the high anticandidal activity of L-norvalyl-FMDP. The strong growth-inhibitory effect of this compound was the consequence of inhibition of the enzyme glucosamine-6-phosphate synthase by the released FMDP. The action of L-norvalyl-FMDP on exponentially growing C. albicans cells resulted in a sharp decrease of incorporation of 14C label from [14C]glucose into chitin, mannoprotein, and glucan. This effect, as well as the growth-inhibitory effect, was fully reversed by exogenous N-acetyl-D-glucosamine. Glucosamine-6-phosphate synthase was proved to be the only essential target for FMDP dipeptides. Scanning electron microscopy of C. albicans cells treated with L-norvalyl-FMDP revealed highly distorted, wrinkled, and collapsed forms. Cells formed long, bulbous chains, and partial lysis occurred.