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PubMed2001

Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations.

BACKGROUND & AIMS: Nonalcoholic chronic pancreatitis is usually idiopathic and often associated with cystic fibrosis gene (CFTR) mutations. It is unknown whether pancreatitis risk correlates with having 1 or 2 CFTR mutations, abnormal epithelial ion transport, or mutations of other genes. METHODS: We tested 39 patients with idiopathic chronic pancreatitis (mean age at diagnosis, 33 years) for common mutations of CFTR and of genes encoding a trypsin inhibitor (PSTI) and trypsinogen (PRSS1). To exclude hereditary pancreatitis, we initially relied on family history and subsequently tested for PRSS1 mutations. Twenty subjects were tested for rare CFTR mutations (DNA sequencing) and 11 were tested for extrapancreatic CFTR function (clinical and physiologic evaluation). RESULTS: Mutations were identified in 24 of 39 subjects. Nine patients had cystic fibrosis-causing mutations, 8 of whom also had mild-variable mutations. Eight others had only mild-variable mutations. Nine subjects had the N34S PSTI mutation and 1 had hereditary pancreatitis (R122H, PRSS1). Pancreatitis risk was increased approximately 40-fold by having 2 CFTR mutations (P < 0.0001), 20-fold by having N34S (P < 0.0001), and 900-fold by having both (P < 0.0001). Subjects with 2 CFTR mutations had abnormal nasal epithelial ion transport and clinical findings suggesting residual CFTR function between that in cystic fibrosis and in carriers. By contrast, subjects with only PSTI mutations had normal CFTR function. CONCLUSIONS: CFTR-related pancreatitis risk correlates with having 2 CFTR mutations and reduced extrapancreatic CFTR function. The N34S PSTI mutation increased risk separately. Testing for pancreatitis-associated CFTR and PSTI genotypes may be useful in nonalcoholic pancreatitis.

Adolescent↗
PubMed1998

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.

Chromosome Mapping↗
PubMed1999

Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carriers of BRCA1 mutations.

BACKGROUND: Breast carcinomas occurring in carriers of BRCA1 gene mutations may have a distinctly different pathway of molecular pathogenesis from those occurring in noncarriers. Data from murine models implicate loss of p53 (also known as TP53) gene function as a critical early event in the malignant transformation of cells with a BRCA1 mutation. Therefore, breast tumors from BRCA1 mutation carriers might be expected to exhibit a high frequency of p53 mutations. This study examined the frequency of p53 mutations in the breast tumors of Ashkenazi Jewish carriers and noncarriers of BRCA1 mutations. METHODS: Tumor DNA from carriers and noncarriers of BRCA1 mutations was screened for mutations in exons 4 through 10 of the p53 gene by use of the polymerase chain reaction and single-strand conformation polymorphism (SSCP) analysis of the amplified DNA. Direct sequencing was performed on gene fragments that showed altered mobility in SSCP analysis. RESULTS: Mutations in the p53 gene were detected in 10 of 13 tumors from BRCA1 mutation carriers versus 10 of 33 tumors from non-carriers (two-sided P = .007). The p53 mutations were distributed throughout exons 4 through 10 and included both protein-truncating and missense mutations in both groups. CONCLUSIONS: A statistically significantly higher frequency of p53 mutations was found in breast tumors from carriers of BRCA1 mutations than from noncarriers, which adds to the accumulating evidence that loss of p53 function is an important step in the molecular pathogenesis of BRCA1 mutation-associated breast tumors. This finding may have implications for understanding phenotypic differences and potential prognostic differences between BRCA1 mutation-associated hereditary breast cancers and sporadic cancers.

Adult↗
PubMed1996

Two mutations in exon XII of the protein S alpha gene in four thrombophilic families resulting in premature stop codons and depressed levels of mutated mRNA.

Sixteen Danish unrelated thrombophilic families with plasma protein S deficiency of type 1 (or III) are currently under investigation in our laboratory for defects in the protein S alpha gene. The present paper describes a part of this work, which deals with the identification and phenotypical presentation of two unique mutations in exon XII of the protein S alpha gene in four of these families. The mutations were identified by SSCP screening followed by nucleotide sequence analysis or by direct nucleotide sequence analysis. The mutation found in one family (D) is a novel deletion of an A in either the codon for Gly448 (GGA) or Ile449 (ATI) resulting in a frameshift and a premature stop codon at position 454. The other mutation shared by three families (F, G and J) is a previously reported C-->T transition within a hypermutable CG dinucleotide sequence converting Arg410 (CGA) to Stop (TGA). All affected individuals are heterozygotes for their mutation and in each family the protein S genotype, the plasma protein S phenotype (not shown for Family J) and the clinical phenotype cosegregate. The two mutations can fully explain the abnormal protein S phenotype since premature stop codons are known to disrupt gene function of the mutated allele. Analysis of protein S mRNA from platelets showed that both mutations result in a marked reduction in the amount of protein S mRNA from the mutated alleles indicating that the mutations exert their deleterious effects on gene expression at the transcriptional level. The Arg410-->Stop mutation in Families F, G and J is in all instances linked to a G at the site of a common neutral dimorphism in the codon for Pro626 (CCA/G) in exon XV. This indicates that the mutation in these families could have arisen in a common ancestor. The Arg410 (CGA)-->Stop (TGA) mutation is also seen in exon XII of the normal protein S alpha gene. This gives rise to the speculation as to whether the mutation in the protein S alpha gene is the result of an interaction with the protein S beta gene leading to double homologous unequal crossing-over or gene conversion of a short DNA sequence. However, this is unlikely since none of the 7 other protein S beta-specific nucleotides are present in the mutated exon XII sequence of the protein S alpha gene. The common Arg506-->Gln Leiden mutation in coagulation factor V is not an additional risk factor for thrombosis in any of the four families studied.

Adult↗
PubMed2000

Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds.

Hereditary nonpolyposis colorectal cancer (HNPCC) describes the condition of a disparate group of families that have in common a predisposition to colorectal cancer in the absence of a premalignant phenotype. The genetic basis of this disease has been linked to mutations in genes associated with DNA mismatch repair. A large proportion of families harbor changes in one of two genes, hMSH2 and hMLH1. Approximately 35% of families in which the diagnosis is based on the Amsterdam criteria do not appear to harbor mutations in DNA-mismatch-repair genes. In this report we present data from a large series of families with HNPCC and indicate that there are subtle differences between families that harbor germline changes in hMSH2 and families that harbor hMLH1 mutations. Furthermore, there are differences between the mutation-positive group (hMSH2 and hMLH1 combined) of families and the mutation-negative group of families. The major findings identified in this study focus primarily on the extracolonic disease profile observed between the mutation-positive families and the mutation-negative families. Breast cancer was not significantly overrepresented in the hMSH2 mutation-positive group but was overrepresented in the hMLH1 mutation-positive group and in the mutation-negative group. Prostate cancer was not overrepresented in the mutation-positive groups but was overrepresented in the mutation-negative group. In age at diagnosis of colorectal cancer, there was no difference between the hMSH2 mutation-positive group and the hMLH1 mutation-positive group, but there was a significant difference between these two groups and the mutation-negative group.

Adolescent↗
PubMed2004

Adaptive amplification and point mutation are independent mechanisms: evidence for various stress-inducible mutation mechanisms.

"Adaptive mutation" denotes a collection of processes in which cells respond to growth-limiting environments by producing compensatory mutants that grow well, apparently violating fundamental principles of evolution. In a well-studied model, starvation of stationary-phase lac(-)Escherichia coli cells on lactose medium induces Lac(+)revertants at higher frequencies than predicted by usual mutation models. These revertants carry either a compensatory frameshift mutation or a greater than 20-fold amplification of the leaky lac allele. A crucial distinction between alternative hypotheses for the mechanisms of adaptive mutation hinges on whether these amplification and frameshift mutation events are distinct, or whether amplification is a molecular intermediate, producing an intermediate cell type, in colonies on a pathway to frameshift mutation. The latter model allows the evolutionarily conservative idea of increased mutations (per cell) without increased mutation rate (by virtue of extra gene copies per cell), whereas the former requires an increase in mutation rate, potentially accelerating evolution. To resolve these models, we probed early events leading to rare adaptive mutations and report several results that show that amplification is not the precursor to frameshift mutation but rather is an independent adaptive outcome. (i) Using new high-resolution selection methods and stringent analysis of all cells in very young (micro)colonies (500-10,000 cells), we find that most mutant colonies contain no detectable lac-amplified cells, in contrast with previous reports. (ii) Analysis of nascent colonies, as young as the two-cell stage, revealed mutant Lac(+)cells with no lac-amplified cells present. (iii) Stringent colony-fate experiments show that microcolonies of lac-amplified cells grow to form visible colonies of lac-amplified, not mutant, cells. (iv) Mutant cells do not overgrow lac-amplified cells in microcolonies fast enough to mask the lac-amplified cells. (v)lac-amplified cells are not SOS-induced, as was proposed to explain elevated mutation in a sequential model. (vi) Amplification, and not frameshift mutation, requires DNA polymerase I, demonstrating that mutation is separable from amplification, and also illuminating the amplification mechanism. We conclude that amplification and mutation are independent outcomes of adaptive genetic change. We suggest that the availability of alternative pathways for genetic/evolutionary adaptation and clonal expansion under stress may be exploited during processes ranging from the evolution of drug resistance to cancer progression.

Adaptation, Biological↗
PubMed1996

BRCA1 germline mutational spectrum in Italian families from Tuscany: a high frequency of novel mutations.

BRCA1 germline mutations confer susceptibility to familial breast and ovarian cancer. Mutational hot spots have never been detected in BRCA1 cDNA. Some mutations have been reported several times whereas some others appear to be population-related. In this study a group of 36 Italian families were analysed for BRCA1 germline mutations. All of them were screened by allele-specific oligonucleotide hybridization (ASO) for three recurrent mutations (185delAG, 5382insC, nt332-T>G). Twenty families, selected because of their high risk of carrying BRCA1 mutations, were subjected to analysis of the entire coding sequence of the gene. A total of eight mutations were found. ASO screening demonstrated only one known mutation in one patient, whereas cycle sequencing revealed five new mutations. Three of these new mutations were frameshifts: one occurred in exon 11 (1499insA), one in exon 16 (4873delCA) and one in the splice site of exon 3 (252delAAgt). Two were missense mutations (Cys64Arg; Asn158Tyr). The same frameshift mutation, 1499insA, was detected in three unrelated families. Haplotype analysis supported the hypothesis that two of these families may have had common ancestors, whereas in the third family the analysis was uninformative. BRCA1 germline mutations were found in one out of two families with ovarian cancer, in five out of eight families with breast-ovarian cancer, and in two out of 11 families with breast cancer. All three families with 1499insA mutations included at least one case of ovarian cancer. The majority of the ovarian cancers (4/5) associated with detectable BRCA1 germline mutations were of serous histotype.

Adult↗
PubMed2000

Description of a new mutation in rhodopsin, Pro23Ala, and comparison with electroretinographic and clinical characteristics of the Pro23His mutation.

OBJECTIVES: To report the clinical characteristics of a family with autosomal dominant retinitis pigmentosa caused by a proline-to-alanine mutation at codon 23 (Pro23Ala) of the rhodopsin gene and to compare this phenotype with that associated with the more common proline-to-histidine mutation at codon 23 (Pro23His). METHODS: We examined 6 patients within a single pedigree. The electroretinograms (ERGs) of 35 patients with known Pro23His mutations and of 22 healthy individuals were reviewed. Scotopic dim flash-response amplitudes, maximum combined-response amplitudes, and photopic-response amplitudes from the ERGs of these patients were plotted against age. The ERG indices of 5 individuals in the Pro23Ala family were compared with those of the patients with Pro23His mutations and of healthy individuals. Multiple linear regression was performed to evaluate the effect of age and mutation type on amplitudes. Mutation detection was performed using single-strand conformation polymorphism analysis, followed by automated DNA sequencing. RESULTS: Patients with the Pro23Ala mutation have a clinical phenotype characterized by onset of symptoms in the second to fourth decades of life, loss of superior visual field with relatively well-preserved inferior fields, and mild nyctalopia. Comparison with patients with the Pro23His mutation demonstrates statistically significant differences (P<.001) in responses to dim flash, maximum combined, and photopic responses between patients with these mutations after controlling for the effects of age. Patients with Pro23Ala mutations were less affected by ERG criteria than patients with Pro23His mutations. Patients with Pro23Ala mutations also differed significantly from healthy patients in all ERG indices examined (P<.001), after controlling for age. CONCLUSION: We describe a rare mutation in codon 23 of rhodopsin causing autosomal dominant retinitis pigmentosa. The retinal dystrophy associated with the Pro23Ala mutation is characteristically mild in presentation and course, with greater preservation of ERG amplitudes than the more prevalent Pro23His mutation. Arch Ophthalmol. 2000;118:1269-1276

Adolescent↗
PubMed1999

Role of p53 gene mutations in human esophageal carcinogenesis: results from immunohistochemical and mutation analyses of carcinomas and nearby non-cancerous lesions.

In order to characterize p53 alterations in esophageal cancer and to study their roles in carcinogenesis, we performed gene mutation and immunohistochemical analysis on 43 surgically resected human esophageal specimens, which contain squamous cell carcinoma (SCC) and adjacent non-cancerous lesions, from a high-incidence area of Linzhou in Henan, China. A newly developed immunohisto-selective sequencing (IHSS) method was used to enrich the p53 immunostain-positive cells for mutation analysis. p53 gene mutations were detected in 30 out of 43 (70%) SCC cases. Among 29 SCC cases that were stained positive for p53 protein, 25 (86%) were found to contain p53 mutations. In five cases of SCC with homogeneous p53 staining, the same mutation was observed in samples taken from four different positions of each tumor. In a well differentiated cancer nest, p53 mutation was detected in only the peripheral p53-positive cells. In tumor areas with heterogeneous p53 staining, either the area stained positive for p53 had an additional mutation to the negatively stained area or both areas lacked any detectable p53 mutation. In the p53-positive non-cancerous lesions adjacent to cancer, p53 mutations were detected in seven out of 16 (47%) samples with basal cell hyperplasia (BCH), eight out of 12 (67%) samples with dysplasia (DYS), and six out of seven (86%) samples with carcinoma in situ (CIS). All mutations found in lesions with DYS and CIS were the same as those in the nearby SCC. In seven cases of BCH containing mutations, only three had the same mutations as the nearby SCC. The results suggest that p53 mutation is an early event in esophageal carcinogenesis occurring in most of the DYS and CIS lesions, and cells with such mutations will progress to carcinoma, whereas the role of p53 mutations in BCH is less clear.

Adult↗
PubMed2005

Simple PCR heteroduplex, SSCP mutation screening methods for the detection of novel catalase mutations in Hungarian patients with type 2 diabetes mellitus.

BACKGROUND: The enzyme catalase is the main regulator of hydrogen peroxide metabolism. Deficiency of catalase may cause high concentrations of hydrogen peroxide and increase the risk of the development of pathologies for which oxidative stress is a contributing factor, for example, type 2 diabetes mellitus. Catalase deficiency has been reported to be associated with increased frequency of diabetes mellitus in a cohort of patients in Hungary. In this cohort, the majority of mutations in the catalase gene occur in exon 2. METHODS: Type 2 diabetic patients (n=308) were evaluated for mutations in intron 1 (81 bp), exon 2 (172 bp) and intron 2 (13 bp) of the catalase gene. Screening for mutations utilized PCR single-strand conformational polymorphism (SSCP) and PCR heteroduplex methods. Verification of detected mutations was by nucleotide sequence analysis. RESULTS: A total of 11 catalase gene mutations were detected in the 308 subjects (3.57%, p<0.001). Five of the 11 were at two previously reported mutation sites: exon 2 (79) G insertion and (138) GA insertion. Six of the 11 were at five previously unreported catalase mutation sites: intron 1 (60) G-->T; intron 2 (7) G-->A and (5) G-->C; exon 2 (96) T-->A; and exon 2 (135) T-->A. The novel missense mutations on exon 2 (96 and 135) are associated with 59% and 48% decreased catalase activity, respectively; the novel G-->C mutation on intron 2 (5) is associated with a 62% decrease in catalase activity. Mutations detected on intron 1 (60) and intron 2 (7) showed no change in catalase activity. The G-->C mutation on intron 2 (5) might be a splicing mutation. The two missense mutations on exon 2 (96) and (135) cause substitutions of amino acids 53 (Asp-->Glu) and 66 (Glu-->Cys) of the catalase protein. These are close to amino acids that are important for the binding of heme to catalase, 44 (Val) and 72-75 (Arg, Val, Val, His). Changes in heme binding may be responsible for the activity losses. CONCLUSION: Mutations that cause decreased catalase activity may contribute to susceptibility to inherited type 2 diabetes mellitus. Exon 2 and neighboring introns of the catalase gene may be minor hot spots for type 2 diabetes mellitus susceptibility mutations.

Acatalasia↗
PubMed2005

P53 gene mutation spectrum and the relationship between gene mutation and protein levels in pterygium.

PURPOSE: To investigate the spectrum of p53 gene mutations and the relationship between gene mutation and p53 protein levels in pterygium. METHODS: Pterygial samples were harvested from 51 patients undergoing pterygium surgery. DNA samples for p53 mutation analyses were extracted from epithelial cells and subjected to DNA sequencing for examination of mutations in exons 4, 5, 6, 7, and 8 of the p53 gene. In situ levels of p53 protein were studied by immunohistochemistry (IHC) and the percentage of positively stained cells quantified. Ten normal conjunctiva samples were included in this study as controls. RESULTS: Mutations within the p53 gene were detected in 8 pterygial samples (15.7%) with only one mutation found in each sample. All the mutations observed were point mutations, with 6 being substitutions and 2 deletions. Three mutations were identified in exon 6, two in exon 7, and a single mutation found in each of exons 4, 5, and 8. P53 protein levels were scored as 0 (negative) in 31 pterygial specimens (60.8%), +1 in 9 samples (17.6%), +2 in 5 samples (9.8%), and +3 in 6 samples (11.8%) by IHC. The 8 samples found to have p53 gene mutations were equally distributed among the different levels of p53 protein observed using IHC, with 2 samples in each group. The two deletion mutations, which caused a frame shift to occur, were found in samples negative for p53 immunostaining (score 0), while substitution mutations were found in samples positively stained (score +1, +2, and +3). CONCLUSIONS: Mutations within p53 gene exons 4-8 were detected in pterygial epithelium and the mutations showed no correlation with p53 protein levels as seen by IHC.

Aged↗
PubMed2003

Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency.

Succinate semialdehyde dehydrogenase (SSADH; ALDH5A1) deficiency, a rare metabolic disorder that disrupts the normal degradation of GABA, gives rise to a highly heterogeneous neurological phenotype ranging from mild to very severe. The nature of the mutation has so far been reported in patients from six families world wide and eight different mutations were described. Here we report the mutational spectrum in 48 additional unrelated families of different geographic origin. We detected 27 novel mutations at the cDNA level, of which 26 could be attributed to changes at the genomic level. Furthermore, six mutations were detected that did not strongly affect SSADH activity when expressed in HEK 293 cells and are considered nonpathogenic allelic variants. Twenty of the mutations were only found in one family. The spectrum of disease-causing mutations from all patients sequenced thus far consists of 25 point mutations, four small insertions, and five small deletions. Seven of these mutations affect splice junctions, seven are nonsense mutations, and 12 are missense mutations. Although there were no mutational hotspots or prevalent mutations responsible for a significant number of cases, 14 out of 37 (38%) of the missense alleles were present in exon 4 or 5. With one exception, the missense mutations we consider to be causative of SSADH deficiency reduced the SSADH activity to less than 5% of the normal activity in our in vitro expression system. This indicates that residual expression is not likely to be an important factor contributing to the large phenotypic differences observed among different families and even among siblings, suggesting that other modifying factors are of great importance in disease pathology.

Aldehyde Oxidoreductases↗
PubMed2000

PMM2 mutation spectrum, including 10 novel mutations, in a large CDG type 1A family material with a focus on Scandinavian families.

Carbohydrate-deficient glycoprotein syndrome type IA (CDG IA) is an autosomal recessive disease characterized clinically by severe involvement of the central and peripheral nervous system, and biochemically by complex defects in carbohydrate residues in a number of serum glycoproteins. CDG IA is caused by mutations in the PMM2 gene located in chromosome region 16p13. In this study, 61 CDG type IA patients (122 chromosomes) were screened for mutations in the PMM2 gene using a combination of SSCP and sequence analysis. More than 95% of the mutations could be detected. All of them were missense mutations. Mutations 422G>A and 357C>A were strikingly more common in the material and comprised 58% of mutations detected. Of the 20 mutations found, 10 were not reported previously. Seven mutations, e.g. 26G>A (five alleles) and 548T>C (seven alleles), were found only in Scandinavian families. The most common genotype was 357C>A/422G>A (36%). Three patients were homozygous, 357C>A/357C>A (two cases), and 548T>C/548T>C (one case). No patients homozygous for the most common mutation 422G>A were detected. The different mutations were clustered e.g., in that most were located in exon 5 (five) and exon 8 (six), while no mutation was detected in exon 2. When the frequencies of each mutation were included, exon 5 comprised 61% (65 chromosomes) of the mutations; in Scandinavian patients the frequency of these mutations was 72%. Thus, analysis of exon five in these patients enables both reliable and time-saving first screening in prenatal diagnostic cases. This could be followed by a second step of additional strategies for the detection of other mutations.

Alleles↗
PubMed2005

Predicting the oncogenicity of missense mutations reported in the International Agency for Cancer Research (IARC) mutation database on p53.

Many mutation databases, comprising thousands of reported mutations, are available. Often the clinical significance of the reported mutations is unknown. In this study we developed an algorithm that allows prediction of the clinical significance of missense mutations reported in a mutation database. Nonsense mutations are used as a referent group for this assessment. We used the International Association for Research on Cancer (IARC) mutation database on TP53 to implement the algorithm. First, on the basis of published data [Nachman MW, Crowell SL. 2000. Genetics 156:297-304], we ascribed mutation rates to every single nucleotide substitution (SNS) in the core domain of the TP53 gene. Second, for every possible SNS we computed the expected number of missense mutations, under the assumption that missense mutations are as oncogenic as nonsense ones. The natural logarithm of the ratio of the observed to the expected number of missense mutations (LR) was used as a quantitative measure of oncogenicity (i.e., the ability of a mutation to produce cancer). We estimated the relative oncogenicity of all missense mutations reported in the IARC p53 mutation database, and constructed a profile of oncogenicity of the missense mutations along the DNA-binding region of p53.

Algorithms↗
PubMed2002

Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: a founder mutation of BRCA1 identified in the Chinese population.

Previous mutational analysis for BRCA gene mutations in sporadic ovarian cancer occurring in Chinese patients in Hong Kong identified six germline BRCA1 mutations and one germline BRCA2 mutation, six of which were novel (Khoo et al., 2000). Knowledge of BRCA gene mutations in the Chinese population is relatively scant. In this study, we focussed on whether any of these mutations could be recurrent in our Chinese population, making use of archival paraffin embedded tissue. A consecutive series of 214 ovarian cancer cases, half of Southern Chinese origin from Hong Kong whilst the other half of Northern Chinese origin from Beijing were used for the study. We identified one further novel mutation, 1081delG, in BRCA1. This was found to occur in two unrelated individuals with shared haplotype as revealed by allelotype analysis, thus demonstrating founder effect. Two other recurrent mutations were also identified, the 2371-2372delTG mutation in BRCA1 and the 3337C>T mutation in BRCA2 recurring in two and three unrelated individuals respectively, giving an overall prevalence 4.7% of recurrent BRCA mutations in ovarian cancer in the Southern Chinese population. Most importantly, all our recurrent mutation carriers were identified from Southern Chinese patients from Hong Kong whilst such mutations were absent in samples from the Northern Chinese. Our findings indicate possible heterogeneity in the BRCA genotype between Northern and Southern Chinese. The identification of a founder mutation and two recurrent mutations moreover, has important implications towards screening strategies for breast and ovarian cancer among Chinese of southern ancestral origin who are now dispersed throughout the world.

Adult↗
PubMed2006

Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: mutations are mainly present in adenocarcinomas with bronchioloalveolar features.

Activating mutations in the tyrosine kinase domain of the HER2 gene have recently been reported in lung adenocarcinomas, mainly in East Asian patients. Our study was devised to evaluate the prevalence and nature of HER2 mutations in lung adenocarcinomas from Caucasian patients. The mutational status of the HER2 gene was evaluated in 403 lung adenocarcinomas by PCR-single strand conformation polymorphism analysis and direct sequencing of Exons 19 and 20. We found HER2 mutations in 9 (2.2%) cases. Seven (78%) of the mutations were in frame duplications/insertions at codons 776-779 (YVMA), the other 2 were base substitutions resulting in aminoacid changes. The hotspot mutation at bases 776-779 was previously found to be the most frequent HER2 mutation in Asiatic patients. The distribution of mutations was significantly different between conventional lung adenocarcinomas (CLAs) and lung adenocarcinomas with bronchioloalveolar features (ABAFs). Seven (6.2%) of 113 ABAFs and 2 (0.7%) of 290 CLA were mutated (p = 0.0025). In addition, the frequency of HER2 mutations was slightly higher in females (4.1%) than in males (1.8%) and in never smokers (3.1%) than in smokers (1.9%), but differences were not statistically significant. This series of tumors was also investigated for EGFR and K-ras mutations. EGFR mutations were observed in 43 (10.7%) cases, and K-ras mutations in 110 (27.3%) cases. EGFR, HER2 and K-ras mutations were found to be mutually exclusive events. The presence of HER2 mutations in a subset of patients with lung adenocarcinoma raise hope to treat these patients with HER2 specific kinase inhibitors.

Adenocarcinoma↗
PubMed2005

Mutations of the FLT3 gene in adult acute myeloid leukemia: determination of incidence and identification of a novel mutation in a Thai population.

FLT3 mutations have been reported to be the most frequent mutation in acute myeloid leukemia (AML). No data currently exist regarding FLT3 mutations in Southeast Asian patients. In this study, the incidence and type of FLT3 mutation in a large series of Thai AML patients were determined. FLT3 internal tandem duplication (ITD) mutations were observed in 24.6%, FLT3 tyrosine kinase domain mutations in 3.1%, and dual mutations in 2.7% of 256 newly diagnosed Thai AML patients. ITD mutations were mostly restricted to the juxtamembrane domain, and the in-frame ITD length varied from 21 to 201 base pairs. Six types of point mutations were identified, including Asp835Tyr, Asp835His, Asp835Glu, Asp835Ala, Ile836, and a novel mutation, Asp835Del/Ile836Val, which resulted in the loss of aspartic acid and substitution of isoleucine by valine. A rare leukemia karyotype, trisomy 11, was found to coexist with this novel FLT3 mutation, whereas the majority of patients with FLT3 mutations had a normal karyotype. Overall, FLT3 mutation was associated with a significantly higher white blood cell count and older age than the wild-type FLT3. In conclusion, the incidence of FLT3 mutation in Thailand is as high as that of western countries. The clinical significance of the novel mutation requires further studies in a larger population.

Acute Disease↗
PubMed1978

Gamma-ray-induced dominant mutations that cause skeletal abnormalities in mice. II. Description of proved mutations.

In a mutation-rate experiment described earlier, 31 dominant skeletal mutations were confirmed by breeding tests. Skeletal abnormalities were detected in the skeletons of some of the sons of irradiated males, and for 31 of these sons the study of skeletons in subsequent generations showed that they transmitted abnormalities. The detailed descriptions of these mutations, together with descriptions of 6 presumed mutations found in a later paper, provide the basis for determining which mutations cause effects that would, if they occurred in humans, cause a serious handicap. Such a determination is necessary before these data can be used to estimate genetic hazard to humans. Furthermore, these descriptions of syndromes caused by individual dominant mutations should be useful to clinicians interested in skeletal defects. The statistical analysis of the frequency of each abnormality in the mutant line versus an approximation of the frequency of the malformation in the absence of new mutations is essential to be sure that a mutation is indeed the cause of each abnormality. These analyses, together with analyses of the correlation of abnormalities caused by individual mutations, clearly demonstrate that dominant mutations exhibit low penetrance for many of their effects. A few of the mutations also cause the death of some heterozygotes. No externally visible effects have been detected in heterozygotes for most of these mutations. Externally visible effects found in some of the heterozygotes for a few of the mutations include hydrocephalus, circling behavior, increased nervous activity, gray coat color, webbing of digits, and small size. Two coat-color mutations were found that caused no detected skeletal abnormalities. The data suggest that a few of the mutations may be reciprocal translocations. In most of the mutant lines tested cytologically, however, there was no indication of chromosomal aberrations.

Animals↗