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PubMed2006

PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas.

PURPOSE: Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic-alpha (PIK3CA) gene in various human solid tumors. More than 75% of those somatic mutations are clustered in the helical (exon 9) and kinase domains (exon 20). The three hot-spot mutations, E542K, E545K, and H1047R, have been proven to elevate the lipid kinase activity of PIK3CA and activate the Akt signaling pathway. The mutational status of PIK3CA in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) has not been evaluated previously. EXPERIMENTAL DESIGN: To evaluate a possible role for PIK3CA in the tumorigenesis of IPMN and IPMC, exons 1, 4, 5, 6, 7, 9, 12, 18, and 20 were analyzed in 36 IPMN/IPMC and two mucinous cystadenoma specimens by direct genomic DNA sequencing. RESULTS: We identified four missense mutations in the nine screened exons of PIK3CA from 36 IPMN/IPMC specimens (11%). One of the four mutations, H1047R, has been previously reported as a hot-spot mutation. The remaining three mutations, T324I, W551G, and S1015F, were novel and somatic. CONCLUSION: This is the first report of PIK3CA mutation in pancreatic cancer. Our data provide evidence that the oncogenic properties of PIK3CA contribute to the tumorigenesis of IPMN/IPMC.

Adult↗
PubMed2001

Secondary ocular involvement in systemic "memory" B-cell lymphocytic leukemia.

OBJECTIVE: Recently, B-cell chronic lymphocytic leukemia (B-CLL) has been subdivided into "naive" B-CLL and "memory" B-CLL on the basis of the presence of somatic mutations in the variable region of the immunoglobulin heavy chain gene (IgH). The aim of the current paper was to report the clinical, histopathologic, and molecular biologic findings of intraocular and ocular adnexal involvement in a patient with systemic B-CLL. DESIGN: Case report. INTERVENTION: Treatment consisted of systemic chemotherapy, conjunctival biopsies, and, ultimately, enucleation of the left eye. METHODS: Histopathologic findings of a bone marrow biopsy, the conjunctival biopsies, and the enucleated eye were compared. Further, extensive immunohistochemistry, polymerase chain reaction (PCR) for the detection of heavy chain (IgH) gene rearrangement, gene scan analysis, and DNA sequencing were performed on all tissues. RESULTS: The tumor manifestations in all specimens demonstrated similar morphologic and immunophenotypic characteristics, consistent with the diagnosis of B-CLL. Immunoglobulin-H PCR and gene scan analysis showed that the B-CLL infiltrates consisted of B cells derived from the same clone. DNA sequencing demonstrated the presence of eight somatic mutations in the variable region of IgH, consistent with "memory" B-CLL. CONCLUSIONS: Secondary ocular manifestations of B-CLL occur relatively commonly during disease progression. In the current case of memory B-CLL, ocular manifestation of the disease occurred 16 years after initial diagnosis, agreeing with clinical studies suggesting that a less aggressive course is seen in "memory" B-CLL than its counterpart, "naive" B-CLL. Somatic mutation analysis in the variable region of IgH in B-CLL should be part of routine staging investigations to aid the prediction of the individual clinical course in B-CLL patients and to determine new therapeutic strategies.

Antibodies, Monoclonal↗
PubMed1997

Severe upper gastrointestinal polyposis associated with sparse colonic polyposis in a familial adenomatous polyposis family with an APC mutation at codon 1520.

BACKGROUND: Familial adenomatous polyposis usually results in colonic polyposis with hundreds to thousands of polyps, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and variable extracolonic features. Recent reports indicate that patients with distal mutations between codons 1445 and 1578 do not express CHRPE and have a high incidence of desmoid tumours. PATIENTS: The family studied has an unusual phenotype of sparse colonic polyposis but profuse upper gastrointestinal polyposis. Affected subjects do not have CHRPE. METHODS: The protein truncation test followed by sequencing identified a 2 base pair deletion at codon 1520 in the APC gene. This results in a frameshift creating a stop codon 13 codons downstream. RESULTS: This family demonstrates that sparse colonic polyposis but severe upper tract polyposis may be associated with mutations between codons 1445 and 1578. CONCLUSIONS: Study of duodenal and colonic polyps in further cases with mutations in this region is warranted. Such mutations may preferentially cause duodenal adenomas and desmoid tumours as somatic mutations in these tumours also occur in this region, unlike colorectal tumours where somatic mutations occur more proximally. This study emphasises the importance of screening the upper gastrointestinal tract even when the colonic disease is mild.

Adenomatous Polyposis Coli↗
PubMed1999

Mutational pattern of the nurse shark antigen receptor gene (NAR) is similar to that of mammalian Ig genes and to spontaneous mutations in evolution: the translesion synthesis model of somatic hypermutation.

The pattern of somatic mutations of shark and frog Ig is distinct from somatic hypermutation of Ig in mammals in that there is a bias to mutate GC base pairs and a low frequency of mutations. Previous analysis of the new antigen receptor gene in nurse sharks (NAR), however, revealed no bias to mutate GC base pairs and the frequency of mutation was comparable to that of mammalian IgG. Here, we analyzed 1023 mutations in NAR and found no targeting of the mechanism to any particular nucleotide but did obtain strong evidence for a transition bias and for strand polarity. As seen for all species studied to date, the serine codon AGC/T in NAR was a mutational hotspot. The NAR mutational pattern is most similar to that of mammalian IgG and furthermore both are strikingly akin to mutations acquired during the neutral evolution of nuclear pseudogenes, suggesting that a similar mechanism is at work for both processes. In yeast, most spontaneous mutations are introduced by the translesion synthesis DNA polymerase zeta (REV3) and in various DNA repair-deficient backgrounds transitions were more often REV3-dependent than were transversions. Therefore, we propose a model of somatic hypermutation where DNA polymerase zeta is recruited to the Ig locus. An excess of DNA glycosylases in germinal center reactions may further enhance the mutation frequency by a REV3-dependent mutagenic process known as imbalanced base excision repair.

Amino Acid Sequence↗
PubMed1997

Mutation analysis of glial cell line-derived neurotrophic factor (GDNF), a ligand for the RET/GDNF receptor alpha complex, in sporadic phaeochromocytomas.

Phaeochromocytomas usually occur sporadically but may also be a feature of three autosomal dominantly inherited cancer syndromes, multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and, very rarely, type 1 neurofibromatosis. Germ-line missense mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2. In VHL, germ-line mutations in one of the three exons of the VHL tumor suppressor gene have been found in the majority of families. Whereas somatic mutations in the VHL gene have been common in sporadic renal cell carcinoma, a component cancer of VHL, somatic mutations in the RET and VHL genes together have been found in approximately 10% of sporadic phaeochromocytomas. Hence, other genes must also contribute to the pathogenesis of sporadic phaeochromocytomas. Recent data have suggested that glial cell line-derived neurotrophic factor (GDNF) is a ligand for RET and acts via a heterotetrameric receptor complex that includes GDNF receptor alpha, which provides ligand binding capabilities, and RET, which provides the signaling component. Thus, both GDNF and GDNFR-alpha are plausible candidate genes for involvement in the pathogenesis of phaeochromocytomas. To investigate the role of GDNF in sporadic phaeochromocytomas, we scanned a panel of 22 tumors. Among these samples, only a conservative sequence variant was detected in exon 2 of GDNF. No disease-associated somatic GDNF mutations or gross gene amplification were detected in these tumors, suggesting only a minor role for GDNF in the genesis of phaeochromocytomas.

Adolescent↗
PubMed2005

EGFR Mutation status in Japanese lung cancer patients: genotyping analysis using LightCycler.

PURPOSE: Recently, somatic mutations of the epidermal growth factor receptor (EGFR) gene were found in approximately 25% of Japanese lung cancer patients. These EGFR mutations are reported to be correlated with clinical response to gefitinib therapy. However, DNA sequencing using the PCR methods described to date is time-consuming and requires significant quantities of DNA; thus, this existing approach is not suitable for a routine pretherapeutic screening program. EXPERIMENTAL DESIGN: We have genotyped EGFR mutation status in Japanese lung cancer patients, including 102 surgically treated lung cancer cases from Nagoya City University Hospital and 16 gefitinib-treated lung cancer cases from Kinki-chuo Chest Medical Center. The presence or absence of three common EGFR mutations were analyzed by real-time quantitative PCR with mutation-specific sensor and anchor probes. RESULTS: In exon 21, EGFR mutations (CTG --> CGG; L858R) were found from 8 of 102 patients from Nagoya and 1 of 16 from Kinki. We also detected the deletion mutations in exon 19 from 7 of 102 patients from Nagoya (all were deletion type 1a) and 4 of 16 patients from Kinki (one was type 1a and three were type 1b). In exon 18, one example of G719S mutation was found from both Nagoya and Kinki. The L858R mutation was significantly correlated with gender (women versus men, P < 0.0001), Brinkman index (600 < or = versus 600, P = 0.001), pathologic subtypes (adenocarcinoma versus nonadenocarcinoma, P = 0.007), and differentiation status of the lung cancers (well versus moderately or poorly, P = 0.0439), whereas the deletion mutants were not. EGFR gene status, including the type of EGFR somatic mutation, was correlated with sensitivity to gefitinib therapy. For example, some of our gefitinib-responsive patients had L858R or deletion type 1a mutations. On the other hand, one of our gefitinib-resistant patients had a G719S mutation. CONCLUSIONS: Using the LightCycler PCR assay, the EGFR L858R mutation status might correlate with gender, pathologic subtypes, and gefitinib sensitivity of lung cancers. However, further genotyping studies are needed to confirm the mechanisms of EGFR mutations for the sensitivity or resistance of gefitinib therapy for the lung cancer.

Adenocarcinoma↗
PubMed2006

Mutational analysis of the APC gene in cribriform-morula variant of papillary thyroid carcinoma.

INTRODUCTION: Familial adenomatous polyposis (FAP) is an inherited autosomal dominant syndrome caused by germline mutations in the adenomatous polyposis coli (APC) gene. Papillary thyroid cancer is one of the extracolonic manifestations of FAP. A characteristic histologic feature of this type of thyroid tumor is the cribriform-morula variant of papillary thyroid carcinoma (CMVPTC). METHODS: To investigate roles of the APC and beta-catenin genes in the development of CMVPTC, we examined germline and somatic mutations of these genes in a female patient with CMVPTC and FAP. The patient had undergone total colectomy at the age of 19 years and total thyroidectomy at age 25 years. RESULTS: Numerous tumors were disseminated in both lobes of the thyroid gland, and histopathologic examination revealed typical CMVPTC. DNA was extracted from peripheral blood leukocytes and 12 CMVPTC tumors, and exons 1-15 of the APC gene and exon 3 of the beta-catenin gene were examined. A germline mutation was detected in exon 13 of the APC gene, and this mutation generated a premature stop codon. Six somatic mutations (922delC, 1602delA, 1821delT, 1920delG, 2706del20, 2804insA) were found in the CMVPTC specimens. All mutations were truncating mutations in the N-terminus of the APC protein. Loss of heterozygosity was not observed in the remaining tumor tissues without somatic APC mutations. There were no mutations of the beta-catenin gene in peripheral blood leukocytes or 12 CMVPTC specimens. CONCLUSIONS: These results suggest that APC mutations play an important role in the development of CMVPTC and occur predominantly in the 5' side of the APC gene between codons 308 and 935.

Adenocarcinoma, Papillary↗
PubMed1994

Childhood cancer around nuclear installations.

There is an increased incidence of childhood cancer, particularly lymphocytic neoplasia, in children who live close to nuclear installations. Possible causes are radiation-induced germ line mutations in occupationally exposed parents, or radiation-induced somatic mutation in the developing cells of the fetus or child due to increased environmental exposure. An alternative possibility is that the socioeconomic characteristics of the communities lead to an altered response to infection in childhood and this increases the risk of lymphocytic neoplasia in particular. For sites other than Sellafield in the UK, the evidence linking childhood cancer to radiation is unconvincing and it is possible that the increase is entirely due to the social characteristics of the communities. In Seascale, a village close to Sellafield, however, the increase is more marked and it is unlikely that social factors alone can explain the change. Furthermore, the environmental discharges from Sellafield are much higher than from other sites, and approach levels which could have a measurable effect on cancer incidence. In spite of a great deal of epidemiological investigation, no clear answer is available. It is argued that in order to solve the problem we must use new knowledge from molecular genetics and measure the rate of somatic mutation in those who work in the nuclear industry and in those who live nearby.

Child↗
PubMed2005

An identity crisis for fps/fes: oncogene or tumor suppressor?

Fps/Fes proteins were among the first members of the protein tyrosine kinase family to be characterized as dominant-acting oncoproteins. Addition of retroviral GAG sequences or other experimentally induced mutations activated the latent transforming potential of Fps/Fes. However, activating mutations in fps/fes had not been found in human tumors until recently, when mutational analysis of a panel of colorectal cancers identified four somatic mutations in sequences encoding the Fps/Fes kinase domain. Here, we report biochemical and theoretical structural analysis demonstrating that three of these mutations result in inactivation, not activation, of Fps/Fes, whereas the fourth mutation compromised in vivo activity. These results did not concur with a classic dominant-acting oncogenic role for fps/fes involving activating somatic mutations but instead raised the possibility that inactivating fps/fes mutations might promote tumor progression in vivo. Consistent with this, we observed that tumor onset in a mouse model of breast epithelial cancer occurred earlier in mice targeted with either null or kinase-inactivating fps/fes mutations. Furthermore, a fps/fes transgene restored normal tumor onset kinetics in targeted fps/fes null mice. These data suggest a novel and unexpected tumor suppressor role for Fps/Fes in epithelial cells.

Animals↗
PubMed1992

Defining the nucleic acid substrate for somatic hypermutation.

Recent reports have more precisely defined the distribution of somatic mutations around rearranged mouse V-D-J genes. The 5' boundary of mutation is most likely in the region of the transcription start site (cap) and/or the promoter (P), implying that transcription may be a prerequisite for mutations to be generated. As more than 95% of somatic mutations lie downstream of the cap site, the transcription unit itself is implicated as the target of the mutational machinery. For heavy chain genes, the 3' boundary can extend into the enhancer region (E). For kappa light chain genes, the 3' boundary extends to approximately 700 bp beyond J kappa-5 (approximately 700 bp upstream of E). In a single study on mutated derivatives of the rearranged mouse lambda 1 light chain V-J gene, it was claimed that the 3' boundary fell within the constant region (C) exon. Although more data are required, the frequency of mutations around V-D-J genes appears asymmetrical, being positively skewed with a single mode centred near the V-D-J coding region and a long tail extending into the 3' non-translated region of the J-C intron. Such a distribution may place constraints on possible molecular mechanisms. It is suggested that the apparent asymmetrical pattern of mutation is best explained by models that assume localized error-prone DNA synthesis generating variable fragment lengths of mutated DNA or cDNA retrotranscripts. The frequency distribution of these lengths of mutated DNA is positively skewed into the 3' J-C intron, with a common terminus at or near the cap site. It is then assumed that they can be integrated into the target V-D-J region via a gene conversion or homologous recombination process. The model invoking reverse transcription may be preferred as it best explains the data without too many ad hoc assumptions.

Animals↗
PubMed1997

Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody-antigen interaction.

Rheumatoid factors are the characteristic autoantibodies of rheumatoid arthritis, which bind to the Fc regions of IgG molecules. Here we report the crystal structure of the Fab fragment of a patient-derived IgM rheumatoid factor (RF-AN) complexed with human IgG4 Fc, at 3.2 A resolution. This is the first structure of an autoantibody-autoantigen complex. The epitope recognised in IgG Fc includes the C gamma 2/C gamma 3 cleft region, and overlaps the binding sites of bacterial Fc-binding proteins. The antibody residues involved in autorecognition are all located at the edge of the conventional combining site surface, leaving much of the latter available, potentially, for recognition of a different antigen. Since an important contact residue is somatic mutation, the structure implicates antigen-driven selection, following somatic mutation of germline genes, in the production of pathogenic rheumatoid factors.

Antigen-Antibody Reactions↗
PubMed1996

Tracking of the V4-34 (VH4-21) gene in human tonsil reveals clonal isotype switch events and a highly variable degree of somatic hypermutation.

The V4-34 (VH4-21) gene has been found to encode certain IgM autoantibodies, and is mandatory for pathological IgM anti-erythrocyte antibodies of I/i specificity. The gene is also commonly used by normal IgM-positive B lymphocytes, but its involvement in B cells which have undergone class switching to IgG or IgA is less clear. In order to track V4-34 gene usage and class switching events during a normal immune response, we have probed RNA in a limited area of human tonsil. Results indicate that the V4-34 gene undergoes class switching to IgG or IgA, with the progeny either remaining unmutated or containing large numbers of somatic mutations. Mutational patterns indicate possible 'hot spots', and some mutations appear deleterious. At the level of individual B cells, we have tracked a clonal isotype switch event from IgM to IgA, with each retaining close to germ-line configuration. In addition, we have followed a clonal switch from a mutated IgM to IgG, with no further accumulation of somatic mutations. These data indicate that the V4-34 gene is involved in a maturing immune response, and that the routes to production of IgG or IgA antibodies are various.

Amino Acid Sequence↗
PubMed2002

Analysis of immunoglobulin VH genes in CD10-positive diffuse large B-cell lymphoma.

CD10, a proteolytic enzyme seen in germinal center cells and in the majority of follicular lymphomas, is occasionally expressed in diffuse large B-cell lymphomas (DLBCL). To clarify the origin and cellular characteristics of CD10-positive DLBCL, we analyzed 36 de novo cases of DLBCL for somatic mutations of the immunoglobulin heavy chain variable region (VH) genes and for their immunophenotypes. Expression greater than that of grade 2 Bcl-6 was observed in 11 of the 30 CD10-negative cases (37%) and in all six CD10-positive cases (100%; P < 0.05) without expression of CD5, CD23, cyclin D1, CD30 or CD138. The average mutation frequencies of the six CD10-positive and 30 CD10-negative DLBCL were 12.9 and 9.8%, respectively. The range of SM frequencies in CD10-positive DLBCL (9.52-18.06) was distinctly narrower than that observed for CD10-negative DLBCL (0.69-26.89). These findings seem to indicate that CD10-positive DLBCL, originating from germinal center B cells, is a genetically and immunophenotypically more homogeneous group than CD10-negative DLBCL. Furthermore, three extranodal lymphomas, in five of the six CD10-positive DLBCL, showed ongoing mutation, indicating that antigen-driven, high-affinity somatic mutation may play an important role in clonal expansion in CD10-positive DLBCL. All four extranodal cases of the six CD10-positive DLBCL showed ongoing mutation and/or bcl-2/JH rearrangement. This result suggests that the cell origin of extranodal CD10-positive DLBCL may be the same as that of follicular lymphomas.

Adult↗
PubMed1991

A novel class of anti-DNA antibodies identified in BALB/c mice.

We have characterized four IgG monoclonal antibodies (mAbs) derived from BALB/c mice that bind double-stranded DNA (dsDNA) with high affinity. The hydridomas were selected for expression of a member of the VHS107 family. Three of the four cell lines use the VH11 gene and one uses the VH1 gene. These antibodies exhibit many characteristics of pathogenic anti-DNA antibodies. They are high affinity and not broadly crossreactive. Unlike the anti-DNA antibodies in autoimmune mice, they exhibit no somatic mutation in their VH genes. These results demonstrate that somatic mutation of VHS107 genes is not necessary for generating high affinity dsDNA binding. The fact that such antibodies have not previously been reported suggests that they are rare and that their expression may be downregulated in both nonautoimmune and autoimmune individuals.

Amino Acid Sequence↗
PubMed2004

Accumulation of mutations and somatic selection in aging neural stem/progenitor cells.

Genomic instability within somatic stem cells may lead to the accumulation of mutations and contribute to cancer or other age-related phenotypes. However, determining the frequency of mutations that differ among individual stem cells is difficult from whole tissue samples because each event is diluted in the total population of both stem cells and differentiated tissue. Here the ability to expand neural stem/progenitor cells clonally permitted measurement of genomic alterations derived from a single initial cell. C57Bl/6 x DBA/2 hybrid mice were used and PCR analysis with strain-specific primers was performed to detect loss of heterozygosity on nine different chromosomes for each neurosphere. The frequency with which changes occurred in neurospheres derived from 2-month- and 2-year-old mice was compared. In 15 neurospheres derived from young animals both parental chromosomes were present for all nine chromosome pairs. In contrast, 16/17 neurospheres from old animals demonstrated loss of heterozygosity (LOH) on one or more chromosomes and seven exhibited a complete deletion of at least one chromosomal region. For chromosomes 9 and 19 there is a significant bias in the allele that is lost where in each case the C57Bl/6 allele is retained in 6/6 neurospheres exhibiting LOH. These data suggest that aging leads to a substantial mutational load within the neural stem cell compartment which can be expected to affect the normal function of these cells. Furthermore, the retention of specific alleles for chromosomes 9 and 19 suggests that a subset of mutational events lead to an allele-specific survival advantage within the neural stem cell compartment.

Alleles↗
PubMed2000

Absence of somatic RET gene mutation in sporadic parathyroid tumors and hyperplasia secondary to uremia, and absence of somatic Men1 gene mutation in MEN2A-associated hyperplasia.

Germline mutations of the MEN1 gene are found in more than 85% of multiple endocrine neoplasia type 1 (MEN 1) patients, and germline mutations of the RET gene are found in more than 95% of multiple endocrine neoplasia type 2 (MEN2) patients. Parathyroid hyperplasia is seen in more than 90% of MEN 1 and about 15% of MEN2A patients. To date, somatic MEN1 mutations are reported in about 20% of sporadic parathyroid tumors. To elucidate the genetic basis of parathyroid tumor development, we examined somatic RET gene mutations in sporadic parathyroid tumors and hyperplasia secondary to uremia, and somatic MEN1 gene mutations in parathyroid hyperplasia from MEN2A patients. A total of 145 parathyroid tumors comprising 129 sporadic parathyroid tumors, 14 hyperplastic lesions secondary to uremia, and two hyperplastic lesions from MEN2A patients were examined. DNA was extracted from fresh frozen parathyroid tissue. Exons 2-10 of the MEN1 gene and exons 10 and 11 of the RET gene were sequenced. No somatic RET gene mutations were found in the 129 sporadic parathyroid tumors or 14 parathyroid hyperplastic lesions secondary to uremia. No somatic MEN1 gene mutations were found in the two parathyroid hyperplasia from MEN2A patients. These data suggest that RET gene mutation may not be involved in the development of sporadic parathyroid tumors and hyperplasia secondary to uremia and that MEN1 gene mutation may not be or is rarely associated with development of parathyroid hyperplasia in MEN2A patients.

Aged↗
PubMed2005

Possibility of selection against mtDNA mutations in tumors.

Several studies of tumors have revealed substantial numbers of clonally expanded somatic mutations in mitochondrial DNA (mtDNA), not observed in adjacent intact tissues. These findings were interpreted as indicating the involvement of mtDNA mutations in tumorigenesis. Such comparisons, however, ignore an important confounding factor: the monoclonal origin of tumors as opposed to the highly polyclonal nature of normal tissues. Analysis of recently published data on the incidence of somatic mutations in nontumor monoclonal cells suggests that, contrary to the prevailing view, the process of tumorigenesis may be accompanied by active selection against detrimental mtDNA mutations.

DNA, Mitochondrial↗