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PubMed2026

Integrated Genomic and Epigenomic Analysis Reveals Epigenetic Plasticity in Disease Progression and Multidrug Resistance in Multiple Myeloma.

UNLABELLED: Multiple myeloma is marked by recurrent cytogenetic abnormalities and mutations that accumulate as the disease progresses. In this study, we sought to elucidate the transitions driving tumorigenesis and therapy resistance in multiple myeloma using a unique cohort of nearly 900 patients spanning premalignant to late-stage refractory multiple myeloma, comprehensively characterized at molecular and clinical levels. Waves of epigenetic dysregulation drove these critical transitions. In this paradigm, genomic and cytogenetic events unlocked epigenetic plasticity, reshaping multiple myeloma cell biology to evade tumor microenvironment constraints and therapeutic pressures. Functional perturbation studies in an isogenic proteasome inhibitor-resistant cell line model demonstrated enhanced reliance on transcriptional cofactors, supporting a mechanistic link between chromatin plasticity and therapy adaptation. Collectively, these findings support a unifying framework in which genomic heterogeneity unlocks gene regulatory plasticity, enabling plasma cells (PC) to evade microenvironmental constraints and therapeutic pressure. These results provide a mechanistic explanation for sequential relapse without new genomic alterations and nominate epigenetic plasticity-mediated PC adaptation as a therapeutic vulnerability in the heterogeneous genetic background of multiple myeloma. SIGNIFICANCE: Assembly and analysis of a multiple myeloma cohort spanning the continuum from premalignant to late relapse that integrates bulk transcriptomics with single-cell multiomic data provides insights into disease progression and epigenetic plasticity.

Multiple Myeloma↗
PubMed2005

Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells.

PURPOSE: The transcription factor CCAAT/enhancer binding protein alpha, encoded by the CEBPA, is crucial for the differentiation of immature granulocytes. Mutation of the CEBPA may play an important role in leukemogenesis and prognosis. We sought to characterize the CEBPA mutation in acute myeloid leukemia (AML) and to clarify if there is a distinct immunophenotype for leukemic cells with the mutation. EXPERIMENT DESIGN: One hundred and four patients with de novo AML were evaluated for the CEBPA mutation and immunophenotype of the leukemic cells. RESULTS: Twenty-two distinct mutations were identified in 16 (15%) of 104 AML patients. Fourteen patients had biallelic mutations, mostly involving both the NH(2)-terminal TAD1 region and the COOH-terminal basic leucine zipper domain (bZIP). The mutations in the bZIP region were always tandem duplications and were located at hot-spot regions for topoisomerase II sites. Sequential study of the CEBPA mutations showed that the mutations disappeared at complete remission but the same mutations reappeared at relapse. None of the patients developed novel mutations during the follow-up period. Patients with CEBPA mutations had significantly higher incidences of CD7 (73%), CD15 (100%), CD34 (93%), and HLA-DR (93%) expression on the leukemic cells. CONCLUSION: These data revealed that most AML with CEBPA mutations were associated with an immunophenotype of HLA-DR(+)CD7(+)CD13(+)CD14(-)CD15(+)CD33(+)CD34(+). The close relationship of CEBPA mutations with the leukemia status of the patients and the concordance of mutation in presenting and relapse samples implicate the CEBPA mutation as a potential marker for monitoring minimal residue disease.

Acute Disease↗
PubMed2005

P53 mutation analysis of colorectal liver metastases: relation to actual survival, angiogenic status, and p53 overexpression.

PURPOSE: To correlate TP53 mutations with angiogenic status of the tumor and prognosis after liver surgery in patients with colorectal liver metastases and to correlate immunohistochemical staining of p53 protein with TP53 gene mutations. EXPERIMENTAL DESIGN: Tumors of 44 patients with surgically treated colorectal liver metastases were analyzed for (a) TP53 mutations using denaturing gradient gel electrophoresis followed by sequencing, (b) microvessel density using the hot spot overlap technique, (c) apoptotic rate in tumor cells and endothelial cells of tumor microvessels using double immunostaining for anti-cleaved caspase 3 and anti-CD34, and (d) expression of p53 protein using immunohistochemistry. RESULTS: TP53 mutations were detected in 36% of the metastases and occurred more frequently in liver metastases from left-sided colon tumors than from right-sided colon tumors (P = 0.04). In metastases with TP53 mutations, microvessel density was higher compared with tumors with wild-type p53. Endothelial cell apoptosis was not different in tumor microvessels from TP53-mutated versus nonmutated tumors. The 5-year actual survival was not influenced by TP53 mutational status, microvessel density, or endothelial cell apoptotic rate of the tumors. Based on immunohistochemical p53 overexpression, the positive and negative predictive values of TP53 mutations were 61% and 82%. CONCLUSIONS: In patients with surgically treated colorectal liver metastases, TP53 mutations and angiogenic status did not influence prognosis. Immunohistochemistry is not a reliable technique for detecting TP53 mutations.

Aged↗
PubMed2005

Relapsing pancreatitis due to a novel compound heterozygosity in the CFTR gene involving the second most common mutation in central and eastern Europe [CFTRdele2,3(21 kb)].

A 43-year-old otherwise healthy female patient presented with mild pancreatitis. Her family history revealed that her only son had cystic fibrosis. Genotyping of the patient demonstrated CFTR compound heterozygosity CFTRdele2,3(21 kb) and R117H and wild type alleles of the poly-T-tract in intron 8 (7T/7T). No mutations were detected in the cationic pancreatic trypsinogen (PRSS1) and the pancreatic secretory trypsinogen inhibitor (SPINK1) genes. CFTRdele2,3(21 kb) has only been described in 2000 and is the second most frequent severe CFTR mutation after DeltaF508 in central and eastern Europe. This haplotype should be included in the genetic panel when evaluating patients of central or eastern European genetic background for possible CFTR related pancreatitis.

Adult↗
PubMed2003

Binet's staging system and VH genes are independent but complementary prognostic indicators in chronic lymphocytic leukemia.

PURPOSE: Rai's and Binet's staging systems have contributed significantly to the identification of major prognostic groups in chronic lymphocytic leukemia (CLL), though they fail to accurately predict disease progression at the individual level. Biologic factors, such as the mutational status of the immunoglobulin heavy-chain variable genes (VH, cytogenetics, CD38 expression, and some serum markers, have recently improved prognostic assessment in CLL. In this study, we analyzed the prognostic value of VH mutational status within the different stages of Binet's classification in 145 patients. PATIENTS AND METHODS: Our series consisted of 83 VH mutated (MT) and 62 VH unmutated (UM) patients. MT cases predominated within Binet's stage A (70%), whereas UM cases predominated among stages B and C (62%). RESULTS: Median overall survival (OS) was 84 months for UM patients and was not achieved for the MT group (70% 12-year survival, P <.0001). Concerning Binet's stage A, both median OS and progression-free survival were significantly shorter for UM patients when compared with those of MT patients (97 months v not achieved, P =.0017; and 42 v 156 months, P <.0001), which compared favorably with the classical A' and A" substaging. The VH mutational profile could also segregate stage B and C patients into two groups with different survival patterns (median OS, 78 v 120 months for UM and MT patients, respectively; P =.002). CONCLUSION: The significant survival differences observed between the VH mutational groups, among stage A and stage B and C patients, indicate that Binet's classification and VH genes are independent prognostic variables and are most likely complementary.

Brazil↗
PubMed1993

Absence of p53 mutations in childhood central nervous system primitive neuroectodermal tumors.

The primitive neuroectodermal tumor of the central nervous system is one of a number of tumors in which deletions on chromosome 17p have been identified. The tumor suppressor gene, p53, is located in the region of the deletion. To determine if the p53 gene is involved in the development of primitive neuroectodermal tumors, deoxyribonucleic acid (DNA) blot analysis, ribonucleic acid blot analysis, and p53 complementary DNA sequencing were performed on 34 primitive neuroectodermal tumors removed from children. No rearrangement in the gene was detected in 21 tumors. The p53 messenger ribonucleic acid was of the expected size in all 18 tumors for which ribonucleic acid was available. Sequencing of p53 Exons 5 through 9 revealed a mutation in the cell line DAOY and in only 1 of 14 tumors examined. A DNA rearrangement was detected in the DNA from one tumor with a probe mapping to the distal portion of 17p. Taken together, these data suggest that the p53 gene is not involved in the development of most primitive neuroectodermal tumors. In addition, a gene of interest may be present on distal 17p.

Adolescent↗
PubMed2000

Tibial hemimelia, meningocele, and abdominal hernia in Shorthorn cattle.

Six genetically related Shorthorn calves were affected with the tibial hemimelia syndrome. The lesions included bilaterally malformed or absent tibia and abdominal hernia in all animals, a long shaggy haircoat, retained testicles in males, and meningocele in three animals. The malformations were similar to those described previously in Galloway calves. Pedigree analysis demonstrated a mechanism by which a recessive allele in a homozygous state could be responsible for the disorder. The condition in these calves was considered the result of a recurrence of a genetic mutation affecting a putative hemimelia locus.

Animals↗
PubMed2006

Successful treatment with adefovir of one patient whose cryoglobulinemic vasculitis relapsed under lamivudine therapy and who was diagnosed to have HBV virologic breakthrough with YMDD mutations.

We report a patient whose cryoglobulinemic vasculitis recurred due to reactivation of lamivudine-resistant HBV. Our patient with hepatitis B-related cryoglobulinemic vasculitis was administered lamivudine. Her vasculitis regressed, ALT normalized, HBV-DNA became negative. Under lamivudine therapy, her cryoglobulinemic cutaneous vasculitis recurred. ALT increased significantly; it was found that tyrosine-methionine-aspartate-aspartate (YMDD) motif in the DNA polymerase gene had been replaced by YIDD. Adefovir was added to lamivudine. During follow-up, her purpura disappeared, ALT normalized, HBV-DNA became negative. Our patient is the first whose cryoglobulinemic vasculitis recurred under lamivudine, who had a HBV virologic breakthrough with YMDD mutation, and was successfully treated with adefovir.

Adenine↗
PubMed1993

N-ras mutation in acute myeloid leukemia: incidence, prognostic significance and value as a marker of minimal residual disease.

The polymerase chain reaction (PCR) and allele specific oligonucleotide (ASO) hybridization have been used to investigate the incidence of N-ras mutation in acute myeloid leukemia (AML). The prognostic significance of these mutations and their value as markers of minimal residual disease have also been assessed. Mutated N-ras alleles were detected in 9 of 69 AML patients (13%). No significant difference in survival or remission duration was found between those patients with an N-ras mutation and those without. Four patients with N-ras mutations at presentation were followed through disease progression. The results showed no consistent pattern of association between the presence of an N-ras mutation and disease state.

Adolescent↗
PubMed1998

[Studies on genes associated with biologic behavior in human lung cancer].

OBJECTIVE: To study alteration of several genes in the process of primary lung cancer. METHODS: A series of 59 lung cancer specimens were analyzed for p53, myc oncogene family and mdrl gene by DNA/PCR sequencing, immunohistochemistry and RT-PCR methods. RESULTS: p53 mutation or/and protein accumulation were found in 37 of 57(65%) cases. Overexpression of myc family oncogenes and mdr1 gene were 27/46 (59%) and 15/48 (31%), respectively. The results also showed that there was no significant correlation between p53 alteration and tumor size, metastasis, stage and relapse, but there was a significant correlation between overexpression of myc family oncogene and these factors. Overexpression of mdrl gene was detected in NSCLC, especially in adenocarcinoma, and was not associated with metastasis and stage of lung cancer. It was also found that aberration of both p53 and myc family oncogenes occurred in 19/30(63%) cases; the relapse rate was 76%. Both overexpression of mdrl and myc gene was 62%; the relapse rate was 83%. CONCLUSION: p53, myc and mdrl genes in cooperation may be involved in the process of lung cancer, but prognostic determinant is myc gene overexpression.

Adenocarcinoma↗
PubMed2001

Increased p53 mutation frequency during tumor progression--results from a breast cancer cohort.

The mutational patterns of the p53 gene for exons 4-9 were analyzed in 30 recurring tumors compared with the p53 status of the corresponding 30 primary breast cancers. The prevalence of p53 mutations was higher, although not statistically significant (P = 0.07), in the evaluable recurring tumors compared with the corresponding primaries, 12 of 29 (41%) versus 7 of 30 (23%). Twenty-one of the patients had unchanged p53 mutation status in the recurring compared with the primary tumors, whereas 8 had an altered mutational status or pattern in the sequential tumor. These findings indicate that p53 mutations may be an important factor for tumor progression in human breast cancer.

Breast Neoplasms↗
PubMed2002

[From gene to disease; the dystrophin gene involved in Duchenne and Becker muscular dystrophy].

Duchenne and Becker muscular dystrophy (DMD and BMD) are progressive disorders, which almost exclusively affect males. DMD is the more severe type with an onset at 2-3 years of age. Patients become wheelchair-bound before the age of 13 and often die due to cardiac arrest or respiratory insufficiency. BMD, a more varying phenotype which may overlap with limb girdle muscular dystrophy (LGMD), has a less severe muscle weakness which starts later than in DMD patients. DMD carriers may show some muscle weakness. The dystrophin gene (2.4 Mb), known to be involved in DMD/BMD, codes for a 427 kilodalton muscle-specific protein named dystrophin as well as several tissue-specific isoforms. Dystrophin, as part of a membrane-bound complex of proteins, connects the cytoskeleton of the muscle cell to the extracellular matrix. Since 1985, when highly reliable carrier detection and prenatal diagnosis at the DNA level became possible, over 250 prenatal tests have been performed. Molecular genetic analysis, highlighted a phenomenon called germinal mosaicism, which explains the recurrence of de novo mutations and led to the discovery of the so-called reading-frame rule, which helps to discriminate between DMD and BMD. Fifteen years after the discovery of the dystrophin gene, mutations can be detected in 95% of the patients, while the remaining 5% are still hiding within this very large gene.

Chromosome Mapping↗