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Biomedical subjects

D Hogg

Publications and source records attributed to D Hogg.

At least 19 recordsLinked to original sources
PubMed2001

A common founder for the V126D CDKN2A mutation in seven North American melanoma-prone families.

One of the most common melanoma-related CDKN2A mutations reported in North America is the V126D mutation. We examined nine markers surrounding CDKN2A in three American and four Canadian families carrying the V126D mutation. All seven families had a haplotype consistent with a common ancestor/founder for this mutation. In addition, the mutation appears to have originated 34-52 generations ago (1-LOD-unit support interval 13-98 generations).

Canada↗
PubMed2001

Crystal structure of mannanase 26A from Pseudomonas cellulosa and analysis of residues involved in substrate binding.

The crystal structure of Pseudomonas cellulosa mannanase 26A has been solved by multiple isomorphous replacement and refined at 1.85 A resolution to an R-factor of 0.182 (R-free = 0.211). The enzyme comprises (beta/alpha)(8)-barrel architecture with two catalytic glutamates at the ends of beta-strands 4 and 7 in precisely the same location as the corresponding glutamates in other 4/7-superfamily glycoside hydrolase enzymes (clan GH-A glycoside hydrolases). The family 26 glycoside hydrolases are therefore members of clan GH-A. Functional analyses of mannanase 26A, informed by the crystal structure of the enzyme, provided important insights into the role of residues close to the catalytic glutamates. These data showed that Trp-360 played a critical role in binding substrate at the -1 subsite, whereas Tyr-285 was important to the function of the nucleophile catalyst. His-211 in mannanase 26A does not have the same function as the equivalent asparagine in the other GH-A enzymes. The data also suggest that Trp-217 and Trp-162 are important for the activity of mannanase 26A against mannooligosaccharides but are less important for activity against polysaccharides.

Amino Acid Sequence↗
PubMed2001

Patterns of CDKN2A gene loss in sequential oral epithelial dysplasias and carcinomas.

The CDKN2A gene locus encodes two different proteins derived from alternative splicing. p16 (exons 1alpha, 2, and 3) acts as a G1 cell cycle regulator, and p14ARF (exons 1beta, 2, and 3) acts to modulate MDM2-mediated degradation of p53. Inactivation of p16 is a common finding in many cancers; however, there is little data on CDKN2A gene abnormalities in oral precancer. In this longitudinal study, we examined changes in the CDKN2A gene locus in sequential epithelial dysplasias and oral carcinomas from 11 patients. Genomic DNA was extracted from laser-microdissected lesional tissue, and exons 1alpha, 1beta, and 2 were analyzed by duplex PCR. Immunohistochemistry was done to identify p16 and p14ARF protein expression. Two adjacent polymorphic microsatellite markers were used for allelotyping. Homozygous deletion of exon 1alpha was identified in 2 of 17 (12%) precancerous lesions. Loss of either exon 1alpha, exon 2, or both was seen in seven of nine (78%) carcinomas. In five of these carcinomas, there was loss of only exon 1alpha. No case showed deletion of exon 1beta. In 5 of 11 patients, microsatellite markers showed differing patterns of allelic imbalance in the precancerous lesions and the subsequent carcinoma, suggesting a complex genetic pattern of progression from dysplasia to carcinoma. We conclude that during oral carcinogenesis homozygous deletion of exon 1alpha of the CDKN2A gene is common but that deletion of exon 2 and 1beta is less frequent. Moreover, our results suggest that the progression from oral precancer to cancer, in some cases, is more complex genetically than predicted by linear models of carcinogenesis.

Actins↗
PubMed2000

Malignant melanoma in patients with multiple endocrine neoplasia type 1 and involvement of the MEN1 gene in sporadic melanoma.

Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome associated primarily with endocrine tumors of the parathyroids, enteropancreas and anterior pituitary. However, tumors of mesenchymal origin such as angiofibroma and collagenoma of the skin have also been associated with the syndrome. This highlights the possibility of an association between MEN 1 and some other types of tumors. Here we report 7 cases of primary malignant melanoma occurring in 7 MEN 1 families, all patients exhibiting classic features of MEN 1. Based on these findings and the previous implication of multiple melanoma tumor suppressor(s) in 11q, including the MEN1 region, we have investigated the involvement of the MEN1 gene in melanoma tumorigenesis. Mutation analysis was performed on a panel of 39 sporadic metastatic melanomas, 13 melanoma cell lines and 20 melanoma families without CDKN2A or CDK4 germline mutations. In addition, 19 sporadic metastatic tumors were screened for loss of heterozygosity (LOH) in 11q13. LOH was detected in 6 tumors (32%), and in 4 of the tumors the pattern of LOH suggested that the deletion included the MEN1 gene locus. A novel somatic nonsense mutation in exon 7 (Q349X) was identified in 1 sporadic tumor which also showed loss of the wild-type allele. We conclude that the MEN1 gene plays a role in the tumorigenesis of a small subgroup of melanoma.

Adult↗
PubMed2000

ARHI is the center of allelic deletion on chromosome 1p31 in ovarian and breast cancers.

In our previous work, we had characterized ARHI as an imprinted putative tumor-suppressor gene in ovarian and breast cancers. ARHI is expressed in primary breast and ovarian cell lines but largely absent from the corresponding malignant tumors. Moreover, the non-imprinted functional allele is typically deleted in malignant cells. Since ARHI had been mapped to 1p31, a common deletion site in breast and ovarian cancer and male germ-cell tumors, in this study, we set out to define precisely the physical location of ARHI at 1p31 and to determine if this location lies within the smallest common region of deletion in breast and ovarian cancers. To this end, we first carried out radiation hybrid mapping of ARHI and surrounding markers, followed by a high-resolution study of loss of heterozygosity at 1p31 in 49 ovarian and breast cancers. Combining a radiation hybrid map and a physical map of the region encompassing ARHI, 3 discrete regions of minimal deletion were found at 1p31 in breast and ovarian cancers. ARHI is the most common deletion region at 1p31. Two other less common regions of deletion were found centromeric to this gene. One of them centered on D1S207 and the other one included and was proximal to D1S488. We also confirmed the preferential loss of non-imprinted functional allele in 7 of 9 tumor specimens. These data support the possibility that ARHI is a tumor-suppressor gene and suggest that additional tumor-suppressor genes may lie proximal to ARHI at 1p31. The data obtained from our study should aid in the identification and characterization of genes in this novel imprinted region.

Breast Neoplasms↗
PubMed2000

Lack of germline CDK6 mutations in familial melanoma.

Germline mutations in genes encoding several components of the retinoblastoma pathway have been linked with inherited predisposition to melanoma. Most commonly, such mutations involve CDKN2A, a cyclin-dependent kinase inhibitor of two kinases, CDK4 and CDK6, which phosphorylate the retinoblastoma protein (pRB) and thereby promote passage through the G1/S cell-cycle restriction point. Less frequently, germline mutations in the CDK4 gene have also been linked with an increased risk of melanoma. Despite the sequence and functional homology between CDK4 and CDK6, the role of germline mutations in CDK6 in melanoma predisposition is unknown. We detected no CDK6 mutations within the p16 (CDKN2A) binding domain in index cases from 60 melanoma-prone kindreds that lacked germline mutations in the coding regions of either CDKN2A or within the entire CDK4 coding region. We conclude that germline mutations in CDK6 do not make a significant contribution to melanoma predisposition.

Amino Acid Sequence↗
PubMed2000

Germline CDKN2A mutation implicated in predisposition to multiple myeloma.

Germline mutations of the CDKN2A (p16(INK4A)) tumor suppressor gene predispose patients to melanoma and pancreatic carcinoma. In contrast, mutations of the murine CDKN2A gene predispose BALB/c mice to pristane-induced plasmacytoma. We describe here a family in which a germline mutation of CDKN2A is present in 4 individuals who developed melanoma as well as in a fifth family member who is suffering from multiple myeloma. To determine whether the CDKN2A mutation predisposed the myeloma patient to her disease, we carried out loss of heterozygosity studies on sorted bone marrow from this individual and observed loss of the wild type CDKN2A allele in the malignant plasma cells. We suggest that germline mutations of CDKN2A may predispose individuals to a wider variety of malignancy than has been hitherto reported, but that the expression of these cancers may depend heavily on the genetic background of the patient. (Blood. 2000;95:1869-1871)

Animals↗
PubMed2000

Viral genome organizer: a system for analyzing complete viral genomes.

The viral genome organizer (VGO) is designed to simplify the characterization and annotation of complete viral genomes (particularly those of large poxviruses) and to help researchers discover new genes and detect gene fragmentation. VGO is based on Genotator [Harris, N.L., 1997. Genome Res. 7, 754-762], an annotation workbench designed for the analysis of eukaryotic genomic sequences. VGO automates a number of database search routines (FASTA, BLASTP, PSI-BLAST and TBLASTN), processes the results through a multiple-alignment viewer (MView; [Brown, N.P., Leroy, C., Sander, C. , 1998. Bioinformatics 14, 380-381]) and serves to manage the hundreds of DNA, protein and database search results files that must be organized when dealing with large complete poxviral genomes. It also directs the generation a self-dotplot of the genome by Dotter [Sonnhammer, E.L.L., Durbin, R., 1995. A dot-matrix program with dynamic threshold control suited for genomic DNA and protein sequence analysis. Gene 167: GC1-10. http://www.sanger.ac. uk/Software/Dotter/] to uncover repeated genes and sequences and provides Internet links to programs for generation of restriction maps and analysis of potential PCR primers. The user-friendly graphical interface displays DNA and protein sequences, links to search results, ORFs, stop-start codons, restriction sites and flags of database searches. Currently, VGO and associated programs run in an X-windows environment on commonly available UNIX machines.

Databases, Factual↗
PubMed2000

Localization to Xq27 of a susceptibility gene for testicular germ-cell tumours.

Testicular germ-cell tumours (TGCT) affect 1 in 500 men and are the most common cancer in males aged 15-40 in Western European populations. The incidence of TGCT has risen dramatically over the last century. Known risk factors for TGCT include a history of undescended testis (UDT), testicular dysgenesis, infertility, previously diagnosed TGCT (ref. 7) and a family history of the disease. Brothers of men with TGCT have an 8-10-fold risk of developing TGCT (refs 8,9), whereas the relative risk to fathers and sons is fourfold (ref. 9). This familial relative risk is much higher than that for most other types of cancer. We have collected samples from 134 families with two or more cases of TGCT, 87 of which are affected sibpairs. A genome-wide linkage search yielded a heterogeneity lod (hlod) score of 2.01 on chromosome Xq27 using all families compatible with X inheritance. We obtained a hlod score of 4.7 from families with at least one bilateral case, corresponding to a genome-wide significance level of P=0.034. The proportion of families with UDT linked to this locus was 73% compared with 26% of families without UDT (P=0.03). Our results provide evidence for a TGCT susceptibility gene on chromosome Xq27 that may also predispose to UDT.

Adolescent↗
PubMed2000

Two p16 (CDKN2A) germline mutations in 30 Israeli melanoma families.

Germline mutations in the p16 (CDKN2A) tumour suppressor gene have been linked to inherited predisposition to malignant melanoma (MM). Variable frequencies of p16 germline mutations were reported in different collections of melanoma families but it can be as high as 50%. Here we describe the results of p16 mutation screening in 30 melanoma kindreds in Israel. The entire coding region of the p16 gene, including exons 1, 2 and 3, flanking exon/intron junctions, and a portion of the 3' untranslated (UTR) region of the gene were examined by single-stranded conformation polymorphism (SSCP) analysis and direct sequencing. Two p16 germline mutations were identified: G101W, which has been previously observed in a number of melanoma kindreds, and G122V, a novel missense mutation. Thus, the frequency of mutations identified in this collection of Israeli families was 7%. Functional analysis indicated that the novel G122V variant retained some capacity to interact with cyclin dependent kinases (CDKs) in vitro, yet it was significantly impaired in its ability to cause a G1 cell cycle arrest in human diploid fibroblasts. This partial loss of function is consistent with the predicted impact of G122V substitution on the 3-dimensional structure of the p16 protein.

Adolescent↗
PubMed2000

The accuracy of non-invasive methods for the detection of obstructive coronary artery disease in the presence of left ventricular hypertrophy.

In the hypertensive patient with electrocardiographic and/or echocardiographic evidence of left ventricular hypertrophy, exercise electrocardiography lacks sensitivity and specificity for the detection of obstructive coronary artery disease and should be avoided. In comparative studies both myocardial perfusion imaging and stress echocardiography are significantly more sensitive and specific for the detection of significant obstructive coronary artery disease, in the presence of left ventricular hypertrophy, and are the investigations of choice.

Coronary Disease↗
PubMed2000

Physical characteristics of the ECAT EXACT3D positron tomograph.

The 'EXACT3D' positron tomograph, which is now in routine clinical research use, was developed with the aim of achieving unprecedented sensitivity, high spatial and temporal resolution and simplicity of design using proven detector technology. It consists of six rings of standard detector blocks (CTI/Siemens EXACT HR+) with 4.39 mm x 4.05 mm x 30 mm elements, giving an axial field of view (FOV) of 23.4 cm. This extended FOV and the absence of interplane septa and retractable transmission rod sources has allowed greatly simplified gantry and detector cassette design. Operation in exclusive 3D mode requires an alternative to the conventional coincidence method for transmission scanning, and a single photon approach using a hydraulically driven 137Cs point source has been implemented. The tomograph has no other moving parts. A single time frame of data without any compression is very large (> 300 Mbyte) and two approaches are employed to overcome this difficulty: (a) adjacent sinograms can be summed automatically into different combinations and (b) listmode (event-by-event) acquisition has been instituted, which is both storage efficient (particularly for acquisition of sparse data sets) and maximizes temporal resolution. The high-speed I/O and computing hardware can maintain a sustained acquisition rate of about 4 million coincidence events per second. A disadvantage of the large axial FOV in 3D is the increased sensitivity to activity outside the coincidence FOV. However, this can be minimized by additional side shielding. The mean spatial resolution is 4.8 +/- 0.2 mm FWHM (transaxial, 1 cm off-axis) and 5.6 +/- 0.5 mm (axial, on-axis). Its absolute efficiency is 5.8% for a line source in air (just spanning the axial FOV) and 10% for a central point source (with thresholds of 350-650 keV). For a uniform 20 cm diameter cylinder, the efficiency is 69 kcps kBq(-1) ml(-1) (after subtraction of a scatter fraction of 42%). Sensitivity relative to the EXACT HR+ (with four rings of blocks) is 2.5 (3D) and 12 (2D) times respectively. The rate of random events in blood flow studies in the brain and body, using 15O-labelled water, can be controlled by limiting the administered dose and inserting additional side shielding.

Cesium Radioisotopes↗
PubMed2000

Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations.

Germline mutations of the CDKN2A tumor suppressor gene have been identified in melanoma kindreds linked to 9p21, and pancreatic adenocarcinoma is the second most common malignancy in some of these families. We hypothesized that unselected patients with both primary cancers, i.e., pancreatic cancer and malignant melanoma, have a genetic predisposition to tumor development, and that this susceptibility may be due to germline CDKN2A mutations. Fourteen patients, with both pathologically verified pancreatic adenocarcinoma and melanoma, were assessed for germline CDKN2A mutations by polymerase chain reaction amplification and sequencing of six overlapping fragments encompassing exons 1alpha and 2. A yeast two-hybrid assay was used to assess the functional consequences of CDKN2A variants. Germline CDKN2A mutations were identified in 2/14 patients: I49S, a novel substitution in exon 1alpha, and M53I, a previously reported missense mutation in exon 2. Both variants lead to compromised CDKN2A function. We conclude that the occurrence of both pancreatic cancer and melanoma, in the same patient, signals an inherited susceptibility to cancer, and that this predisposition is, in some cases, due to germline CDKN2A mutations. This finding has important implications not only for the proband, but also for other family members.

Adenocarcinoma↗
PubMed1999

Chromosomal deletions occur in restricted regions of 5q in testicular germ cell cancer.

Since the biologic behavior and molecular genetic changes observed in testicular germ cell cancer differ from those seen in more common epithelial tumors, it is likely that hitherto uncharacterized genes play a role in the development of germ cell tumors. Our previous work on testicular germ cell cancer suggested that chromosome 5q might contain one or more novel tumor suppressor genes that play a role in this malignancy. In this study, we performed a high resolution loss of heterozygosity (LOH) study of testicular cancer using 37 informative markers on chromosome 5. We detected allelic losses in 20/48 (42%) specimens and identified three common sites of loss on chromosome 5q14, 5q21 and 5q34-qter, defined respectively by minimal regions of deletion of < or = 1 cM, 10 cM and approximately 20 (cM). Using an overlapping series of YACs and radiation hybrid mapping, we have constructed a physical map of the 5q14 deletion that should aid in the isolation and characterization of the putative tumor suppressor gene located therein.

Chromosome Deletion↗
PubMed1999

Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma.

Approximately 8-12% of melanoma is inherited in an autosomal dominant fashion with variable penetrance. A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families. CDKN2A (also known as P16, INK4, p16INK4A and MTS1) is allelic to this locus and encodes a cdk4/cdk6 kinase inhibitor that constrains cells from progressing through the G1 restriction point. Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease, there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers. We show here that a subset of these kindreds possess a G-->T transversion at base -34 of CDKN2A, designated G-34T. This mutation gives rise to a novel AUG translation initiation codon that decreases translation from the wild-type AUG. The G-34T mutation is not seen in controls, segregates with melanoma in families and, on the basis of haplotyping studies, probably arose from a common founder in the United Kingdom. Characterization of this and other CDKN2A non-coding mutations should have an impact on current efforts to identify susceptible melanoma-prone families and individuals.

5' Untranslated Regions↗
PubMed1998

CDKN2A mutations in multiple primary melanomas.

BACKGROUND: Germ-line mutations in the CDKN2A tumor-suppressor gene (also known as p16, p16INK4a, and MTS1) have been linked to the development of melanoma in some families with inherited melanoma. Whether mutations in CDKN2A confer a predisposition to sporadic (nonfamilial) melanoma is not known. In some patients with sporadic melanoma, one or more additional primary lesions develop, suggesting that some of these patients have an underlying genetic susceptibility to the cancer. We hypothesized that this predisposition might be due to germ-line CDKN2A mutations. METHODS: We used the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct DNA sequencing to identify germ-line mutations in the CDKN2A gene in patients with multiple primary melanomas who did not have family histories of the disease. A quantitative yeast two-hybrid assay was used to evaluate the functional importance of the CDKN2A variants. RESULTS: Of 33 patients with multiple primary melanomas, 5 (15 percent; 95 percent confidence interval, 4 percent to 27 percent) had germ-line CDKN2A mutations. These included a 24-bp insertion at the 5' end of the coding sequence, three missense mutations (Arg24Pro, Met53Ile, and Ser56Ile), and a 2-bp deletion at position 307 to 308 (resulting in a truncated CDKN2A protein). In three families, CDKN2A mutations identical to those in the probands were found in other family members. In two families with mutations, we uncovered previously unknown evidence of family histories of melanoma. CONCLUSIONS: Some patients with multiple primary melanomas but without family histories of the disease have germ-line mutations of the CDKN2A gene. The presence of multiple primary melanomas may signal a genetic susceptibility to melanoma not only in the index patient but also in family members, who may benefit from melanoma-surveillance programs.

Adult↗
PubMed1998

Expression of p16 induces transcriptional downregulation of the RB gene.

The RB and p16(INK4A) tumor suppressor genes function in the same pathway of cell cycle control. Previous evidence indicates that the p16(INK4A) gene is transcriptionally repressed by the RB gene product, pRB. In this study using human ovarian cancer cell lines, we found that RB protein and mRNA were expressed at higher levels in cell lines lacking p16 than in those with normal p16. Since this suggests a potential role of p16 in regulating the cellular level of pRB, we studied the effect of wild-type p16(INK4A) on expression of the RB gene. Introduction of p16(INK4A), carried by an adenovirus vector, into p16-negative cell lines dramatically decreased expression of RB protein and mRNA. Nuclei run-off assays demonstrated that p16 expression induced transcriptional downregulation of the RB gene. These results indicate that expression of RB is inversely regulated by p16. The findings reveal a new dimension of pRB-p16 interaction and should have implications for p16(INK4A)-mediated gene therapy.

Adenoviridae↗