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Biomedical subjects

D G Evans

Publications and source records attributed to D G Evans.

At least 73 records · Page 4Linked to original sources
PubMed1999

Probability of bilateral disease in people presenting with a unilateral vestibular schwannoma.

BACKGROUND: Some 4%-5% of those who develop vestibular schwannomas have neurofibromatosis type 2 (NF2). Although about 10% of these patients present initially with a unilateral vestibular schwannoma, the risk for a patient with a truly sporadic vestibular schwannoma developing contralateral disease is unknown. METHODS: A United Kingdom survey of 296 patients with NF2 was reviewed for laterality of vestibular schwannoma at presentation and the presence of other NF2 related features. The time to presentation of bilateral disease was calculated for patients presenting with a unilateral tumour. Mutation analysis of the NF2 gene was carried out on all available cases presenting initially with unilateral disease. RESULTS: Of 240 patients with NF2 with vestibular schwannomas, 45 (18%; 32 sporadic, 13 familial) had either a unilateral tumour or delay in detection between the first and contralateral tumours. Among those tested for NF2 mutations, eight of 27 and nine of 13 were identified among sporadic and familial cases respectively. Sporadic cases showed a high female to male ratio and 19 of 32 have not as yet developed a contralateral tumour (mean 4.1 years after diagnosis of the first). Thirteen of 32 sporadic patients developed a contralateral tumour (mean 6.5 years after the first tumour diagnosis, range 0-22 years) compared with 11 of 13 familial patients (mean delay 5 years, range 0-16 years). Seven of the 45 patients had neither a family history of NF2 nor evidence of related tumours at initial presentation (six before the age of 35 years). CONCLUSION: The risk of patients with sporadic unilateral vestibular schwannomata developing a contralateral tumour in the absence of family history or other features of NF2 is low, but those presenting with other neurogenic tumours in addition to vestibular schwannoma are at high risk of harbouring an NF2 mutation in at least a proportion of their somatic cells.

Adolescent↗
PubMed1999

Utilisation of prophylactic mastectomy in 10 European centres.

Increasingly women at high risk of breast cancer are opting for prophylactic surgery to reduce their risks. Data from 10 European centres that offer a risk counselling and screening service to women at risk show different approaches to the option of preventive surgery, although most centres adhere to a protocol including at least two risk counselling sessions and a psychological assessment. Thus far the combined centres have data on 174 women who have undergone prophylactic mastectomy with in excess of 400 women years of follow up. Operations were carried out on women with lifetime risks of 25-80%, with an average annual expected incidence rate of 1% per women. No breast cancers have occurred in this cohort. Long term follow up on an extended group of women will be necessary to truly address the risk of subsequent breast cancer and the psychological sequelae.

Adult↗
PubMed1999

A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer.

The frequency, origin, and phenotypic expression of a germline MSH2 gene mutation previously identified in seven kindreds with hereditary non-polyposis cancer syndrome (HNPCC) was investigated. The mutation (A-->T at nt943+3) disrupts the 3' splice site of exon 5 leading to the deletion of this exon from MSH2 mRNA and represents the only frequent MSH2 mutation so far reported. Although this mutation was initially detected in four of 33 colorectal cancer families analysed from eastern England, more extensive analysis has reduced the frequency to four of 52 (8%) English HNPCC kindreds analysed. In contrast, the MSH2 mutation was identified in 10 of 20 (50%) separately identified colorectal families from Newfoundland. To investigate the origin of this mutation in colorectal cancer families from England (n=4), Newfoundland (n=10), and the United States (n=3), haplotype analysis using microsatellite markers linked to MSH2 was performed. Within the English and US families there was little evidence for a recent common origin of the MSH2 splice site mutation in most families. In contrast, a common haplotype was identified at the two flanking markers (CA5 and D2S288) in eight of the Newfoundland families. These findings suggested a founder effect within Newfoundland similar to that reported by others for two MLH1 mutations in Finnish HNPCC families. We calculated age related risks of all, colorectal, endometrial, and ovarian cancers in nt943+3 A-->T MSH2 mutation carriers (n=76) for all patients and for men and women separately. For both sexes combined, the penetrances at age 60 years for all cancers and for colorectal cancer were 0.86 and 0.57, respectively. The risk of colorectal cancer was significantly higher (p<0.01) in males than females (0.63 v 0.30 and 0.84 v 0.44 at ages 50 and 60 years, respectively). For females there was a high risk of endometrial cancer (0.5 at age 60 years) and premenopausal ovarian cancer (0.2 at 50 years). These intersex differences in colorectal cancer risks have implications for screening programmes and for attempts to identify colorectal cancer susceptibility modifiers.

Age Factors↗
PubMed1999

Neurofibromatosis type 2: genetic and clinical features.

For decades, neurofibromatosis type 2 (NF2) was misclassified with the more common neurofibromatosis type 1 (NF1), until 1987 when it was found via genetic linkage analysis that the gene for NF1 was localized to chromosome 17 and the gene for NF2 was localized to chromosome 22. Large, population-based studies have shown that vestibular schwannomas (VS), the hallmark of NF2, do not occur at increased frequency in patients with NF1. Typical clinical features of NF2 are bilateral VS or a family history of NF2, plus either unilateral VS or any two of the following: meningioma, glioma, neurofibroma, schwannoma or posterior subcapsular lenticular opacities. Presymptomatic genetic tests are now possible in the majority of families, and it is hoped that somatic gene therapy will be developed for the treatment of this disease.

Adult↗
PubMed1999

A clinical study of type 1 neurofibromatosis in north west England.

A clinical study of patients on the North West Regional Genetic Register with neurofibromatosis type 1 (NF1) identified 523 affected cases from 304 families. In those for whom relevant information was available, 86.7% (383 of 442) had more than six café au lait patches, 83.8% (310 of 370) had axillary freckling, 42.3% (151 of 357) had inguinal freckling, and 63% (157 of 249) had Lisch nodules. Cutaneous neurofibromas were present in 59.4% (217 of 365) and 45.5% (150 of 330) were noted to have subcutaneous tumours. Plexiform neurofibromas were present in 15.3% (80 of 523). A positive family history of NF1 was found in 71.2% (327 of 459) and 28.8% (132 of 459) of affected patients were considered to be the result of a new mutation. Learning difficulties of varying severity occurred in 62% (186 of 300). CNS tumours associated with NF1 were reported in 9.4% (49) of patients, optic gliomas occurring in 25 of these, 4.8% of patients. Some degree of scoliosis was reported for 11.7% (61), 1.9% (10) had pseudoarthrosis, 4.3% (23) had epilepsy, and 2.1% (11) had spinal neurofibromas. Actuarial analyses were carried out for both optic glioma and malignant nerve sheath tumours and the data are presented.

Adolescent↗
PubMed1999

The accuracy of diagnoses as reported in families with cancer: a retrospective study.

Assessment of risk of developing hereditary cancer and subsequent clinical surveillance is largely based on family history. It is considered standard practice to confirm as many diagnoses as possible in cancer families. Our aim was (1) to assess inaccuracies in reporting of cancers by families, (2) to assess the need for confirmation of diagnosis, and (3) to estimate how many families would have been entered unnecessarily or excluded from screening. A retrospective study of 595 case notes was performed in two centres. Methods of confirmation included information from the cancer registries, death certificates, hospital notes, and histopathological records. Accuracy varied by site of cancer and by the closeness of the relationship to the affected person. Reported abdominal malignancies were inaccurate in 20%, whereas 5% of reported breast cancers were inaccurate. In two families the family history of cancer proved fictitious. Management was altered in 231213 (11%) families following cancer confirmation. The results of the study favour verification of cancer diagnoses particularly if decisions regarding surveillance or prophylactic surgery are based on the family history.

Family Health↗
PubMed1999

Germline mutations of the LKB1 (STK11) gene in Peutz-Jeghers patients.

Germline mutations of the LKB1 (STK11) serine/threonine kinase gene (chromosome 19p13.3) cause Peutz-Jeghers syndrome, which is characterised by hamartomas of the gastrointestinal tract and typical pigmentation. Peutz-Jeghers syndrome carries an overall risk of cancer that may be up to 20 times that of the general population. Here, we report the results of a screen for germline LKB1 mutations by DNA sequencing in 12 Peutz-Jeghers patients (three sporadic and nine familial cases). Mutations were found in seven (58%) cases, in exons 1, 2, 4, 6, and 9. Five of these mutations, two of which are identical, are predicted to lead to a truncated protein (three frameshifts, two nonsense changes). A further mutation is an in frame deletion of 6 bp, resulting in a deletion of lysine and asparagine; the second of these amino acids is conserved between species. The seventh mutation is a missense change in exon 2, converting lysine to arginine, affecting non-conserved amino acids and of uncertain functional significance. Despite the fact that Peutz-Jeghers syndrome is usually an early onset disease with characteristic clinical features, predictive and diagnostic testing for LKB1 mutations will be useful for selected patients in both familial and non-familial contexts.

AMP-Activated Protein Kinase Kinases↗
PubMed1999

Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer.

Germline mutations in the MSH2 and MLH1 mismatch repair genes account for most cases of hereditary non-polyposis colon cancer syndrome (HNPCC). In addition, germline MSH2 and MLH1 mutations have been detected in patients with non-HNPCC early onset colorectal cancer. Germline MSH6 mutations appear to be rare in classical HNPCC families, but their frequency in young colorectal cancer cases has not been studied previously. In a population based study of early onset colorectal cancer (<50 years) investigated for tumour microsatellite instability (MSI), we identified a subgroup of tumours with MSI for mono- but not dinucleotide repeat markers (m-MSI+ group). In contrast to tumours with classical MSI for dinucleotide markers (d-MSI+), the m-MSI+ group cancers were mainly left sided (6/7). As MSH6 mutations in yeast and human cell lines are associated with weak (and preferential mononucleotide) MSI, the complete MSH6 gene coding region was sequenced in blood DNA from the five m-MSI+ cases available for analysis. A germline nonsense mutation was identified in an isolated case of early onset colorectal cancer (age 43 years). These results support previous findings that germline MSH6 mutations may not be associated with classical MSI and suggest a role for germline MSH6 mutations in isolated early onset colorectal cancer.

Adult↗
PubMed1998

Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.

The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.

Adolescent↗
PubMed1998

Genetic and functional studies of a germline TP53 splicing mutation in a Li-Fraumeni-like family.

We report an extensive Li-Fraumeni-like family in which there is an unusual spectrum of tumours at relatively late onset. A germline TP53 splice donor mutation in exon 4 is present in all affected family members available for testing. The mutation abolishes correct splicing of intron 4 and techniques of RT-PCR have identified three different aberrant transcripts from the mutant TP53 allele. Using the yeast functional assay to analyse transcripts in cells from a number of family members with the mutant allele, TP53 appears wild-type. Functional studies have been carried out on cells from patients with and without cancer who carry the germline mutation, and on cells from unaffected individuals from the same family who do not carry the mutation. Using a number of functional endpoints known to distinguish between cells carrying mutant or wild-type TP53 alleles, we were unable to discriminate normal (wt/wt) from heterozygous (wt/mut) cells by lymphocyte apoptosis and fibroblast survival following low dose rate ionising radiation exposure. However germline mutation carriers show increased sensitivity to radiation-induced chromosome damage in the G2 phase of the cell cycle, and decreased transient and permanent G1 arrest. These studies demonstrate the importance of fully characterising the effects of TP53 germline mutations, and may explain some of the phenotypic features of this family.

Adult↗
PubMed1998

Diversity in the variable region of Helicobacter pylori cagA gene involves more than simple repetition of a 102-nucleotide sequence.

CagA, a product of cytotoxin-associated gene A cagA, is an important virulence-related antigen of Helicobacter pylori (HP). CagA varies in size from 128 kDa to about 140 kDa and this variation is believed to be generated by a 102-nucleotide (NT) repeat sequence in the so-called variable region of cagA. However, this explanation has not previously been tested by comparing the NT sequences of cagA derived from a number of different isolates of HP. In this study we first compared the size of PCR products obtained from 54 different isolates of HP with oligonucleotide primers designed to amplify a cagA fragment predicted to be at least 1059 NT, including the variable region of the gene. As expected, the size of the PCR products varied considerable, from 1110 to 1822 NT, but the majority (50 of 54) measured 1335 NT or less. The deduced amino acid (AA) sequences of 9 representative amplicons and 4 other known sequences were compared with the following result: Within the variable region of cagA there are actually two adjacent variable regions, which we label as proximal and distal. The proximal-variable region of CagA extends from a motif of 4 to 6 asparagine residues to a 7-AA repeat sequence (KIDQLNQ); the distal-variable region is confined between KIDQLNQ and a well-conserved duplicate, KIDNLNQ. Despite these shared features CagA of every HP strain examined to date has a variable region with a unique AA sequence.

Amino Acid Sequence↗
PubMed1998

False family history of breast cancer in the family cancer clinic.

AIMS: Awareness of hereditary breast and ovarian cancer in both the general public and the medical profession is increasing. Individuals who may be at risk on the basis of a family history are requesting risk determination and appropriate management in a variety of settings. Risk determination relies largely on pedigree analysis and epidemiological data. METHODS: We describe five individuals presenting in the family cancer or genetic counselling clinic where a factitious family or personal history led to erroneous risk estimation. Common factors in these families are a history of benign breast disease, poor communication within families, long survival with early onset or bilateral disease, a lack of detailed knowledge of the illness and treatment in close relatives and inconsistencies in the history in repeated consultations.

Adult↗
PubMed1998

Screening by mammography, women with a family history of breast cancer.

The aim of this study was to describe the experience of screening women under the age of 50 years with a family history of breast cancer. 1259 women attended the Family History Clinic in Manchester for their first and subsequent consultations between 30 September 1992 and 30 April 1997. All women were under the age of 50 years at the initial consultation and had a lifetime risk of breast cancer of 1 in 6 or greater. Seven prevalent, seven incident and two interval cancers were detected. The number of invasive cancers expected to occur if this high risk population had not been screened was 8.45 (in 2722 person years at risk). 12 invasive cancers were detected, giving a ratio of 1.42 (95% confidence interval 0.73-2.48). The overall cancer detection rates in this young, at risk population were similar to those in older women in the National Health Service Breast Screening Programme. The number of cancers detected in the study was greater than expected in this population. As the numbers were small, a national trial needs to be undertaken to confirm these results and to determine the long term effects of screening.

Adult↗
PubMed1998

Current policies for surveillance and management in women at risk of breast and ovarian cancer: a survey among 16 European family cancer clinics. European Familial Breast Cancer Collaborative Group.

The recent isolation of breast cancer predisposing genes (BRCA1 and BRCA2) allows the identification of carriers within affected families. These carriers have a 50-85% risk of developing breast or ovarian cancer and need careful follow-up. The purpose of this study was to evaluate the management and screening protocols implemented in high risk families at various family cancer clinics in Europe. A questionnaire was mailed to the members of the European Familial Breast Cancer Collaborative Group (n = 30) requesting information on the following issues: indication for surveillance of breasts and ovaries, the recommended protocol, coordination of the screening examination, prophylactic surgery, the specific management of breast cancer in a mutation carrier and the use of oestrogen. 16 centres from nine countries responded. Most centres recommend surveillance of the breasts if the lifetime risk exceeds 15-20%. The surveillance protocol that is generally advised comprises monthly self breast examination, examination by a specialist every 6 months and annual mammography, all starting from an age between 25 and 35 years. Surveillance of the ovaries is recommended in BRCA1 and BRCA2-mutation carriers, in members from breast/ovarian cancer families and in some centres in 'breast cancer only' families with an early onset of breast cancer. The recommended protocol includes gynaecological examination, sonography and estimation of CA-125 at yearly intervals starting from the age 30-35 years. Prophylactic mastectomy is considered for proven mutation carriers in some centres. Most centres consider prophylactic oophorectomy in mutation carriers and some centres also consider it for members of breast/ovarian cancer families. This survey provides insight into the guidelines for surveillance and management of familial breast cancer used at various family cancer clinics in Europe; this insight may contribute to the appropriate management of these high risk women. It should be emphasised that most recommendations are based on experts' opinion rather than on any specific studies.

Adult↗