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PubMed2002

Mutational status of overexpressed p16 in head and neck cancer: evidence for germline mutation of p16/p14ARF.

Inactivation of the p16 tumor suppressor gene is a common phenomenon in squamous cell carcinoma of the head and neck (SCCHN). Less commonly described is the observation of p16 overexpression in SCCHN. Since overexpression of p16 is a potent predictor of outcome in other cancers, we were interested in determining the level of expression of p16 in our SCCHN specimens as a prerequisite to later prognostic studies. We were also interested in determining the mutational status of p16 in these tumors, in order to determine whether the combination of overexpression and gene alteration may predict a different clinical outcome from overexpression alone. A total of 84 specimens of SCCHN were selected for study. These specimens were obtained from all major sites within the oral cavity, oropharynx, pharynx and larynx. The level of expression of p16 in SCCHN specimens was measured by semi-quantitative RT-PCR. In 35 cases, RNA was also isolated from matched normal tissue obtained from a negative tumor margin. In the other 49 cases, the expression level was compared with the level of expression measured in pooled normal RNA obtained from 10 specimens of normal epithelial tissue. Overexpression of p16 was documented when the level of expression in the tumor specimen was 2-fold or greater above the level of expression found in normal tissue. A total of 46 specimens demonstrated overexpression of p16 (55%). All specimens demonstrating overexpression were then subject to sequence analysis. Thirty specimens (65%) showed p16-specific gene alterations, ranging from intragenic deletions to single point mutations, and 15 of these cases concomitantly affect p14ARF. A single specimen demonstrated a silent point mutation within the p16 reading frame. This mutation produces a stop codon at residue 85 in the context of the p14ARF reading frame, predicting premature termination of p14ARF within a previously determined nucleolar localization signal. This observation suggests that in some cases at least, p14ARF may be a selective target for alteration, independently of p16. Analysis of a normal tissue specimen obtained from a negative tumor margin, and a blood sample obtained approximately five years after surgery indicate that this p14ARF-specific alteration may represent a germline mutation.

Carcinoma, Squamous Cell↗
PubMed1995

Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma.

BACKGROUND AND OBJECTIVES: Medullary thyroid carcinoma (MTC) occurs both sporadically and in the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical management of both the patient and family. The susceptibility gene for MEN 2 is the RET proto-oncogene. Systematic analysis for germline mutations of the RET proto-oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases. DESIGN AND PATIENTS: Sixty-seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by histopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin-embedded tissue and subsequently used for polymerase chain reaction amplification. MEASUREMENTS: Polymerase chain reaction based RET mutation analysis was performed by direct double-stranded cycle sequencing of exons 10, 11, 13 and 16, within which the majority of MEN2 mutations have been shown to occur. RESULTS: In this series, there was one proven case of germline mutation in RET codon 620, which previously has been shown to be responsible for MEN 2, thus indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found. CONCLUSIONS: A figure of 1.5% germline mutations in 67 apparently sporadic MTC is lower than the incidence of familial disease reported in previous series involving clinical and biochemical screening. The presence of a germline mutation in the RET proto-oncogene in a patient with MTC indicates heritable disease. The absence of germline RET exon 10, 11, 13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.

Adolescent↗
PubMed2000

Cryptic von Hippel-Lindau disease: germline mutations in patients with haemangioblastoma only.

OBJECTIVES: Central nervous system haemangioblastoma (HAB) is a major feature of von Hippel-Lindau (VHL) disease, and it is estimated that about 30% of HAB patients have VHL disease. Consequently, it is widely recommended that sporadic HAB patients are screened for clinical and radiological features of VHL disease because of the risk of multiple tumours. We investigated the frequency of VHL germline mutations in patients with HAB only with no clinical or radiological evidence of VHL disease to define the role of molecular genetic analysis in the management of such patients. METHODS: Eighty four patients with a single HAB (23 Dutch, 61 UK) and four with multiple HAB (two Dutch, two UK) were studied by direct sequencing of the coding region and quantitative Southern blotting. RESULTS: A VHL germline mutation was found in three of 69 (4.3%) single HAB patients aged 50 years or less (three of 84 (3.6%) total single HAB patients). A germline VHL mutation was detected in a 44 year old woman with a solitary cerebellar HAB, as well as in four clinically unaffected close relatives, and in two single HAB cases presenting at the ages of 29 and 36 years. Germline VHL mutations were detected in two of four cases with multiple HAB. CONCLUSIONS: Early detection of VHL disease is important to reduce morbidity and mortality and therefore we recommend that, in addition to conventional clinical and radiological investigations, VHL gene mutation analysis should be offered to all HAB patients younger than 50 years. HAB patients aged >50 years will have a lower a priori risk of VHL disease and further data are required to evaluate the role of routine molecular genetic investigations in late onset HAB cases. The failure to detect germline VHL mutations in some patients with multiple HAB may indicate the presence of somatic mosaicism or additional HAB susceptibility genes.

Adolescent↗
PubMed1995

Spectrum of germline mutations in the RB1 gene: a study of 232 patients with hereditary and non hereditary retinoblastoma.

Germline mutations in the RB1 gene confer hereditary predisposition to retinoblastoma. We have performed a mutation survey of the RB1 gene in 232 patients with hereditary or non hereditary retinoblastoma. We systematically explored all 27 exons and flanking sequences as well as the promotor. All types of point mutations are represented and are found unequally distributed along the RB1 gene sequence. In the population we studied, exons 3, 8, 18 and 19 are preferentially altered. The range of frequency of detection of germline mutations is about 20%, indicating that other mechanisms of inactivation of RB1 should be involved. The spectrum of mutations presented here should help to improve the clinical management of retinoblastoma and to understand the molecular mechanisms leading to tumorigenesis.

Base Sequence↗
PubMed2001

[Germline mutations of the ret proto-oncogene in Chilean patients with hereditary and sporadic medullary thyroid carcinoma].

BACKGROUND: Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by MTC only (FMTC) or coexistence of MTC with other endocrine neoplasia (NEM 2A, 2B). Germline mutations of the RET proto-oncogene (cRet) are found in the inherited forms and in some apparently sporadic MTC cases. AIM: To study RET mutations in 8 families with MEN 2. MATERIAL AND METHODS: RET mutations were screened in peripheral blood DNA from 18 patients and 87 high risk carriers belonging to 8 MEN 2 families and 52 sporadic MTC. Exons 10, 11, 13, 14, 15 and 16 of the c-Ret were amplified by polymerase chain reaction (PCR) and examined by direct sequencing of PCR products and/or restriction enzyme analysis. RESULTS: Five MEN 2A and one FMTC families with a germline mutation at codon 634, one MEN 2A and one FMTC family carrying a mutation at codon 620 were identified. Mutations were found in 23 out of 87 high risk carriers. In addition, we detected a S891A (exon 15) germline mutation in a sporadic MTC patient and in one out of her three sons and V804M (exon 14) in another sporadic MTC case and in one out of his six relatives, indicating in both cases the presence of a sporadic misclassified familial disease. CONCLUSIONS: These results underscore the importance of routine application of c-Ret testing in all cases of MTC either familial or sporadic.

Adolescent↗
PubMed2006

Factors predicting the occurrence of germline mutations in candidate genes among patients with cutaneous malignant melanoma from South Italy.

Clinical predictors for germline mutations of candidate genes in large clinic based population of patients with cutaneous malignant melanoma (CMM) are widely awaited. Using denaturing high-performance liquid chromatography (DHPLC) analysis and DNA sequencing, 557 consecutively-collected CMM patients originating from South Italy were screened for CDKN2A germline mutations; subsets of them were screened for mutations in the BRAF and BRCA2 genes. Seven CDKN2A mutations were detected in 14 (2.5%) CMM patients. Relative risk of carrying a CDKN2A mutation for CMM patients was demonstrated to significantly increase with the presence of familial recurrence of melanoma (risk ratio (RR)=6.31; p=0.0009), multiple primary melanomas (RR=3.43; p=0.0014), and early onset age (RR=4.56; p=0.0026). All CDKN2A mutations were observed in non-Sardinian patients (14/441; 3.2%), whereas BRAF and BRCA2 genes were found mutated in Sardinian patients (3/116; 2.6%). Such indicators of the presence of CDKN2A mutations will be useful in counselling patients about undergoing genetic testing. Our findings strongly suggest that mutation rates of candidate cancer genes may deeply vary among CMM patients from different geographical areas.

Adult↗
PubMed2001

Germline mutations in BRCA1 and BRCA2 in breast-ovarian families from a breast cancer risk evaluation clinic.

PURPOSE: Data from the Breast Cancer Linkage Consortium suggest that the proportion of familial breast and ovarian cancers linked to BRCA1 or BRCA2 may be as high as 98% depending on the characteristics of the families, suggesting that mutations in BRCA1 or BRCA2 may entirely account for hereditary breast and ovarian cancer families. We sought to determine what proportion of families with both breast and ovarian cancers seen in a breast cancer risk evaluation clinic are accounted for by coding region germline mutations in BRCA1 and BRCA2 as compared to a linkage study group. We also evaluated what clinical parameters were predictive of mutation status. PATIENTS AND METHODS: Affected women from 100 families with at least one case of breast cancer and at least one case of ovarian cancer in the same lineage were screened for germline mutations in the entire coding regions of BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis, a polymerase chain reaction-based heteroduplex analysis, or direct sequencing. RESULTS: Unequivocal deleterious mutations were found in 55% (55 of 100) of the families studied. Mutations in BRCA1 and BRCA2 accounted for 80% and 20% of the mutations overall, respectively. Using multivariate analysis, the strongest predictors of detecting a mutation in BRCA1 or BRCA2 in this study group were the presence of a single family member with both breast and ovarian cancer (P <.0009; odds ratio [OR], 5.68; 95% confidence interval [CI], 2.04 to 15.76) and a young average age at breast cancer diagnosis in the family (P <.0016; OR, 1.69; 95% CI, 1.23 to 2.38). CONCLUSION: These results suggest that at least half of breast/ovarian families evaluated in a high-risk cancer evaluation clinic may have germline mutations in BRCA1 or BRCA2. Whether the remaining families have mutations in noncoding regions in BRCA1, mutations in other, as-yet-unidentified, low-penetrance susceptibility genes, or represent chance clustering remains to be determined.

Adult↗
PubMedDate not supplied

A novel germline mutation in the von Hippel-Lindau gene in patients in Kuwait.

OBJECTIVE: To determine the germline mutation in an extended family in which 1 member was diagnosed clinically with von Hippel-Lindau (VHL) disease and to investigate 3 generations of the family. SUBJECTS AND METHODS: The polymerase chain reaction-single strand conformation polymorphism sequencing techniques were used to identify the germline mutation in the VHL gene in the patient and also to study 9 other members of the extended family over 3 generations. RESULTS: The patient and 3 other members of the family were shown to have the same mutation in the splice donor site of the first intron. The mutation was identified as IVS1 + 1 G-->T. CONCLUSION: The findings of this study indicate the presence of VHL mutation in a Kuwaiti family with Arab parentage. It is hoped that the study would contribute to understanding the types of mutation in VHL in the Middle East. Its early detection and diagnosis would help in genetic counseling of VHL patients.

Adult↗
PubMed2001

Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms.

BACKGROUND & AIMS: Germline mutations in one of four mismatch repair genes have been found in the majority of families with hereditary nonpolyposis colorectal cancer (HNPCC), but only in a small part of families with atypical HNPCC. The recently cloned EXO1 gene might be involved in the pathogenesis of HNPCC because the EXO1 protein strongly interacts with the MSH2 protein. To determine its role in HNPCC, EXO1 was scanned for germline mutations. METHODS: All 14 exons of EXO1 were scanned for mutations in index patients from 33 families with HNPCC fulfilling the Amsterdam criteria and in 225 index patients suspected of HNPCC. RESULTS: Germline variants of EXO1 were detected in 14 patients, including one splice-site mutation in a family with HNPCC and 13 missense mutations in patients with atypical HNPCC. These variants did not occur in more than 200 control individuals. From 13 of these 14 patients, tumors were available for analysis of microsatellite instability and loss of heterozygosity. Six of the tumors showed microsatellite instability. Heterozygosity analysis showed one case without EXO1 allelic loss and 12 tumors with loss of the mutant allele and retention of the normal one. CONCLUSIONS: The results indicate a possible association of germline EXO1 variants with HNPCC and atypical HNPCC.

Base Pair Mismatch↗
PubMed2006

[A novel APC gene germline mutation in a familial adenomatous polyposis pedigree].

OBJECTIVE: To detect the adenomatous polyposis coli (APC) gene germline mutation in the proband and her family members with familial adenomatous polyposis (FAP). METHODS: The diagnosis of a patient with FAP was validated by colonoscopy, pathology and the family history. The systematic screening with multiplex ligation-dependent probe amplification (MLPA), denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing were carried out to detect APC gene germline mutations. RESULTS: A novel mutation c.1999 C >T (Q667X) of APC, which leads to premature termination of the protein, was identified in this family. This mutation manifested an aggressive form of FAP with early onset of colorectal adenocarcinoma and colonic adenoma. CONCLUSION: The mutation of APC Q667X is the cause of clinical phenotype of this family with FAP, and the prophylactic colectomy for the affected family members should be considered.

Adenomatous Polyposis Coli↗
PubMed1999

Detection of a novel germline mutation in the von Hippel-Lindau tumour-suppressor gene by fluorescence-labelled base excision sequence scanning (F-BESS).

The von Hippel Lindau (VHL) syndrome is an inherited multi-tumour disorder characterised by clinical heterogeneity and high penetrance. The VHL gene has been shown to be a tumour-suppressor gene. A carrier of a germline mutation will be predisposed to a high variety of benign and malign tumours affecting different organ systems. As treatment of VHL malformations in presymptomatic stages will improve significantly the clinical outcome and the patient's quality of life, early and unambiguous detection of a germline mutation is mandatory. Direct sequencing especially of large genes might be laborious and time consuming. Therefore, most laboratories apply single strand conformational polymorphism (SSCP) analysis as an initial screening technique. Major disadvantages of this approach are the requirement of specialised equipment and a limited detection rate of about 70%. To overcome these problems, we applied the modified technique of fluorescence-labelled base excision sequence scanning (F-BESS). A young patient without family history of VHL with two hemangioblastoma of the cerebellum, pancreatic cysts and angiomatosis retinae was presented. Applying F-BESS, we detected a frameshift in exon 2 as a de novo germline mutation. Direct sequencing revealed an insertion of C at position 631/632. This is a novel VHL mutation, which results in truncation of the VHL protein omitting the Elongin-binding domain. Applying SSCP on the same DNA, no alteration could be detected. Three further family members were tested negative for the mutation by F-BESS in accordance with lack of any clinical VHL features. As F-BESS appears to be a reliable, fast and unexpensive method, we recommend this technique as an initial screening method.

Adult↗
PubMed1993

Absence of germline mutations of exons 5 to 8 of the P53 gene in 26 breast cancer families from the north of France.

We looked for germline mutations of exons 5 to 8 of the P53 gene in 27 female patients from 26 families originating from the north of France who had breast cancer and at least one first degree relative also affected with breast cancer. Detection of the mutations was made by single strand conformation polymorphism analysis. No mutation was found in any patient, confirming that germline mutations of the P53 gene are very rare in familial breast cancer (apart from Li Fraumeni families).

Adult↗
PubMed2006

Evaluation of models to predict BRCA germline mutations.

The selection of candidates for BRCA germline mutation testing is an important clinical issue yet it remains a significant challenge. A number of risk prediction models have been developed to assist in pretest counselling. We have evaluated the performance and the inter-rater reliability of four of these models (BRCAPRO, Manchester, Penn and the Myriad-Frank). The four risk assessment models were applied to 380 pedigrees of families who had undergone BRCA1/2 mutation analysis. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operator characteristic (ROC) curve were calculated for each model. Using a greater than 10% probability threshold, the likelihood that a BRCA test result was positive in a mutation carrier compared to the likelihood that the same result would be expected in an individual without a BRCA mutation was 2.10 (95% confidence interval (CI) 1.66-2.67) for Penn, 1.74 (95% CI 1.48-2.04) for Myriad, 1.35 (95% CI 1.19-1.53) for Manchester and 1.68 (95% CI 1.39-2.03) for BRCAPRO. Application of these models, therefore, did not rule in BRCA mutation carrier status. Similar trends were observed for separate BRCA1/2 performance measures except BRCA2 assessment in the Penn model where the positive likelihood ratio was 5.93. The area under the ROC curve for each model was close to 0.75. In conclusion, the four models had very little impact on the pre-test probability of disease; there were significant clinical barriers to using some models and risk estimates varied between experts. Use of models for predicting BRCA mutation status is not currently justified for populations such as that evaluated in the current study.

Area Under Curve↗
PubMedDate not supplied

[Management of multiple endocrine neoplasia syndrome type 2 families in association with rare germline mutations of the RET proto-oncogene].

INTRODUCTION: Heredity of MEN2 syndromes is caused by a heterozygous germline mutation in the RET proto-oncogene. This study describes families with rare noncysteine codon 790/791 mutations and discusses the genotype-phenotype correlation plus the therapeutic options. PATIENTS AND METHODS: Forty-five patients with a putative sporadic MTC were screened for RET germline mutations by direct DNA sequencing. Family members of identified index cases underwent genetic analysis. Gene carriers were examined clinically and biochemicaly and underwent prophylactic thyroidectomy. RESULTS: Five index patients were identified. In the kindreds three L790F and one Y791F carriers were detected. The thyroid gland histology of L790F carriers revealed MTC in 2 patients and C-cell hyperplasia in 2 additional patients. The Y791F carrier had a normal histology. CONCLUSIONS: Codon 790/791 mutations had diverse penetrance: prophylactic thyreoidectomy in children is a justifiable approach for codon 790 mutation carriers, but should depend on the clinical course of codon 791 carriers.

Adolescent↗
PubMed1993

Identification of germline mutations in the RB1 gene by denaturant gradient gel electrophoresis and polymerase chain reaction direct sequencing.

Germline mutations in the RB1 gene confer hereditary predisposition to retinoblastoma. The majority of these mutations occur de novo and differ from one patient to another. Cytogenetics and Southern blotting were shown to detect less than 15% of constitutional rearrangements. In this study we used the polymerase chain reaction (PCR) combined with denaturant gradient gel electrophoresis (DGGE) to detect point mutations or small deletions and insertions in a pool of 120 unrelated retinoblastoma patients. Partial DGGE analysis of the RB1 gene enabled us to identify sequence alterations generating stop codons, leading to amino acid substitution or affecting splice sites as well as several polymorphisms. Most of the nucleotide changes detected are flanked by direct repeats. The approach described here has proved to be a useful method for the detection of germline mutations in the RB1 gene.

Base Sequence↗
PubMed1998

Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancer.

Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a consequence of a dominantly inherited susceptibility to accumulate somatic mutations. The disorder is manifested as a familial aggregation of colorectal cancers diagnosed at an early age and, to a lesser degree, of cancers of the endometrium, ovary, urinary tract, and organs of the gastrointestinal tract other than the colon. In more than half of the HNPCC families investigated, the cancer predisposition has been linked to germline mutations in one of the 2 genes hMLHI or hMSH2, involved in post-replicative DNA-mismatch repair. Twenty-four Swiss families affected with colorectal cancer were screened for germline mutations in these 2 genes, and pathogenic mutations were identified in over 70% of the families fulfilling the Amsterdam criteria (AC), but in only 10% of the families not completely fulfilling these criteria. One of the reported mutations, discovered in an extended HNPCC kindred from the Swiss Alps, is shown to be a founding mutation. Unexpectedly, all the mutations identified are in the hMLHI gene, where all but one are novel sequence alterations. Our data suggest that an unusually high proportion of Swiss HNPCC patients may harbour a germline mutation in the hMLHI gene.

Adaptor Proteins, Signal Transducing↗
PubMed2005

A patient with TP53 germline mutation developed Bowen's disease and myelodysplastic syndrome with myelofibrosis after chemotherapy against ovarian cancer.

Here we report a case of myelodysplastic syndrome (MDS) with myelofibrosis associated with Bowen's disease. A female patient had undergone an operation and chemotherapy for ovarian cancer when she was 65 years old, and she developed MDS at the age of 70 years old. PCR-single strand conformation polymorphism (SSCP) analysis of peripheral blood mononuclear cells, a Bowen's disease lesion, and normal skin showed an abnormal peak in TP53 exon5. Direct sequencing revealed that they all had missense mutation in codon 175 (G to A) of arginine switched to histidine, suggesting a germline mutation of TP53. It was speculated that p53 function was lost by TP53 germline mutation with the loss of a wild type allele induced by the chemotherapy against ovarian cancer, leading to the development of MDS. No therapeutic effects of low dose melphalan or cyclosporine A on MDS were observed, however one month of 30 mg/day prednisolone administration induced a hematological response.

Aged↗
PubMed2002

Analysis of BRCA1, TP53, and TSG101 germline mutations in German breast and/or ovarian cancer families.

About 5%-10% of breast cancers are considered to be hereditary and associated with germline mutations of specific genes. As yet, the most frequently affected genes identified are BRCA1 and BRCA2, but also other genes such as TP53 are supposed to influence the predisposition toward breast cancer. In the present study, we analyzed patients of 19 German families with early onset breast cancer and/or a family history of breast and/or ovarian cancer for the presence of mutations in BRCA1 and TP53. In addition, we screened for germline mutations in the putative tumor suppressor gene TSG101. For this purpose we used direct sequence analysis of the entire coding regions for all three genes and, in the case of BRCA1, single-strand conformation polymorphism analysis and protein transcription-translation assays. We identified eight previously described polymorphisms and several aberrations in BRCA1: 1 unclassified missense mutation, 3 small protein truncating mutations, 1 novel pseudoexon, and 5 splicing variants. No mutation was detected in TP53. Analysis of TSG101 transcripts revealed an aberrant transcript in two breast cancer patients belonging to the same family, suggesting TSG101 as a predisposing gene in hereditary breast cancer.

Adult↗