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At least 1,657 records · Page 92Linked to original sources
PubMed2006

Immunoglobulin gene analysis in polyneuropathy associated with IgM monoclonal gammopathy.

Antineural antibody activity is the implicated pathogenic mechanism in polyneuropathy associated with monoclonal gammopathy. Recognition of antigen depends on immunoglobulin variable regions, encoded by V genes. We studied V(H)DJ(H) and V(L)J(L) gene use in monoclonal B cells by clonal analysis in 20 patients with polyneuropathy and IgM monoclonal gammopathy. V genes associated with bacterial responses appear over-represented and V(H)3-23 was preferentially used, without association with specific D, J(H) or V(L)J(L). V genes revealed somatic mutation and intraclonal variation was found in 9 of 20 patients. Polyneuropathy associated with monoclonal gammopathy may be caused by an immune response to bacterial antigens, which recruit somatically mutated autoreactive B cells.

Aged↗
PubMed2003

Incomplete DJH rearrangements as a novel tumor target for minimal residual disease quantitation in multiple myeloma using real-time PCR.

The hypervariable regions of immunoglobulin heavy-chain (IgH) rearrangements provide a specific tumor marker in multiple myeloma (MM). Recently, real-time PCR assays have been developed in order to quantify the number of tumor cells after treatment. However, these strategies are hampered by the presence of somatic hypermutation (SH) in VDJH rearrangements from multiple myeloma (MM) patients, which causes mismatches between primers and/or probes and the target, leading to a nonaccurate quantification of tumor cells. Our group has recently described a 60% incidence of incomplete DJH rearrangements in MM patients, with no or very low rates of SH. In this study, we compare the efficiency of a real-time PCR approach for the analysis of both complete and incomplete IgH rearrangements in eight MM patients using only three JH consensus probes. We were able to design an allele-specific oligonucleotide for both the complete and incomplete rearrangement in all patients. DJH rearrangements fulfilled the criteria of effectiveness for real-time PCR in all samples (ie no unspecific amplification, detection of less than 10 tumor cells within 10(5) polyclonal background and correlation coefficients of standard curves higher than 0.98). By contrast, only three out of eight VDJH rearrangements fulfilled these criteria. Further analyses showed that the remaining five VDJH rearrangements carried three or more somatic mutations in the probe and primer sites, leading to a dramatic decrease in the melting temperature. These results support the use of incomplete DJH rearrangements instead of complete somatically mutated VDJH rearrangements for investigation of minimal residual disease in multiple myeloma.

DNA Primers↗
PubMed1996

Evaluation of a plasmid-based transgenic mouse model for detecting in vivo mutations.

To study in vivo somatic mutations a C57BL/6 transgenic mouse model was constructed harboring multiple chromosomally integrated copies of the plasmid pUR288, which carried the lacZ reporter gene as the mutational target. We previously demonstrated that lacZ-containing plasmids could be rescued from their integrated state efficient enough to detect mutations in lacZ by positive selection. The smaller size of the plasmid vector, as compared with our earlier transgenic mouse model based on bacteriophage lambda vectors, should offer considerable advantages in terms of rescue efficiency and sensitivity to large size alterations in the lacZ gene. To evaluate the plasmid-based mouse model for its suitability to detect in vivo mutations, we determined mutant frequencies in different organs of untreated and ethyl nitrosourea (ENU)-treated animals using a new, improved protocol. The rescue efficiencies obtained were as high as 200,000/micrograms genomic DNA; millions of transformants could be obtained in one single experiment. The average spontaneous mutant frequency in four different organs of 4- to 8-week-old mice ranged from 4.41 to 6.82 x 10(-5), compared with a mutant frequency of the same plasmid grown in Escherichia coli of approximately 1 x 10(-5) or less. Single treatments with 100 and 250 mg ENU/kg body wt resulted in a 7- and 14-fold increase, respectively, in spleen mutant frequency at 14 days after i.p. administration of the alkylating agent. Restriction enzyme analysis showed that a considerable portion of spontaneous mutants were size changes varying from approximately 100 to 3000 bp. Some mutant plasmids contained mouse genomic sequences, which is indicative of large genetic rearrangement events involving the 3' flanking regions of the transgene cluster. Among the ENU-induced mutants, size changes comprised only a minor fraction of the total, which is in keeping with the known ENU mutation spectra in vitro and in vivo. The high rescue efficiency of this plasmid-based model, in combination with its sensitivity to a broad spectrum of mutations, including large deletions, makes it very suitable as a general in vivo mutagenicity test system.

Animals↗
PubMed2025

U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.

The mechanisms by which somatic mutations of splicing factors, such as U2AF1S34F in lung adenocarcinoma, contribute to cancer pathogenesis are not well understood. Here, we used prime editing to modify the endogenous U2AF1 gene in lung adenocarcinoma cells and assessed the resulting impact on alternative splicing. These analyses identified KRAS as a key target modulated by U2AF1S34F. One specific KRAS mutation, G12S, generates a cryptic U2AF1 binding site that leads to skipping of KRAS exon 2 and generation of a non-functional KRAS transcript. Expression of the U2AF1S34F mutant reverts this exon skipping and restores KRAS function. Analysis of cancer genomes reveals that U2AF1S34F mutations are enriched in KRASG12S-mutant lung adenocarcinomas. A comprehensive analysis of splicing factor/oncogene mutation co-occurrence in cancer genomes also revealed significant co-enrichment of KRASQ61R and U2AF1I24T mutations. Experimentally, KRASQ61R mutation leads to KRAS exon 3 skipping, which in turn can be rescued by the expression of U2AF1I24T. Our findings provide evidence that splicing factor mutations can rescue splicing defects caused by oncogenic mutations. More broadly, they demonstrate a dynamic process of cascading selection where mutational events are positively selected in cancer genomes as a consequence of earlier mutations.

Journal Article↗
PubMed1983

Monoclonal antibodies reveal the structural basis of antibody diversity.

Hybridoma technology has made it possible to introduce into continuous culture normal antibody-forming cells and to obtain large amounts of the immunoglobulin produced by each of these cells. Examination of the structure of a number of monoclonal antibodies that react with a single antigen has provided new information on the structural basis of the specificity and affinity of antibodies. Comparisons of families of monoclonal antibodies derived from a single germ line gene revealed the importance of somatic mutation in generating antibody diversity. Monoclonal antibodies that react with variable regions of other monoclonals allow the further dissection and modulation of the immune response. Finally, the continued somatic instability of immunoglobulin genes in cultured antibody-forming cells makes it possible to determine the rate of somatic mutation and to generate mutant monoclonal antibodies that may be more effective serological reagents.

Amino Acid Sequence↗
PubMed2007

Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women.

PURPOSE: Somatic mutations of PIK3CA, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase, have recently been shown to play an important role in the pathogenesis and progression of human breast cancers. In this study, the frequency of PIK3CA mutations and their relationship with clinicopathologic and biological variables were investigated in Japanese breast cancers. EXPERIMENTAL DESIGN: Mutational analysis of PIK3CA was done in 188 primary breast cancers of Japanese women. Relationship of these mutations with various clinicopathologic variables [histologic type, tumor size, histologic grade, lymph node status, estrogen receptor (ER)-alpha and progesterone receptor status, and prognosis], biological variables [phospho-AKT (pAKT) and HER2 expression determined by immunohistochemistry], and p53 mutation status was studied. RESULTS: Missense mutations of PIK3CA were found in 44 of 158 invasive ductal carcinomas, 4 of 10 invasive lobular carcinomas, 1 of 4 mucinous carcinomas, 2 of 2 squamous carcinomas, and 2 of 2 apocrine carcinomas, but no mutation was found in 12 noninvasive ductal carcinomas. PIK3CA-mutated tumors were found to be more likely to be ER-alpha positive (P < 0.05) and pAKT positive (P < 0.05). There was no significant association between PIK3CA mutations and p53 mutation status. PIK3CA mutations were significantly (P < 0.05) associated with a favorable prognosis, and multivariate analysis showed that PIK3CA mutation status was a significant (P < 0.05) prognostic factor independent of the other conventional prognostic factors. CONCLUSIONS: The frequency of PIK3CA mutations in Japanese breast cancers is similar to that of Caucasian breast cancers. Association of PIK3CA mutations with positive pAKT and positive ER-alpha suggests that PIK3CA mutations might exert their effects through activation of the phosphatidylinositol 3-kinase/AKT/ER-alpha pathway. PIK3CA mutations seem to have a potential to be used as an indicator of favorable prognosis.

Breast Neoplasms↗
PubMed1990

Isotype switch and idiotype variation in hairy cell leukemia.

Hairy cell leukemia (HCL) cells are B lymphocytes expressing monoclonal surface bound immunoglobulins, B cell specific antigens, and activation markers. Based on immunophenotyping analysis, HCL cells have been reported to express simultaneously multiple Ig heavy chain isotypes. This is in contrast with the majority of other B cell malignancies. To analyse the tumor cell Ig in more detail, we have prepared somatic cell hybridomas from two patients with HCL. In both cases we found that the tumor cell derived hybridomas secreted IgM, IgG, or IgA indicating that a class-switch event does occur within the monoclonal tumor cell population. However these hybridomas expressed only single isotypes. The clonal relatedness of the tumor-derived Ig was shown by Ig gene analysis and by reactivity with a panel of idiotype specific antibodies. The tumor Ig of one patient analysed showed a striking variability in idiotope expression, indicative of somatic mutations of the expressed Ig genes. To our knowledge this is the first example of HCL and of a B cell malignancy other than follicular lymphoma for which somatic mutations have been demonstrated. This finding might be important for the therapeutic approach based on monoclonal anti-idiotype antibodies.

Antibodies, Anti-Idiotypic↗
PubMed1997

Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer.

The androgen receptor (AR) contains glutamine (CAG) and glycine (GGC) repeats that are each polymorphic in length. We screened clinically localized prostate cancers for somatic mutations in the length of the CAG and GGC repeats in the AR gene and characterized the length of these repeats in the germ-line AR gene. Somatic mutations were rare, and the range of germ-line repeat lengths in men with prostate cancer was within the range of normal in the general population. Most allele frequencies in Caucasian men with clinical prostate cancer were remarkably comparable to those in the general Caucasian population. However, a subpopulation of the men with clinical prostate cancer had a substantially higher frequency of AR alleles with 16 or 17 CAGs (6 of 59 men, 10%) than did the general population (6 of 370 alleles, 1.6%), and a different subpopulation of the men with prostate cancer had a higher frequency of AR alleles with 12 or 13 GGCs (7 of 54 men, 13%) than did the general population (1 of 110 alleles, 0.9%). Of the men with prostate cancer who had an AR gene with 16 or 17 CAGs, 83% had lymph node-positive disease, despite the lack of clinical evidence of metastatic spread. This suggests that a short AR CAG allele may be a risk factor for the development of clinically unsuspected lymph node-positive prostate cancer among men undergoing radical prostatectomy and raises the question of whether this short repeat length played an active role in the development of aggressive prostate cancer. The odds of having a germ-line AR gene with a short CAG repeat (</=17 CAGs) were substantially higher in Caucasian men with lymph node-positive prostate cancer than in Caucasian men with lymph node-negative disease or in the general Caucasian population. The odds of having a short germ-line AR CAG were the same for men with lymph node-negative prostate cancer as for the general Caucasian population. The odds of having a germ-line AR gene with a short glycine repeat (</=14 GGCs) were substantially higher in men with prostate cancer than in the general population, but the frequency of alleles with a short GGC repeat was the same in men with lymph node-positive versus lymph node-negative disease. This suggests that a short GGC repeat may be a risk factor for the development of clinical prostate cancer, a hypothesis that needs to be tested in cohort and case-control studies.

Adenocarcinoma↗
PubMed2026

Tumor Mutational Concordance and Recurrence Timing in Hepatocellular Carcinoma.

INTRODUCTION: In hepatocellular carcinoma (HCC), intrahepatic recurrence includes true recurrence from clonal relapse and multicentric recurrence from de novo tumorigenesis. Recurrence timing is used to distinguish these types; however, its accuracy remains unclear. This study aimed to classify recurrent tumors based on somatic mutational concordance and assess the validity of recurrence timing. METHODS: Whole-exome sequencing was performed on paired primary and recurrent HCC tumors from 49 patients enrolled in a prospective institutional omics project. Tumors with &#x2265; 10 shared somatic mutations were classified as true recurrence. Clinicopathological features, recurrence timing, driver mutation patterns, and survival outcomes were compared between recurrence types. Mutational concordance was quantified using shared variant counts and the Jaccard similarity index. RESULTS: Of the 49 patients, 22 (44.9%) showed true recurrence and 27 (55.1%) had multicentric recurrence. Multicentric recurrence tumors harbored no shared variants or only a single shared variant with the primary tumor. True recurrence was associated with significantly higher concordance in histological differentiation and Edmondson-Steiner grading and greater retention of CTNNB1, TP53, ARID1A, and KEAP1 mutations. The number of shared variants (median: 115 vs. 0, and p&#xa0;<&#xa0;0.001) and the Jaccard index (median: 0.44 vs. 0.00 and p&#xa0;<&#xa0;0.001) were significantly higher in the true recurrence group. Recurrence timing was inconsistently correlated with mutational concordance, although a 3-year cutoff yielded significant separation. CONCLUSION: Recurrence timing alone insufficiently reflects clonal relationships. Genomic profiling offers a reliable framework for distinguishing between recurrence types and guiding HCC management.

clonal relapse↗
PubMed2004

Somatic mitochondrial mutations in melanoma resection specimens.

As epidemiological data suggest ultraviolet (UV) radiation to be the major environmental factor for the development of melanoma, we screened this malignancy for UV-specific C right curved arrow T and CC right curved arrow TT DNA mutations as described in squamous and basal cell carcinomas of the skin. Mitochondrial (mt) DNA was addressed which is known to be highly more susceptible for mutations than nuclear DNA. In the mt genome we chose part of the non-coding displacement-loop (D-loop) containing two hypermutable (C)n tracts especially prone for C right curved arrow T and CC right curved arrow TT changes. A total of 69 melanoma resection specimens was investigated by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) electrophoresis, followed by DNA cloning and sequencing. We detected alterations of the mt D-loop fragment in 4/34 (12%) melanoma primary tumours and in 7/35 (20%) cutaneous and subcutaneous metastases which was no statistically higher proportion upon Fisher's exact test (p=0.17). Among these 11 positive cases, 9 exhibited alterations in the (C)n microsatellite sequences indicating microsatellite instability (MSI) of mtDNA (C)n tracts. Besides 7 insertions and 2 deletions of nucleotides, 11 mutations occurred including only 4 UV-specific C right curved arrow T mutations in a nodular melanoma of the skin and in two subcutaneous metastases. CC right curved arrow TT mutations were not detected in any tissue sample. As (C)n tract alterations occurred in 2/9 primary melanomas with subsequent metastasis, whereas all 20 non-metastasizing cutaneous melanomas were not affected, these somatic changes may reflect genomic imbalance during tumour progression and may be useful for the assessment of patients' prognosis.

Base Sequence↗
PubMed2002

Most immunoglobulin heavy chain switch mu rearrangements in B-cell chronic lymphocytic leukemia are internal deletions.

We investigated 38 cases of B-cell chronic lymphocytic leukemia (B-CLL) for the presence of non-productive rearrangements in the S(mu) regions and defined for the first time the molecular nature of these rearrangements. Southern blot analysis revealed S(mu) region rearrangements in 13 cases (34%) and polymerase chain reactions (PCRs) indicated that these rearrangements consisted of internal deletions of the S(mu) region. Long-distance PCRs localized the S(mu) deletions in the V(H)DJ(H) rearranged allele in most cases. We investigated if S(mu) deletions were related to V(H) somatic mutations that, together with isotype switch recombination, are indicative of the B-cell maturation stage. No significant correlation between the presence of S(mu) deletions and V(H) somatic mutations was found, indicating that the two processes are independent in B-CLL. Moreover no significant correlation between S(mu) deletions and prognosis was observed. Having shown that S(mu) internal deletions are not chromosome translocations rules out their involvement in the onset of malignancy, while their localization in the V(H)DJ(H) rearranged alleles suggests a possible role in the stabilization of the isotype of the expressed immunoglobulin.

Base Sequence↗
PubMed2001

Chromosome aberration assays in Pisum for the study of environmental mutagens.

From a literature survey, 117 chemicals are tabulated that have been assayed in 179 assays for their clastogenic effects in Pisum. Of the 117 chemicals that have been assayed, 65 are reported at giving a positive reaction (i.e. causing chromosome aberrations), 30 positive with a dose response, five borderline positive. Seventeen chemicals gave a negative response. Eighty-one percent of the chemicals gave a definite positive response. A c-mitotic effect was detected from treatment with 17 chemicals. In addition to the above tabulation of chemicals, 39 chemicals have been reported with an antimitotic effect. Thirteen assays have been recorded for five types of radiation, which with the exception of ultrasound reacted positively. The results of assays with 38 chemicals and/or radiations in combined treatments, as well as 15 chemicals and three types of radiations that induce somatic mutations are tabulated. The Pisum sativum (2n=14) bioassay has been shown to be a very good plant bioassay for assessing chromosome damage both in mitosis and meiosis for somatic mutations induced by chemicals, radiations, and environmental pollutants. For some chemicals, the Pisum assay is not as sensitive in assessing clastogenicity as the Allium assay, although this should be considered in relative terms. Pisum fulvum (2n=14) has been used in clastogenic studies also, but to a much lesser extent.

Biological Assay↗
PubMed1994

[Variable-regions of immunoglobulin H-chain genes encoding anti-TSH receptor antibodies].

We have established EBV-transformed human B cell clones producing monoclonal anti-TSH receptor antibodies from two patients with Graves' disease. We then isolated and characterized immunoglobulin VH genes of 5 B cell clones with the TBII activity and 4 B cell clones with the TSAb activity. We found that VH gene families used in the 5 TBII clones were all VH-III, while those of the 4 TSAb clones were diverse, including VH-II, -III, -IV and -V. Most of VH segments used in TBII and TSAb are commonly used in other autoantibodies and fetal liver repertoire. The frequency of somatic mutations in TBII was higher than that in TSAb. Since the same germline VH segment (V3-23) was used for both TBII and TSAb, the frequency and position of somatic mutations may be important for generation of TBII and TSAb.

Autoantibodies↗
PubMed2005

Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR.

Somatic activating mutations in EGFR identify a subset of non-small cell lung cancer that respond to tyrosine kinase inhibitors. Acquisition of drug resistance is linked to a specific secondary somatic mutation, EGFR T790M. Here we describe a family with multiple cases of non-small cell lung cancer associated with germline transmission of this mutation. Four of six tumors analyzed showed a secondary somatic activating EGFR mutation, arising in cis with the germline EGFR mutation T790M. These observations implicate altered EGFR signaling in genetic susceptibility to lung cancer.

Antineoplastic Agents↗
PubMed2000

BCL10 gene mutations rarely occur in lymphoid malignancies.

BCL10, a gene involved in apoptosis signalling, has recently been identified through the cloning of chromosomal breakpoints in extranodal (MALT-type) marginal zone lymphomas carrying the t(1;14)(p22;q32) translocation. BCL10 was also found mutated in these cases as well as in other types of lymphoid and solid tumors, suggesting that its inactivation may play an important pathogenetic role; however, this has been questioned by recent studies showing a lack of somatic mutations in human cancers. We report the mutation analysis of exons 1-3 of the BCL10 gene in DNAs from 228 cases of lymphoid malignancies (30 B cell chronic lymphocytic leukemias, 123 B and 45 T non-Hodgkin's lymphomas and 30 multiple myelomas). Somatic mutations were detected in four cases (approximately 2%): one small lymphocytic, one follicular and two diffuse large cell lymphomas. The mutations were all within exon 3 and have not been previously reported. Our data suggest that BCL10 mutations may play only a limited role in the pathogenesis of lymphoid neoplasms.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Comparative studies of somatic and ongoing mutations in immunoglobulin heavy-chain variable region genes in diffuse large B-cell lymphomas of the stomach and the small intestine.

CONTEXT: Many diffuse large B-cell lymphomas (DLBCLs) of the stomach are believed to represent high-grade transformation of low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, which is of memory B-cell origin, displaying evidence for positive antigen selection and a low level of ongoing somatic mutation of the rearranged immunoglobulin heavy-chain variable region (V(H)) genes. The pattern of somatic mutation has been studied little in intestinal DLBCLs. OBJECTIVE: To assess evidence for antigen selection and the levels of ongoing mutation, we analyzed the ratio of replacement to silent mutations, as well as the frequency of intraclonal sequence variation in gastric and small intestinal DLBCLs that showed no concomitant low-grade component. DESIGN: Genomic DNA was extracted from formalin-fixed paraffin blocks of gastric (n = 6) and small intestinal (n = 6) DLBCLs. The complementarity-determining region 2 and framework region 3 sequences (<200 base pairs) of the rearranged immunoglobulin V(H) gene were obtained from polymerase chain reaction-amplified product, and the ratio of replacement-to-silent mutations and the frequency of intraclonal sequence variation were determined. RESULTS: Clustering of replacement mutations in complementarity-determining region 2 with a high (>2.9) ratio of replacement-to-silent mutations was observed in 5 gastric DLBCLs, whereas it was recognized in only 1 intestinal DLBCL. Intraclonal sequence variation was observed in 6 intestinal and 5 gastric DLBCLs. The frequency of ongoing mutation was much higher in the intestinal (median, 0.33%) than in the gastric DLBCLs (median, 0.13%), but the difference was not statistically significant (P =.09). CONCLUSIONS: The mutation pattern was consistent with positive antigen selection in gastric DLBCLs, but not in the intestinal tumors. Ongoing mutation was much more frequent in the intestinal than in the gastric DLBCLs. These findings suggest that positive antigen selection plays a major role in a significant proportion of gastric tumors, whereas germinal center reaction with aberrant mutation is important in small intestinal DLBCLs.

Adult↗
PubMed2001

The androgen receptor gene and its influence on the development and progression of prostate cancer.

Prostate adenocarcinoma has the highest incidence of any malignancy and is the second leading cause of cancer-related deaths in men in industrialized countries. The development and progression of prostate cancer are dependent on testosterone and dihydrotestosterone; the androgen receptor is the vehicle through which these androgens exert their regulation on prostate cellular proliferation and differentiation. As a result, much effort has been devoted to elucidating the role of the androgen receptor in prostate cancer. The CAG and GGN trinucleotide repeats in exon 1 of the androgen receptor gene have been linked to prostate cancer risk and progression in some studies. Also, androgen receptor gene amplification may be a mechanism of prostate cancer cell adaptation to hormonal therapy. In addition, androgen receptor somatic mutations can result in receptors that have altered binding specificity when compared with wild-type receptors and heightened affinity for hormones other than testosterone and dihydrotestosterone. Gene amplification and somatic mutations, coupled with the fact that various growth factors have been shown to stimulate androgen receptor activity independently of androgens, may enable prostate cancer cells to grow despite testicular-androgen ablation. Unfortunately, current medical therapy for metastatic prostate cancer is deficient, hormone-refractory prostate cancer is a major obstacle in treatment, and, as a result, prostate cancer mortality is still significant. Further study of the function of the androgen receptor will offer a better understanding of prostate cancer pathogenesis and progression, aiding the development of more effective treatments for this disease.

Adenocarcinoma↗