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PubMed2000

Variable heavy chain gene analysis of follicular lymphomas: correlation between heavy chain isotype expression and somatic mutation load.

The expansion of follicular lymphomas (FLs) resembles, both morphologically and functionally, normal germinal center B-cell growth. The tumor cells proliferate in networks of follicular dendritic cells and are believed to be capable of somatic hypermutation and isotype switching. To investigate the relation between somatic mutation and heavy chain isotype expression, we analyzed the variable heavy (V(H)) chain genes of 30 FL samples of different isotypes. The V(H) genes of the FLs were heavily mutated (29.3 mutations on average). In addition, isotype-switched lymphomas contained more somatic mutations than immunoglobulin M-positive lymphomas (33.8 mutations per V(H) gene versus 23.0, respectively). In all but one of the FLs, the ratios of replacement versus silent mutations in the framework regions were low, independent of the absolute number of somatic mutations and the level of intraclonal variation. Analysis of relapse samples of 4 FLs showed no obvious increase in somatic mutation load in most FLs and a decrease in intraclonal variation in time. In 3 of 4 cases, we obtained evidence for selection of certain subclones, rather than clonal evolution. Our findings question if intraclonal variation is always a reflection of ongoing somatic hypermutation. This may have implications for the concept of antigen-driven lymphomagenesis. (Blood. 2000;95:2922-2929)

Adult↗
PubMed1997

Somatic mutation leads to efficient affinity maturation when centrocytes recycle back to centroblasts.

Although most mutations are deleterious, an interplay between somatic mutation and selection within germinal centers (GC) results in rapid generation of high affinity memory B cells. How high affinity B cells with large numbers of mutations are generated and preserved within GC containing at their peak only a few thousand cells has been puzzling. We have developed a model of somatic mutation and B cell expansion within a GC that resolves this puzzle. We show that the frequent recycling of Ag-selected centrocytes back into centroblasts can lead to efficient affinity maturation. Memory cells are generated in large numbers even when most of the selected centrocytes recycle back into centroblasts. Our model suggests that a germinal center reaction in which the output of cells is low up to the point of GC dissociation, followed by the release of centrocytes into the periphery, is advantageous for generating high affinity memory.

Animals↗
PubMed2004

Accumulation of somatic mutation in mitochondrial DNA and atherosclerosis in diabetic patients.

A point mutation of mitochondrial DNA at nucleotide position 3243 A to G is responsible for the genetic cause of diabetes. Otherwise, this mutation is also reported to occur as a somatic mutation, possibility because of oxidative stress. Because diabetes may cause oxidative stress, we hypothesized that accumulation of the somatic A3243G mutation in mitochondrial DNA may be accelerated by diabetes. DNA was extracted from blood samples of 290 nondiabetic healthy subjects (aged 0-60 years) and from 383 type 2 diabetic patients (aged 18-80 years). Then, the extent of somatic A3243G mutation in total mitochondrial DNA was detected by real-time polymerase chain reaction (PCR) using the TaqMan probe. The genotyping of ACE I/D or p22phox C242T was done by PCR or PCR-restriction fragment length polymorphism. Although the level of the A3243G mutation was negligible in the newborn group, it increased in healthy subjects aged 20-29 and 41-60 years. In diabetic patients, the mutational rate increased along with age and the duration of diabetes. In the middle-aged group (41-60 years old), the A3243G mutation accumulates fourfold higher in the diabetic patients than in the healthy subjects. Moreover, multiple regression analysis revealed that the most critical factor associated with this mutation in diabetic patients was the duration of diabetes. Furthermore, the genotype of DD, DI-CC (ACE-p22phox) has the highest mutational rate and the thickest intima-media thickness of the carotid artery. In conclusion, diabetes accelerates the accumulation of the somatic A3243G mutation in mitochondrial DNA, and this somatic mutation may be a marker for the duration of diabetes and atherosclerosis.

Adolescent↗
PubMedDate not supplied

Somatic mutation in mitochondrial DNA and nuclear microsatellite instability in gastric cancer.

It was reported that somatic mutations in the mitochondrial DNA (mtDNA) are associated with high-frequency microsatellite instability (MSI-H) of the nuclear in gastric cancers. However, no correlation between mtDNA mutations and nuclear MSI-H was found in colorectal, breast, and renal cancers. Therefore, the association between mtDNA mutations and nuclear MSI-H in gastric cancers is controversial. We examined mtDNA mutations and nuclear MSI in a large panel of gastric cancers. One-hundred and five gastric cancers were selected. Mutations in the mononucleotide repeat (D310) of mtDNA and nuclear MSI at 5 microsatellite loci were examined by microsatellite assay. Somatic mutations in the mtDNA and nuclear MSI-H were detected in 16 (15%) and 14 (13%) of the gastric cancers, respectively. mtDNA mutations were detected in 2 of the 14 (14%) and 14 of the 91 (15%) tumors with and without nuclear MSI-H, respectively. There was no significant difference between them. These results suggest that somatic mutations in the mtDNA and nuclear MSI-H play important roles in gastric carcinogenesis, and that mtDNA mutations may not be associated with nuclear MSI-H in gastric cancers.

Adult↗
PubMed1996

Somatic mutations in human Ig variable genes correlate with a partially functional CD40-ligand in the X-linked hyper-IgM syndrome.

X-linked hyper-IgM (HIGM-1) syndrome is a rare disorder resulting from mutations in the CD40-ligand (CD40L) gene. This defect is associated with normal or elevated serum levels of IgM, and with low to undetectable levels of serum IgG, IgA, and IgE. We analyzed the somatic mutation status in Ig V genes from three unrelated HIGM-1 patients by reverse-transcription PCR and sequence analysis. Two patients (B.S. and P.S.) expressed unmutated VH6 genes. In contrast, one patient (A.T.) was found to express mutated VH6 genes. Whether the presence of somatic mutations in this patient was related to a functional CD40L was assessed by deriving T cell clones from his peripheral blood cells. Upon activation, these T cell clones expressed weakly and transiently surface CD40L, and were able to induce limited isotype switch of normal native B cells, indicating residual CD40L function. Altogether, our results 1) confirm the central role played by CD40L in the generation of somatic mutation (patients B.S. and P.S.), 2) provide an unusual illustration of the relative dissociation between somatic mutation and isotype switching (patient A.T.), and 3) demonstrate a further complexity of the X-linked HIGM syndrome that may occur despite a partially functional CD40L.

B-Lymphocytes↗
PubMed2026

Impact of Somatic Mutations on Treatment Response and Resistance in Chronic Myeloid Leukemia.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have transformed the treatment of chronic myeloid leukemia (CML); yet, diverse molecular responses and resistance persist. BCR::ABL1 kinase-domain (TKD) mutations constitute just a fraction of this resistance, and the impact of additional somatic mutations on disease progression and early molecular response remains incompletely defined. METHODS: This single-centre cohort study analyzed 109 NGS-tested patients with CML, comprising 44 with TKI-resistant disease and 65 newly diagnosed patients. Targeted next-generation sequencing using a 135-gene myeloid panel was performed on 109 patients. An additional pilot subgroup of 30 TKI-resistant patients underwent BCR::ABL1 kinase-domain analysis by PCR/Sanger sequencing and was analyzed separately. Molecular response was assessed using BCR::ABL1 transcript levels on the International Scale and interpreted according to ELN 2020 recommendations. RESULTS: Somatic mutations were identified in 52.3% of TKI-resistant and 29.2% of newly diagnosed patients. All Cohort 1 blast-crisis patients were mutation-positive, and several concurrent abnormalities were more common in Cohort 1 than in Cohort 2, indicating clonal complexity. In Cohort 2, MMR was achieved in 28/39 (71.8%) mutation-negative and 6/13 (46.2%) mutation-positive patients. Mutation-positivity at baseline was associated with reduced MMR chances but not statistically significant (odds ratio 0.34; 95% confidence interval 0.09-1.23; p = 0.099). ASXL1 emerged as the most common non-ABL1 mutation but was not statistically significant. CONCLUSIONS: In this Indian CML cohort, somatic mutations were prevalent in TKI-resistant disease, linked to advanced phase and clonal complexity, and demonstrated a non-significant trend toward lower early MMR at diagnosis, highlighting the importance of genomic testing in this context.

Humans↗
PubMed1995

Burkitt's lymphoma is a malignancy of mature B cells expressing somatically mutated V region genes.

BACKGROUND: The developmental stage from which stems the malignant B cell population in Burkitt's lymphoma (BL) is unclear. An approach to answering this question is provided by the sequence analysis of rear-ranged immunoglobulin (Ig) variable region (V) genes from BL for evidence of somatic mutations, together with a phenotypic characterization. As somatic hypermutation of Ig V region genes occurs in germinal center B cells, somatically mutated Ig genes are found in germinal center B cells and their descendents. MATERIALS AND METHODS: Rearranged V kappa region genes from 10 kappa-expressing sporadic and endemic BL-derived cell lines (9 IgM and 1 IgG positive) and three kappa-expressing endemic BL biopsy specimens were amplified by polymerase chain reaction and sequenced. In addition, VH region gene sequences from these cell lines were determined. RESULTS: All BL cell lines and the three biopsy specimens carried somatically mutated V region genes. The average mutation frequency of rearranged V kappa genes from eight BL cell lines established from sporadic BL was 1.8%. A higher frequency (6%) was found in five endemic cases (three biopsy specimens and two BL cell lines). CONCLUSIONS: The detection of somatic mutations in the rearranged V region genes suggests that both sporadic and endemic BL represent a B-cell malignancy originating from germinal center B cells or their descendants. Interestingly, the mutation frequency detected in sporadic BL is in a range similar to that characteristic for IgM-expressing B cells in the human peripheral blood and for mu chain-expressing germinal center B cells, whereas the mutation frequency found in endemic BL is significantly higher.

B-Lymphocytes↗
PubMed2001

Somatic mutation in human T-cell leukemia virus type 1 provirus and flanking cellular sequences during clonal expansion in vivo.

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma, shows intrapatient genetic variability. Although HTLV-1 can replicate via the reverse transcription of virion RNA to a double-stranded DNA provirus (the conventional manner for retroviruses), its predominant mode of replication is via the clonal expansion (mitosis) of the infected cell. This expansion is achieved by the viral oncoprotein Tax, which keeps the infected CD4 T lymphocyte cycling. Because Tax also interferes with cellular DNA repair pathways, we investigated whether somatic mutations of the provirus that occur during the division of infected cells could account for HTLV-1 genetic variability. METHODS: An inverse polymerase chain reaction strategy was designed to distinguish somatic mutations from reverse transcription-associated substitutions. This strategy allows the proviral sequences to be isolated together with flanking cellular sequences. Using this method, we sequenced 208 HTLV-1 provirus 3' segments, together with their integration sites, belonging to 29 distinct circulating cellular clones from infected individuals. RESULTS: For 60% of the clones, 8%-80% of infected cells harbored a mutated HTLV-1 provirus, without evidence of reverse transcription-associated mutations. Mutations within flanking cellular sequences were also identified at a frequency of 2.8 x 10(-4) substitution per base pair. Some of these clones carried multiple discrete substitutions or deletions, indicating progressive accumulation of mutations during clonal expansion. The overall frequency of somatic mutations increased with the degree of proliferation of infected T cells. CONCLUSIONS: These data indicate that, in vivo, HTLV-1 variation results mainly from postintegration events that consist of somatic mutations of the proviral sequence occurring during clonal expansion. The finding of substitutions in flanking sequences suggests that somatic mutations occurring after integration, presumably coupled with selection, help move the cellular clones toward a transformed phenotype, of which adult T-cell leukemia/lymphoma is the end point.

Adult↗
PubMed1994

Evidence that the clonogenic cell in multiple myeloma originates from a pre-switched but somatically mutated B cell.

There is still much controversy about the precursor cell type in multiple myeloma (MM). Some authors claim that it is a pre-B cell, others state that it is a memory B cell or plasmablast. We have recently shown that the VDJ region of the MM immunoglobulin heavy chain gene is somatically hypermutated and antigen selected, without intraclonal variation or evolution in time. By using a patient-specific PCR approach we have now obtained evidence that the premyeloma cell can be situated in the pre-switched B-cell compartment and that heavy chain switching can occur without further somatic mutation. Based on the MM immunoglobulin sequences derived from the bone marrow, patient-specific CDR2 and CDR3 oligonucleotides were designed. B lymphocytes were separated from plasma cells based on the expression of CD19 and HLA class II or surface bound IgM using immunomagnetic beads. The expressed Ig sequences were amplified by RT-PCR using patient specific CDR2 primers and isotype specific primers (C mu, C gamma, and C alpha). Myeloma-specific Ig sequences were detected by a myeloma-specific CDR3 probe and sequenced. In one out of five cases we found in the peripheral blood clonally related IgM and IgA sequences with the same somatic mutations as the MM-IgG sequence. In another case of an IgG MM we found in the bone marrow clonally related IgA sequences with the same somatic mutations. These findings, together with the fact that myeloma-Ig genes contain somatic mutations without intraclonal variation, suggest that the clonogenic cell in multiple myeloma can originate from a pre-switched but somatically mutated B cell.

Amino Acid Sequence↗
PubMed2006

Does tumorigenesis select for or against mutations of the DNA repair-associated genes BRCA2 and MRE11?: considerations from somatic mutations in microsatellite unstable (MSI) gastrointestinal cancers.

BACKGROUND: The BRCA2 and MRE11 proteins participate in the repair of double-strand DNA breaks by homologous recombination. Germline BRCA2 mutations predispose to ovarian, breast and pancreatic cancer, while a germline MRE11 mutation is associated with an ataxia telangiectasia-like disorder. Somatic mutations of BRCA2 are rare in typical sporadic cancers. In tumors having microsatellite instability (MSI), somatic truncating mutations in a poly [A] tract of BRCA2 are reported on occasion. RESULTS: We analyzed gastrointestinal MSI cancers by whole gene BRCA2 sequencing, finding heterozygous truncating mutations in seven (47%) of 15 patients. There was no cellular functional defect in RAD51 focus-formation in three heterozygously mutated lines studied, although other potential functions of the BRCA2 protein could still be affected. A prior report of mutations in primary MSI tumors affecting the IVS5-(5-15) poly [T] tract of the MRE11 gene was confirmed and extended by analysis of the genomic sequence and protein expression in MSI cancer cell lines. Statistical analysis of the published MRE11 mutation rate in MSI tumors did not provide evidence for a selective pressure favoring biallelic mutations at this repeat. CONCLUSION: Perhaps conflicting with common suspicions, the data are not compatible with selective pressures during tumorigenesis promoting the functional loss of BRCA2 and MRE11 in MSI tumors. Instead, these data fit closely with an absence of selective pressures acting on BRCA2 and MRE11 gene status during tumorigenesis.

Apoptosis Regulatory Proteins↗
PubMed1998

Somatic mutations, acetylator status, and prognosis in colorectal cancer.

BACKGROUND: Somatic mutations in K-ras and TP53 may be associated with both acetylator status and prognosis in colorectal cancer. AIMS: To determine whether cancers with somatic mutations are more frequent in fast acetylators and whether mutations or acetylator status influence prognosis after colorectal surgery. PATIENTS: One hundred consecutive subjects undergoing elective surgery for colorectal cancer. METHODS: Acetylator status was determined by polymerase chain reaction (PCR) genotyping for polymorphism in the N-acetyltransferase 2 (NAT2) gene. Mutations in K-ras (codon 12) and TP53 were determined by PCR analysis using restriction enzyme digestion and single strand conformation polymorphism respectively. Survival from colorectal cancer for up to five years after diagnosis was analysed using the Kaplan-Meier product limit estimator. Cox proportional hazards regression was used to compare survival rates after adjusting for tumour stage. RESULTS: Mutations in K-ras and TP53 were independent of acetylator status. By log rank test, survival was significantly reduced in subjects with TP53 mutations (p = 0.003) but was not significantly related to acetylator status or the presence of K-ras mutations. After adjustment for tumour stage, subjects with both TP53 and K-ras mutations had a 4.2-fold case fatality (95% confidence interval 1.5 to 11.6) when compared with that of a TP53 negative reference group. CONCLUSION: The presence of both TP53 and K-ras mutations in colorectal tumours is an adverse prognostic marker which is independent of tumour stage.

Acetylation↗
PubMed1999

The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's 'two-hit' hypothesis.

APC is often cited as a prime example of a tumor suppressor gene. Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis). Most sporadic colorectal cancers also have two APC mutations. Clues from attenuated polyposis, missense germline variants with mild disease and the somatic mutation cluster region (codons 1,250-1,450) indicate, however, that APC mutations might not result in simple loss of protein function. We have found that FAP patients with germline APC mutations within a small region (codons 1,194-1,392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose 'second hits' tend to occur by truncating mutations in the mutation cluster region. Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1,300 providing the greatest advantage. Allelic loss is selected strongly in cells with one mutation near codon 1,300. A different germline-somatic APC mutation association exists in FAP desmoids. APC is not, therefore, a classical tumor suppressor. Our findings also indicate a new mechanism for disease severity: if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow.

Adenoma↗
PubMed2000

Neonatal immunity and somatic mutation.

Neonatal animals are able to mount an effective immune response, both humoral and cellular, when immunized using conditions that maximize stimulation of antigen presenting cells, T cells, and B cells. In adults, somatic mutation is a key feature of the humoral immune response because it contributes to the generation of high affinity memory B cells. Recent evidence that B cells in neonatal mice and human infants can somatically mutate their immunoglobulin heavy chains suggests that neonates can utilize somatic mutation not only to diversify their restricted germline antibody repertoire, but also to improve upon this repertoire by the generation of B cells which can produce higher affinity antibodies. By extrapolation, if vaccination of children early in life resulted in somatic mutation and affinity maturation, this could provide a more protective antibody response to childhood diseases.

Animals↗
PubMed2002

Detection of gsp somatic mutation through direct sequencing of heteroduplex alleles disclosed by denaturing gradient gel electrophoresis.

BACKGROUND: The identification of somatic mutations in tissues is often difficult when the number of normal alleles in the tissue far exceeds the number of mutant ones. We found that the identification of gsp mutation was not possible by direct sequencing and present a new approach that improves the identification of gsp somatic mutations. MATERIAL/METHODS: Genomic DNA was extracted from frozen tissue of a human ovarian stromal Leydig cell tumor. Exons 8 and 9 of the Gsa gene were amplified by PCR and despite the abnormal migration pattern at this first DGGE, direct sequencing of the PCR product did not reveal mutations, probably due to the small amount of mutant alleles. To improve this amount, the PCR products were re-amplified using as template the excised products of the mutant homoduplex and heteroduplex bands obtained at the first DGGE. RESULTS: This approach resulted in the enhancing of the mutant homoduplex bands whereas the heteroduplex bands remained unchanged at the second DGGE. Direct sequencing of the second round PCR clearly identified the mutation R201C in the ovarian Leydig cell tumor. CONCLUSIONS: We have demonstrated a relatively rapid, convenient and reliable method to improve gsp somatic mutation detection combining a second DGGE of the PCR products obtained from the heteroduplexes and mutant homoduplex bands disclosed in a first DGGE followed by direct sequencing.

Alleles↗
PubMed2001

Induction and repair of DNA damage as measured by the Comet assay and the yield of somatic mutations in gamma-irradiated tobacco seedlings.

The advantage of using the tobacco (Nicotiana tabacum var. xanthi) mutagenicity assay is the ability to analyze and compare on the same plants under identical treatment conditions both the induced acute DNA damage in somatic cells as measured by the Comet assay and the yield of induced leaf somatic mutations. Gamma-irradiation of tobacco seedlings induced a dose-dependent increase in somatic mutations from 0.5 (control) to 240 per leaf (10Gy). The increased yield of somatic mutations was highly correlated (r = 0.996) with the increased DNA damage measured by the Comet assay immediately after irradiation. With increased dose of gamma-irradiation, the averaged median tail moment values ( +/- S.E.) significantly increased from 1.08 +/- 0.10 (control) to 20.26 +/- 1.61 microm (10Gy). Nuclei isolated from leaves 24h after irradiation expressed tail moment values that were not significantly different from the control (2.08 +/- 0.11). Thus a complete repair of DNA damage induced by gamma-irradiation and measurable by the Comet assay was observed, whereas the yield of somatic mutations increased in relation to the radiation dose. Data on the kinetics of DNA repair and of DNA damage induced by gamma-radiation on isolated tobacco nuclei, and on nuclei isolated from irradiated leaves and roots are presented.

Comet Assay↗
PubMed1999

Somatic mutations in the BRCA1 gene in Chinese sporadic breast and ovarian cancer.

Inherited mutations in the BRCA1 gene confer increased susceptibility to breast and ovarian cancer. Its role in sporadic carcinogenesis is not well defined. Somatic mutations in breast cancers have not been reported and to date there are only three reports of somatic mutations in sporadic ovarian cancers. To investigate the contribution of BRCA1 mutations to sporadic breast and ovarian cancer in the Chinese population, we analysed 62 samples from Chinese women using the protein truncation test. There were 40 cases of breast cancer under age 50 and 22 cases of ovarian cancer, all unselected for family history. There was no age selection for the ovarian cancers. We found two somatic BRCA1 mutations in exon 11, one in a breast cancer and the other in an ovarian cancer, both of which result in truncated proteins. Our results indicate that somatic BRCA1 mutations, like somatic mutations in the BRCA2 gene, though very rare, can be found in both breast and ovarian cancers and support a tumor suppressor function for BRCA1 in sporadic tumors.

Adult↗
PubMed1999

[Haldane's rule and somatic mutations].

Haldane's rule stating that viability and fertility in the heterogametic sex of hybrids are lower than in the homogametic sex is explained on the basis of the assumption that diploidy is aimed at protecting individuals having large body size and large genomes from somatic mutations. The presence of hemizygous sex chromosomes, which are effectively haploid in the heterogametic sex, results in the phenotypic expression of all deleterious somatic mutations arising in them. In the homogametic sex, somatic mutations that affect one out of two identical sex chromosomes are not expressed because the unaffected chromosome functions normally. Thus, the heterogametic sex is more sensitive to the harmful effect of somatic mutations. In hybrids, this difference may be critical. Consequently, when genetic distance between hybridizing species increases, the heterogametic sex of hybrids loses viability and fertility earlier than the homogametic sex, which agrees with Haldane's rule. On the basis of Haldane's rule and data on the small size of natural hybrid zones, restrictions on maximum heterozygosity compatible with viability were established.

Heterozygote↗
PubMed1999

Somatic mutation of the APC gene in thyroid carcinoma associated with familial adenomatous polyposis.

We report the existence of both germline and somatic mutations of the APC gene in thyroid carcinomas from familial adenomatous polyposis (FAP) patients. One papillary thyroid carcinoma from a 210-year-old woman, with germline mutation of the APC gene (TCA to TGA at codon 1110), showed a somatic mutation of AAAAC deletion between codons 1060 and 1063. Another somatic mutation of CAG to TAG at codon 886 was also found in one of multiple thyroid carcinomas from a 26-year-old woman with attenuated FAP and germline mutation at codon 175 (C deletion). This is the first evidence that total absence of the normal function of the APC gene is involved in development of thyroid carcinomas in FAP.

Adenomatous Polyposis Coli↗