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PubMedDate not supplied

[From human andro- and parthenogenesis (hydatidiform moles and benign ovarian teratomas) to cancer].

Genomic imprinting is a process that appeared in mammals. This phenomenon blocks the normal development of parthenogenic and androgenic conceptuses, that is to say benign ovarian teratomas and hydatidiform moles respectively. Pathological modifications of these conceptuses depend on whether the chromosomes come from the mother or father. These pathologies are associated with an accidental anomaly during gametogenesis and/or fertilizing. These reproductive anomalies are sporadic and some familial cases may exist suggesting a genetic control of such diseases. The human andro- and parthenogenetic conceptuses, but more frequently the moles, may be invasive (choriocarcinoma). An imbalance of the imprinting genes may initiate the deregulation of other genes, including oncogenes and anti-oncogenes, which can explain the cancerous modification. Immunological and environmental factors must be also considered (presence of the only paternal chromosomes in the choriocarcinoma). Numerous works on this subject are published and some recent important discoveries underline the roles of genes HOX, Tim P3, E-cad and p-16, and the recurrent chromosome anomalies 7q21+and 8p21- in the mole to choriocarcinoma processing. Although these phenomena are complex and heterogeneous, the andro- and parthenogenote conceptuses are particularly interesting models with which to understand developmental disorders and cancerous progression.

Embryonic Development↗

PubMed2002

Prevalence of somatic alterations in the colorectal cancer cell genome.

Although a small fraction of human cancers have increased rates of somatic mutation because of known deficiencies in DNA repair, little is known about the prevalence of somatic alterations in the vast majority of human cancers. To systematically assess nonsynonymous somatic alterations in colorectal neoplasia, we used DNA sequencing to analyze approximately 3.2 Mb of coding tumor DNA comprising 1,811 exons from 470 genes. In total, we identified only three distinct somatic mutations, comprising two missense changes and one 14-bp deletion, each in a different gene. The accumulation of approximately one nonsynonymous somatic change per Mb of tumor DNA is consistent with a rate of mutation in tumor cells that is similar to that of normal cells. These data suggest that most sporadic colorectal cancers do not display a mutator phenotype at the nucleotide level. They also have significant implications for the interpretation of somatic mutations in candidate tumor-suppressor genes.

Colorectal Neoplasms↗

PubMed2026

SCLC TumorMiner: A genomics platform for small cell lung cancer precision oncology.

Small cell lung cancer (SCLC) is among the most aggressive malignancies. Unlike many other cancers, it is not represented in The Cancer Genome Atlas, and available datasets are fragmented across institutions, disease stages, and treatment settings. RNA sequencing provides a powerful and cost-effective approach, but the high dimensionality of transcriptomic data and the heterogeneity of patient cohorts pose significant challenges. To address such challenges, we developed SCLC TumorMiner (https://discover.nci.nih.gov/SclcTumorMinerCDB/), which includes 50 tumor samples from relapsed patients at the National Cancer Institute (NCI) and 154 samples from untreated patients at the University of Cologne and Tongji University. SCLC TumorMiner enables molecular classification, genomic pathway analyses, risk stratification, identification of predictive cell-surface biomarkers such as DLL3 or TROP2, and drug-response biomarkers such as SLFN11. SCLC TumorMiner illustrates profound differences between untreated and relapsed patient samples. Additionally, "MyPatient", one of SCLC TumorMiner's modules, is presented as a medical assistant application prototype.

SCLC↗

PubMed2002

Allelic imbalances in human bladder cancer: genome-wide detection with high-density single-nucleotide polymorphism arrays.

BACKGROUND: Bladder cancer is characterized by genomic instability. In this study, we investigated whether genome-wide screening using single-nucleotide polymorphism (SNP) arrays could detect allelic imbalance (loss or gain of at least one allele) in bladder cancers. METHODS: For microarray analysis, DNA was isolated from microdissected bladder tumors and leukocytes from 11 patients. The stage T1 tumor (connective tissue invasive) and the subsequent stage T2-4 tumor (muscle invasive) were available from eight of these patients, and only the first muscle-invasive stage T2-4 tumor was available from three of the 11 patients. The microarray contained 1494 biallelic polymorphic sequences. For microsatellite analyses, DNA was isolated from tumors and leukocytes of nine patients with primary T2-4 tumors and 13 patients with Ta (noninvasive) tumors. All statistical tests were two-sided. RESULTS: We assigned a genotype to 1204 loci, 343 of which were heterozygous. Allelic imbalance was detected in known areas of imbalance on chromosomes 6, 8, 9, 11, and 17, and a new area of imbalance was detected on the p arm of chromosome 6. Microsatellite analysis of nine other T2-4 tumors and 13 Ta tumors showed that allelic imbalance was more frequent in T2-4 tumors than in Ta tumors (P<.001). We detected 8.5 allelic imbalances (median) in 348 informative loci in T1 tumors and 28 allelic imbalances (median) in 329 informative loci in T2-4 tumors. When pairs of T1 and T2-4 tumors were analyzed from eight patients, 68% of imbalances detected in T1 tumors (146 imbalances) occurred in the subsequent T2-4 tumors (99 imbalances). Homozygous TP53 mutations were more often associated (P =.005) with high allelic imbalance than with low allelic imbalance. CONCLUSION: SNP arrays are feasible for high-throughput, genome-wide scanning for allelic imbalances in bladder cancer.

Allelic Imbalance↗

PubMed1993

Relaxation of imprinted genes in human cancer.

Genomic imprinting, or parental allele-specific expression of genes, has been demonstrated at the molecular level in insects and mice but not in man. Imprinting as a potential mechanism of human disease is suggested by paternal uniparental disomy of 11p15 in Beckwith-Wiedemann syndrome and by maternal uniparental disomy of 15q11-12 in Prader-Willi syndrome. Beckwith-Wiedemann syndrome is characterized by multiorgan overgrowth and predisposition to embryonal tumours such as Wilms' tumour of the kidney. A loss of heterozygosity of 11p15 is also frequently found in a wide variety of tumours, including Wilms' tumour and lung, bladder, ovarian, liver and breast cancers; 11p15 also directly suppresses tumour growth in vitro. Two genes in this band, H19 and insulin-like growth factor-II (IGF2) undergo reciprocal imprinting in the mouse, with maternal expression of H19 (ref. 13) and paternal expression of IGF2 (ref. 14). Here we find that both of these genes show monoallelic expression in human tissues and, as in mouse, H19 is expressed from the maternal allele and IGF2 from the paternal allele. In contrast, 69% of Wilms' tumours not undergoing loss of heterozygosity at 11p showed biallelic expression of one or both genes, suggesting that relaxation or loss of imprinting could represent a new epigenetic mutational mechanism in carcinogenesis.

Alleles↗

PubMed1994

p53 mutations and MDM-2 amplification in renal cell cancers.

Genomic DNA from 53 primary human renal cell tumors was screened for the presence of mutations in the tumor suppressor gene p53, using the polymerase chain reaction and single-strand conformation polymorphism analysis, followed by direct sequencing of DNA. Five cases showed mobility shifts. Sequencing of these samples revealed two cases of nonsense mutations (codons 182, 192), one case of a missense mutation (codon 285), and two cases of silent mutations at codon 213. The frequency of mutations altering the p53 (3/53 = 6%) was low when compared with the reported frequencies (15% to 65%) of allelic loss of 17p (location of p53) in renal cell cancers, suggesting the possible existence of another tumor suppressor gene in the region of the p53 gene, which when mutated is associated with these cancers. All three tumors with p53 mutations were cases with poor prognosis, i.e., highest pathological grade and/or advanced Robson stage. The human equivalent of the murine double-minute-2 was not amplified in the renal cell tumors. In summary, alterations of p53 may be associated with the development of renal cell carcinoma of higher grade and/or stage.

Base Sequence↗

PubMed1991

p53 gene mutations in Barrett's epithelium and esophageal cancer.

Genomic DNA was extracted from archival pathology specimens comprising 10 squamous and 14 adenocarcinomas, including 7 with Barrett's epithelium adjacent to tumor, and corresponding normal esophagus from the resection margin. The polymerase chain reaction was used to amplify selected exons of p53 which were analyzed for mutations using single-strand conformation polymorphism analysis. Mutations were localized to exon 8 for 1 adenocarcinoma and to exon 5 for 1 squamous tumor and 4 of 7 Barrett's specimens. Sequencing confirmed mutations at codons 273 (CGT----CAT; adenocarcinoma) and 176 (TGC----TTC; squamous) and in Barrett's epithelium at codons 152 (CCG----CTG), 155 (ACC----GCC) and 175 (CGC----CAC). Specimens of Barrett's epithelium from separate sites had identical p53 mutations suggesting a clonal origin. Cancers arising in mutant epithelium did not have mutations corresponding to those found in the Barrett's specimens suggesting that other events are required for tumorigenesis.

Adenocarcinoma↗

PubMed2003

The genetics and genomics of cancer.

The past decade has seen great strides in our understanding of the genetic basis of human disease. Arguably, the most profound impact has been in the area of cancer genetics, where the explosion of genomic sequence and molecular profiling data has illustrated the complexity of human malignancies. In a tumor cell, dozens of different genes may be aberrant in structure or copy number, and hundreds or thousands of genes may be differentially expressed. A number of familial cancer genes with high-penetrance mutations have been identified, but the contribution of low-penetrance genetic variants or polymorphisms to the risk of sporadic cancer development remains unclear. Studies of the complex somatic genetic events that take place in the emerging cancer cell may aid the search for the more elusive germline variants that confer increased susceptibility. Insights into the molecular pathogenesis of cancer have provided new strategies for treatment, but a deeper understanding of this disease will require new statistical and computational approaches for analysis of the genetic and signaling networks that orchestrate individual cancer susceptibility and tumor behavior.

Alleles↗

PubMed2006

SATR-1 hypomethylation is a common and early event in breast cancer.

Genome stability and normal gene expression are maintained by a fixed and predetermined DNA methylation pattern, which becomes abnormal in malignant cells. Hypomethylation of satellite DNA sequences is frequently found in tumors and has been associated with an increased frequency of DNA rearrangements and chromosome instability. In this work, we used methylation-sensitive arbitrarily primed polymerase chain reaction (MSAP-PCR) to identify differentially methylated DNA fragments in normal and tumor breast samples. We identified a novel differentially methylated fragment located on chromosome 5 with high similarity to a SATR-1 satellite sequence. This fragment was found to be hypomethylated in 63% of breast tumor cell lines and in 86% of breast tumors relative to normal breast tissue. We found that normal tissue adjacent to breast tumors displayed a variable decrease in methylation and that the decrease observed for most of these adjacent samples was higher than observed for normal breast tissue derived from reduction mammoplasty. The methylation decrease was, however, significantly higher in tumor samples than in adjacent tissue (chi2= 154, 1 df, P < 10(-4)), suggesting that SATR-1 hypomethylation frequently occurs in the early stages of tumor development. Our results highlight the importance of global DNA hypomethylation as a contributing factor in breast tumorigenesis.

Base Sequence↗

PubMed1994

Dinucleotide repeat polymorphisms at nine loci in sporadic colorectal cancer.

Genomic instability in the form of microsatellite alterations at nine loci on chromosomes 2p, 8p, 10p, 11p, and nm23-H1 locus on 17q21.3 were studied in sporadic colorectal tumors. Alterations in dinucleotide repeats in tumor DNA as larger allele, smaller allele, or loss of heterozygosity (LOH) were observed. Forty percent of tumor showed an RER+ phenotype. A significantly high number of alterations was detected at loci of chromosome 8p. The markers on chromosomes 2p, 10p, and 11p did not show such significant alteration. LOH was found to be associated with the nm23-H1 locus. No correlation was found between the age, site of tumor occurrence, or metastasis and the microsatellite instability.

Adenocarcinoma↗

PubMed2026

Kynurenine metabolism-related gene signature for prognostic stratification in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a major global health burden with high mortality rates and limited therapeutic options. The identification of reliable biomarkers for early diagnosis and prognosis prediction is urgently needed. Kynurenine metabolism, a critical pathway in immune regulation and tumor progression, has been implicated in various cancers. However, its prognostic value in HCC has not been fully elucidated. This study aimed to develop a prognostic risk model based on kynurenine metabolism-related genes (KMRGs) for HCC patients. METHODS: Transcriptomic and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) databases. A prognostic risk model was established using least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. Survival analysis and functional enrichment analysis were conducted to validate the predictive performance of the model and to investigate the underlying mechanisms. ALDH8A1 was ultimately identified as a target gene based on survival analysis, and its impact on tumor cell migration was assessed using the HCC cell line. RESULTS: A prognostic model based on seven KMRGs was established. The high-risk group exhibited significantly worse overall survival compared to the low-risk group. Functional enrichment analysis in high-risk patients highlighted significant enrichment in core biological processes, including spliceosome assembly and ribonucleoprotein complex biogenesis. Furthermore, a nomogram integrating the risk score and clinical pathological features was developed, demonstrating moderate predictive performance for HCC prognosis. CONCLUSIONS: This study successfully constructed a prognostic risk model based on seven KMRGs, providing a valuable tool for predicting clinical outcomes in HCC patients. These findings highlight the potential role of kynurenine metabolism in HCC progression and offer new insights for future therapeutic strategies.

ALDH8A1↗

PubMed2001

Environment, genome and cancer.

Cancer is one of the most serious diseases that threaten human being today. To some degree, it is a genetic disease but environmental and other nongenetic factors clearly play a role in many stages of neoplastic process. Genetic factors by themselves are thought to explain only about 5% of all cancer. The remainder can be attributed to external, 'environment' factors that act in conjunction with both genetic and acquired susceptibility. Of note, part of the susceptibility is owing to the variety of human genome. So, environment, human genome and cancer have much to do with each other. Combining all of the information from epidemiology and from research works in laboratory with policy-making and clinical works, purifying the environment, giving special protection to the high risk population, the mortality of cancer may decrease gradually in the future.

Carcinogens, Environmental↗

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↗

PubMed2004

The rise and fall of genomic methylation in cancer.

Changes in genomic methylation and its significance in carcinogenesis is in the spotlight once again, though the focus is not on the usual suspects, DNA hypermethylation and tumour suppressor gene (TSG) silencing. Several recent reports provide compelling evidence of the relevance of genomic hypomethylation in cancer. These findings provide the best evidence so far that links the loss of DNA methylation and chromosomal instability with cancer development. This review article discusses these recent findings and reflects on the antithetical association between DNA methylation and carcinogenesis and the re-examination of studies performed almost two decades ago.

Animals↗

PubMed2006

Molar pregnancy, childhood cancer and genomic imprinting - is there a link?

The United Kingdom Childhood Cancer Study (UKCCS) is a national multi-centre case-control study that was designed to evaluate the potential aetiological role of prenatal events in childhood cancer. The obstetric records of 2692 mothers of children diagnosed with cancer and 4864 mothers of children without cancer were available for analysis. Overall, 1754 (65%) case mothers and 3220 (66%) control mothers had at least one prior pregnancy before the birth of the index child. Of these, 12 (0.68%) of the former and 9 (0.28%) of the latter had a prior molar pregnancy (odds ratio 2.5, 95% confidence interval 1.1 - 6.1). Both childhood cancer and molar pregnancy are rare neoplastic events, and the numbers are small. Nonetheless, whilst the associations were strongest for common precursor B-cell acute lymphoblastic leukaemia (OR 5.2, 95% CI 1.9 - 14.7) and sarcoma (OR 6.2, 95% CI 1.3 - 30.3), the spread across the remaining diagnostic groups suggests that the relationship, if confirmed, may be of a generalized, rather than specific, type. This is the first time that an association between childhood cancer and hydatidiform mole has been reported. The UKCCS's systematic use of clinical records permitted a more precise characterization of reproductive events than is possible in investigations that rely on individuals own accounts, and we are confident that our findings cannot be explained by recall bias or other methodological limitations. Accordingly, we suggest that there may be an aetiologic connection between molar pregnancy and childhood cancer, and speculate here on the various genetic/epigenetic mechanisms that could be involved.

Adolescent↗

PubMed2026

Associations of neighborhood deprivation with breast cancer tumor genomics, targeted treatment use, and survival.

PURPOSE: Neighborhood environments appear to influence breast cancer biology and outcomes. This study evaluated somatic, treatment, and outcome differences by Area Deprivation Index in patients with metastatic breast cancer. METHODS: Retrospective, population-based cohort study using clinical and genomic data gathered between 2015 and 2024 at four academic institutions in the United States. The outcomes were differences in circulating tumor DNA mutation profiles, PI3K inhibitor use, and survival between patients with metastatic breast cancer living in high deprivation (Area Deprivation Index ≥ 60 by national rank) and low deprivation (< 60) neighborhoods. RESULTS: Among 1127 patients with metastatic breast cancer, 335 (29.7%) lived in high deprivation areas. These patients were more likely to have TP53 mutations (Odds ratio 1.49, 95% Confidence Interval 1.07-2.08, P = 0.018). Among hormone receptor-positive, HER2-negative patients eligible for PI3K inhibitors, those from high deprivation areas were less likely to receive them (17.4% vs. 36.7%, p = 0.02). Median survival from the time of circulating tumor DNA testing was significantly shorter in the high deprivation group (24 months versus 28 months, p = 0.04) and for Black patients in the high deprivation group versus Black patients in low deprivation group and all White patients (15 months versus 25-28 months, p = 0.02). CONCLUSIONS: We found that patients with metastatic breast cancer living in high deprivation neighborhoods were more likely to have TP53 mutations, an indicator of aggressive disease biology, less likely to receive PI3K inhibitors, and had shorter overall survival compared to patients living in low deprivation neighborhoods by Area Deprivation Index.

Humans↗

PubMed1999

Identification of a 5-cM region of common allelic loss on 8p12-p21 in human breast cancer and genomic analysis of the hEXT1L/EXTR1/EXTL3 gene in this locus.

The short arm of chromosome 8 is frequently lost in many human carcinomas including breast cancer, suggesting the presence of a tumor suppressor gene(s) in this region. We identified a gene termed hEXT1L/EXTR1/EXTL3 (hEXT1L hereinafter) that was mapped to chromosome bands 8p12-p21 where frequent LOHs of this region was reported in breast cancer. The existence of the third breast cancer susceptibility gene was also suggested in this region by linkage analysis. We further performed LOH analysis in 8p12-p21 in 34 breast cancers and identified a 5-cM region of common allelic loss that overlapped with the locus for positive lod score in familial breast cancer. We further analyzed genomic alterations of hEXT1L in tumors in which frequent LOHs of 8p were reported. A total of 327 cancers (313 primary tumors and 14 cancer cell lines) including 22 primary breast cancers were analyzed, but none of the tumors had somatic mutations: only one thyroid cancer patient without any family history of cancer had a 9-bp insertion in the constitutional DNA. These results suggest that mutations of hEXT1L do not play a major role in the development of sporadic cancers including breast cancer, and that other tumor suppressor gene(s) exists in the 5-cM region identified in this study.

Alleles↗

PubMedDate not supplied

Absence of mutatins in the analysis of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic humangastric cancer using genomic DNA and intron primers.

Mutations in the transforming growth factor beta type II receptor (TGFbetaRII) gene have been detected in several human cancers that represent the phenotype of genomic instability. To establish a basis for diagnosis of cancer patients, we previously determined the exon-intron organization of the TGFbetaRII gene. The results indicated that TGFbetaRII protein is encoded by 567 codons in 7 exons. In this study, we further determined the nucleotide sequences surrounding these 7 exons and designed 8 sets of intron-based primers to examine the entire coding region of the TGFbetaRII gene. By using these primers, we screened for mutations of the TGFbetaRII gene in DNAs of 32 sporadic gastric cancer patients in whom one case showed MI+ (3.1%) at two loci. We found no mutations, and these data support other recent evidence that TGFbetaRII mutations rarely occur except in colon and gastric tumors with MI.

Chromosome Mapping↗