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Biomedical subjects

D G Evans

Publications and source records attributed to D G Evans.

At least 91 records · Page 5Linked to original sources
PubMed1998

Somatic mosaicism: a common cause of classic disease in tumor-prone syndromes? Lessons from type 2 neurofibromatosis.

Blood samples from 125 families with classic type 2 neurofibromatosis with bilateral vestibular schwannomas were analyzed for mutations in the NF2 gene. Causative mutations were identified in 52 families. In five families, the first affected individual in the family (the index case) was a mosaic for a disease-causing mutation. Only one of nine children from the three mosaic cases with children are affected. Four of these nine children inherited the allele associated with the disease-causing mutation yet did not inherit the mutation. NF2 mutations were identified in only 27/79 (34%) of sporadic cases, compared with 25/46 (54%) of familial cases (P<.05). In 48 families in which a mutation has not been identified, the index cases have had 125 children, of whom only 29 are affected with NF2 and of whom only a further 21 cases would be predicted to be affected by use of life curves. The 50/125 (40%) of cases is significantly less than the 50% expected eventually to develop NF2 (P<.05). Somatic mosaicism is likely to be a common cause of classic NF2 and may well account for a low detection rate for mutations in sporadic cases. Degrees of gonosomal mosaicism mean that recurrence risks may well be <50% in the index case when a mutation is not identified in lymphocyte DNA.

Adult↗
PubMed1998

Helicobacter pylori cagA status and s and m alleles of vacA in isolates from individuals with a variety of H. pylori-associated gastric diseases.

The cagA gene was detected in 100% of 16 Helicobacter pylori isolates from patients with gastric carcinoma versus 78% of 18 isolates from patients with duodenal ulcers (P = 0.344) and only 64% of 22 isolates from patients with gastritis only (P = 0.005) in Brazil. Also, there was a significant association between isolation of cagA+ s1-type vacA H. pylori in cases of stomach cancer and ulcers as opposed to cases of gastritis only (P = 0.004), but this was not true in Houston (P = 0.238), where 94% of all isolates were cagA+.

Alleles↗
PubMed1998

An evaluation of common breast cancer gene mutations in a population of Ashkenazi Jews.

OBJECTIVES: In view of the recent reports of recurrent mutations in BRCA1 and BRCA2 in the Ashkenazi Jewish population, we have undertaken to assess the frequency of these mutations in this population attending for genetic counselling and risk assessment of familial breast cancer. DESIGN: Mutation screening for the 185delAG and the 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 was performed on DNA samples from either subjects affected by breast or ovarian cancer or obligate gene carriers. The likelihood of the cancers being hereditary in each family was calculated. SUBJECTS: Blood samples were obtained from 26 affected subjects or obligate gene carriers from 23 Ashkenazi Jewish families, all with a history of either early onset breast or ovarian cancers, or multiple cases of breast or ovarian cancer. RESULTS: Twelve mutations have been identified in the 23 families (52%) of which eight (67%) were the 185delAG mutation, three (25%) were the 6174delT mutation, and one (8%) was the 5382insC mutation. While the majority of these mutations were identified in families with a greater than 50% probability of being hereditary under the CASH segregation model, three mutations were identified in families with a 35% or less probability. CONCLUSIONS: Genetic screening of the recurrent mutations in Ashkenazi Jewish families will lead to the availability of predictive testing in a reasonably large proportion, even if the family history of breast/ovarian cancer is not particularly strong. In our view it is possible to reassure high risk unaffected members of these families, if the screening is negative for these mutations, even if a sample from an affected member of the family is unavailable for previous screening.

Adult↗
PubMed1998

Differential diagnosis of type 2 neurofibromatosis: molecular discrimination of NF2 and sporadic vestibular schwannomas.

Patients who present with unilateral vestibular schwannomas either at a young age or with additional features of type 2 neurofibromatosis (NF2) are at risk of developing bilateral disease and transmitting a risk of neurogenic tumours to their offspring. We have identified 15 patients from a series of 537 with unilateral vestibular schwannomas who also had one or more of the following: other tumours (10/15), features of NF2 (3/15), or a family history of neurogenic tumours (5/15). No germline NF2 mutations were detected and in 7/9 cases where tumour material was available for analysis a germline mutation in the NF2 gene has been excluded. Although a possibility of gonosomal mosaicism still exists, exclusion tests for the offspring are now possible. We suggest a general strategy, based on analysis of tumour DNA, for distinguishing sporadic and familial cases of tumours caused by two hit mechanisms. Application of this strategy suggests that most instances of unilateral vestibular schwannoma which do not fulfil criteria for NF2 represent chance occurrences.

Adult↗
PubMed1998

Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations.

Blood samples from 125 unrelated families with classical type 2 neurofibromatosis (NF2) with bilateral vestibular schwannomas have been analysed for mutations in the NF2 gene. A further 17 families fulfilling modified criteria for NF2 have also been analysed. Causative mutations have been identified in 54 (43%) classical families and six (35%) of those fulfilling modified criteria. Forty-two cases from 38 families with truncating mutations had an average age at onset of symptoms of 19 years and diagnosis at 22.4 years. Fifty-one cases from 16 families with splice site mutations (15 from six), missense mutations (18 from six), and large deletions (18 from five) had an average age of onset of 27.8 years and at diagnosis of 33.4 years. Subjects with truncating mutations were significantly more likely to have symptoms before 20 years of age (p<0.001) and to develop at least two symptomatic CNS tumours in addition to vestibular schwannoma before 30 years (p<0.001). There were also significantly fewer multigenerational families with truncating mutations. Four further truncating mutations were in mosaic form and were associated with milder disease than other similar mutations. This large study has confirmed the previous impression that truncating mutations are associated with severe disease, but caution has to be exercised in using mutation type to predict disease course.

Adult↗
PubMed1998

Men in breast cancer families: a preliminary qualitative study of awareness and experience.

In inherited forms of breast cancer, attention in clinical genetics services has focused on women because they are most at risk of developing cancer. Men at risk of transmitting a predisposing gene mutation are less likely to have a genetic test than the women in these families. This preliminary study investigates the perspective of the brothers of women with familial breast cancer and is based on qualitative analysis of 22 semistructured interviews using an attenuated form of Grounded Theory. There is an awareness among these men (without having had genetic counselling) that the breast cancer in their families is inherited. Some of them harbour fear of developing cancer themselves and many are concerned that their daughters might develop breast cancer. Some appeared to use avoidance as a coping strategy. The men were very often excluded from family conversations about breast cancer. Implications for the provision of genetic counselling for these families are discussed.

Adaptation, Psychological↗
PubMed1998

Appearances can be deceptive: an APC 1893del4 mutation with unusual properities. Mutations in brief no. 171. Online.

During a systematic search for germ-line APC mutations causative of familial adenomatous polyposis, we discovered what appeared to be an insertion mutation while simply checking exon 14PCR products by agarose gel electrophoresis (AGE). On AGE, exon 14PCR product from the known affected member of this family gave two bands: one of normal length, the other retarded on the gel equivalent to an increase in length of some 20-25 bp. Direct sequencing of DNA purified from the two bands gave identical results, and was consistent with amplification from the same two alleles: one wild-type, and the other having an 1893del4 mutation. This suggested that the normal length band on AGE consisted of DNA homoduplexes (normal:normal and mutant:mutant) and the retarded band consisted of DNA heteroduplexes (normal:mutant and mutant:normal). This hypothesis was tested by subjecting purified material from each of the two bands alone to a single cycle of heat denaturation and annealing, which showed that either band was equally capable of regenerating both bands. Because the anomalous migration of the heteroduplexes is observed in the presence of ethidium bromide, it implies that they have a cruciform of cruciform-like structure. This case illustrates the necessity to be aware of anomalous DNA migration and always sequence all putative mutations.

Adenomatous Polyposis Coli↗
PubMed1998

Genetics of cancer: current knowledge and future possibilities.

For many years there has been scepticism among clinicians and cancer epidemiologists as to whether cancer was a genetic disease or could be hereditary. It is only in the last 10 years that developments in molecular biology have proven the hereditary nature of a small proportion of certain common cancers. That cancer is now indisputably 'genetic' at the cellular level is beyond dispute.

Breast Neoplasms↗
PubMed1997

Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families.

We have previously reported on the analysis of TP53 coding mutations in 12 classic Li-Fraumeni syndrome (LFS) families plus 9 families that were Li-Fraumeni-like (LFL) families (J. M. Birch et al., Cancer Res., 54: 1298-1304, 1994). Mutations were found in 6 of 12 LFS families and in 1 of 9 LFL families. We have now extended these studies to include an additional nine LFS and nine LFL families, and TP53 mutations have been detected in eight of nine LFS families and in three of nine LFL families. Six of the new mutations described here are the same as those previously identified in other Li-Fraumeni families and are missense mutations at codons 245, 248, and 273 (in two families); a nonsense mutation at codon 209; and a mutation at the splice donor site in exon 4. The other five mutations are novel germ-line mutations and include missense mutations at codons 136 and 344, a 2-bp deletion within codon 191, a splice acceptor mutation in intron 3, and a 167-bp deletion of part of exon 1 and intron 1. In addition, we have detected a codon 175 mutation in a family previously reported as TP53 negative. To summarize all of the data from the families we have studied in this and our previous report (J. M. Birch et al., Cancer Res., 54: 1298-1304, 1994), mutations have been detected in 15 of 21 LFS families (71%) and in 4 of 18 LFL families (22%). These figures are somewhat higher than those previously reported by us and others for the frequency of TP53 mutations in LFS and LFL families. This could reflect our analysis of all 11 exons of TP53, including noncoding regions, as well as the use of direct sequencing rather than other less-sensitive mutation detection methods.

Female↗
PubMed1997

Carbohydrate binding specificity of the neutrophil-activating protein of Helicobacter pylori.

The possible interaction of the neutrophil-activating protein of Helicobacter pylori with target cell glycoconjugates was investigated by the binding of 125I-labeled recombinant protein to glycosphingolipids from human neutrophils in solid phase assays. Thereby, a distinct binding of the neutrophil-activating protein to four bands in the acid glycosphingolipid fraction from human neutrophils was detected, whereas no binding to the non-acid glycosphingolipids or polyglycosyl ceramides from these cells was obtained. When using glycosphingolipids not present in the cell membrane of human neutrophils, it was found that the neutrophil-activating protein also bound to sulfated glycosphingolipids as sulfatide and sulfated gangliotetraosyl ceramide. Comparison of the binding preferences of the protein to reference glycosphingolipids from other sources suggested that in human granulocytes, the neutrophil-activating protein of H. pylori preferentially recognizes glycoconjugates with a terminally unsubstituted NeuAcalpha3Galbeta4GlcNAcbeta3Galbeta4GlcNAcbeta sequence.

Bacterial Proteins↗
PubMed1997

A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li-Fraumeni patients carrying a mutation to the TP53 gene.

We have studied a total of 36 tumours from 28 patients with germline mutations to the TP53 gene for loss of heterozygosity at TP53 using techniques of both direct sequencing and restriction fragment length polymorphism analysis. All patients were from families conforming to the definition of classical Li-Fraumeni syndrome (LFS) or were Li-Fraumeni-like (LFL). The data we have obtained show that loss of the wild-type TP53 gene is observed in under half (44%) of all tumours, and that the pattern of LOH at TP53 may be mutation specific. LOH has been observed in premalignant as well as invasive tumours. Two tumours (6%) show loss of the mutant allele and retention of the wild-type. To confirm that TP53 is indeed the target for LOH events on chromosome 17, we have used additional microsatellite repeats to examine patterns of allelic imbalance along the length of chromosome 17. Data from this analysis indicate that TP53 is the target of loss, but reveal some other interesting patterns of allelic imbalance at other loci on chromosome 17.

Chromosome Deletion↗
PubMed1997

APC mutations in familial adenomatous polyposis families in the Northwest of England.

We have investigated a series of FAP patients in the Northwest of England in order to identify and characterise the specific APC mutations. Using SSCP, we found 27 mutations in a total of 50 families investigated. The mutations were predominantly frameshift or nonsense mutations and there were two splice site changes. We have described two patients with severe Gardner's phenotype from different ethnic backgrounds who share the same mutation at codon 1537. Although the frequency of the most common mutation appears low, it is not dissimilar to that reported by other groups.

Adenomatous Polyposis Coli↗
PubMed1997

The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma.

Individuals with naevoid basal cell carcinoma (Gorlin) syndrome are at increased risk of developing medulloblastoma in childhood. We have shown that approximately 5% of patients with Gorlin syndrome will develop this complication in the first few years of life, and in addition 10% of patients with medulloblastoma diagnosed at age 2 years or under have Gorlin syndrome. One out of three medulloblastomas occurring in patients with Gorlin syndrome was shown to have lost the wild-type allele on 9q, indicating that the Gorlin locus probably acts as a tumour suppressor in the development of this tumour. We have also confirmed this role in a basal cell carcinoma (BCC) from the same individual. Information from these families would suggest that Gorlin syndrome is more common than previously recognized and may not always be diagnosed on clinical grounds alone even in middle life.

Basal Cell Nevus Syndrome↗
PubMed1997

Risk of subsequent primary cancers in patients with carcinoma of the Ampulla of Vater.

Data were collected on subsequent primary cancers occurring in 194 individuals diagnosed with ampullary carcinoma during 1979-92 in the north western region of England, UK. Four cancers were identified compared with 6.62 expected (relative risk 0.60), suggesting that individuals with ampullary carcinoma are not at increased risk of developing subsequent primary cancers.

Adult↗
PubMed1997

Tc-99m-HMPAO white blood cell scan for diagnosis of acute appendicitis in patients with equivocal clinical presentation.

OBJECTIVE: The authors' goal was to evaluate the accuracy of Technetium 99m-HMPAO-labeled leukocyte imaging for screening patients with atypically presenting appendicitis and to determine how availability of this test affected practice patterns of surgeons at the authors' medical center. SUMMARY BACKGROUND DATA: Appendicitis can be difficult to diagnose and in equivocal cases usually requires inpatient observation. The delay may increase morbidity and costs. A test that rules out acute appendicitis could be cost effective if it allowed early discharge from the emergency department. Previously, there have been no simple, rapid, accurate noninvasive methods for improving diagnostic accuracy in patients with equivocal presentations of appendicitis. METHODS: Patients referred to rule out appendicitis were analyzed. Patients were imaged up to 3 hours after injection of 10-mCi 99mTc-HMPAO-labeled autologous leukocytes (Tc-WBC), and when the scans became positive, imaging was terminated and the requesting physician notified of the results. Diagnostic accuracy was established by surgical and histopathologic findings or by absence of symptoms after 1 month clinical follow-up. The source of referral, hospital length of stay, disposition of patients, and ancillary tests (ultrasound, computed tomographic scan, and barium enema) were analyzed. RESULTS: One hundred twenty-four patients were studied from November 1991 through December 1995. Fifty-eight percent of positive scans showed uptake within 1 hour of injection and 73% by 2 hours. The Tc-WBC scan correctly identified an inflammatory source of abdominal pain in 65 of 66 cases (sensitivity = 98%) and was correctly negative in 55 of 58 cases (specificity = 95%). The scan correctly diagnosed appendicitis in 50 of 51 cases (sensitivity = 98%) and correctly excluded appendicitis in 62 of 73 cases (specificity = 85%). Outpatient referrals increased from 38% to 87%. In those patients with negativescans, inpatient observation, number of adjunctive tests, and length of stay decreased significantly. CONCLUSIONS: The high sensitivity and negative predictive value of Tc-WBC imaging may permit patients to be screened and discharged from the emergency department. Focally positive scans often indicate disease requiring operation but not in all cases. The Tc-WBC imaging reduced the negative laparotomy rate to 3.9% while reducing admission rates and hospital length of stay.

Acute Disease↗