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PubMed2001

[Etiological study on human rotavirus infections in children with acute gastroenteritis].

OBJECTIVE: To understand the etiology of human rotavirus infections in children with acute gastroenteritis in China. METHODS: The investigation covered 1968 feces infants and children with acute gastroenteritis in 19 provinces and cities in China. Feces samples collected from 1968 infants and children with diarrhea, 148 children, 135 newborns and 37 adults without diarrhea, 36 adults with diarrhea were examined by polyacrylamide gel electrophoresis (PAGE). 1493 feces samples were examined by ELISA; 388 feces samples from sick children and 57 feces samples from children and adults without diarrhea were examined by EM. Bacterial culture were analyzed in 645 feces samples. RESULTS: Human rotavirus RNA (HRV RNA) was detected in 804(40.9%) of 1968 feces samples examined. No virus was detected in the feces samples of children and adults without diarrhea. Rotavirus antigen was detected in 500 (33.5%) of the 1493 feces samples. According to the genome profile of PAGE, 801 (99.6%) of the 804 rotavirus RNA positive belonged to group A virus, and the other 3 (0.4%) belonged to group C virus. According to the different migration of 10 and 11 segments on PAGE, the RNA pattern of group A rotavirus could be subdivided into two patterns: long and short patterns. The 527 (66.8%) positive HRV RNA was in the long pattern, while the 267 (33.3%) positive were in the short pattern. Among the rest 6 appeared to be mixed types, and the examined one was uncertain. Four different genotypes of HRV RNA in long and short patterns were identified respectively. They were types 4232, 4222, 3232 and 3222. The eight electropherotype genomes of HRV RNA varied not only in different years or seasons but also with the ages of patients and regions where the patients live. CONCLUSION: Rotavirus infections are the major cause of diarrhea of infants and young children throughout China.

Acute Disease↗
PubMed2002

Mixing of maize and wheat genomic DNA by somatic hybridization in regenerated sterile maize plants.

Intergeneric somatic hybridization was performed between albino maize ( Zea mays L.) protoplasts and mesophyll protoplasts of wheat ( Triticum aestivum L.) by polyethylene glycol (PEG) treatments. None of the parental protoplasts were able to produce green plants without fusion. The maize cells regenerated only rudimentary albino plantlets of limited viability, and the wheat mesophyll protoplasts were unable to divide. PEG-mediated fusion treatments resulted in hybrid cells with mixed cytoplasm. Six months after fusion green embryogenic calli were selected as putative hybrids. The first-regenerates were discovered as aborted embryos. Regeneration of intact, green, maize-like plants needed 6 months of further subcultures on hormone-free medium. These plants were sterile, although had both male and female flowers. The cytological analysis of cells from callus tissues and root tips revealed 56 chromosomes, but intact wheat chromosomes were not observed. Using total DNA from hybrid plants, three RAPD primer combinations produced bands resembling the wheat profile. Genomic in situ hybridization (GISH) using total wheat DNA as a probe revealed the presence of wheat DNA islands in the maize chromosomal background. The increased viability and the restored green color were the most-significant new traits as compared to the original maize parent. Other intermediate morphological traits of plants with hybrid origin were not found.

Journal Article↗
PubMed2025

Genetic Evolution Between HIV-1 Groups M and O: HIV-1/MO Recombinant Forms.

HIV exhibits significant genetic diversity, with genetic recombination being a major evolutionary process. The co-circulation of HIV-1/M and HIV-1/O variants has led to the description of 20 HIV-1/M+O dual infections since 1998. Despite the genetic divergence between these variants, HIV-1/M+O dual infections have resulted in the emergence of HIV-1/MO intergroup recombinant forms, with 20 unique HIV-1/MO recombinant forms (URF_MO) currently described, raising the question of a possible benefit of the recombination and the modalities of their emergence. This review summarized the current knowledge of HIV-1/MO recombinant forms, including their virological and genetic characteristics, phylogenetic analysis, genome profiles, and breakpoints number and location. This study also identified the potential impacts of HIV-1/MO recombination on diagnosis, monitoring, and treatment, as well as the replicative capacity of such recombinants. This review highlighted the greater diversity and complexity of HIV-1/MO recombinants than originally thought, offering new research perspectives on their emergence and virological properties.

HIV-1↗
PubMed2026

Advancing genetic evaluation of milk yield and composition using a genomic-polygenic model in smallholder dairy cattle farms in Thailand.

Improving the accuracy of genetic evaluation in smallholder dairy systems is essential for sustainable productivity. However, traditional polygenic models (PM) are often constrained by incomplete pedigree, heterogeneous management, and limited genotyping resources. This study evaluated a genomic-polygenic model (GPM) relative to a PM using data from a multibreed dairy population raised under Thai tropical smallholder conditions. Phenotypic records for 305-day milk yield (MY), fat percentage (FP), protein percentage (PP), and somatic cell count (SCC) from 14,417 first-lactation cows across 1,321 farms were analyzed together with genotypes from 5,479 animals generated using GeneSeek Genomic Profiler (GGP) arrays ranging from 9 K to 150 K SNPs. Both models included herd-year-season of calving, age at first calving, and heterosis as fixed effects, and additive genetic and residual components treated as random. The GPM yielded higher additive genetic variances and heritability estimates and produced more biologically consistent antagonistic correlations among traits than the PM. Prediction accuracy was improved for all animal groups under the GPM, with the largest gain observed in genotyped young sires (18.36%). Pedigree connectedness analysis indicated that genotyping animals with low to moderate relationships enhances accuracy cost-effectively. Despite persistent challenges associated with heterogeneous management and limited pedigree depth, the results demonstrate the practical value of genomic-polygenic evaluation for smallholder multibreed dairy populations in tropical environments.

Animals↗
PubMed2006

Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma.

Aggressive adult T-cell leukemia/lymphoma (ATLL) such as acute and lymphoma types are fatal diseases with poor prognosis. Although these 2 subtypes feature different clinicopathologic characteristics, no detailed comparative analyses of genomic/genetic alterations have been reported. We performed array-based comparative genomic hybridization for 17 acute and 49 lymphoma cases as well as real-time quantitative polymerase chain reaction (PCR) to identify the target genes of recurrently amplified regions. Comparison of the genome profiles of acute and lymphoma types revealed that the lymphoma type had significantly more frequent gains at 1q, 2p, 4q, 7p, and 7q, and losses of 10p, 13q, 16q, and 18p, whereas the acute type showed a gain of 3/3p. Of the recurrent high-level amplifications found at 1p36, 6p25, 7p22, 7q, and 14q32 in the lymphoma type, we were able to demonstrate that CARMA1 is a possible target gene of the 7p22 amplification for the lymphoma type but not for the acute type. Furthermore, we found BCL11B overexpression in the acute type regardless of the 14q32 gain/amplification, but no or low expression of the gene in the lymphoma type. These results suggest that acute and lymphoma types are genomically distinct subtypes, and thus may develop tumors via distinct genetic pathways.

Adult↗
PubMed2004

Novel chromosomal imbalances in mantle cell lymphoma detected by genome-wide array-based comparative genomic hybridization.

Mantle cell lymphoma (MCL) is an aggressive, highly proliferative B-cell non-Hodgkin lymphoma, characterized by the specific t(11;14)(q13;q32) translocation. It is well established that this translocation alone is not sufficient to promote MCL development, but that additional genetic changes are essential for malignant transformation. We have identified such additional tumorigenic triggers in MCL tumors, by applying genome-wide array-based comparative genomic hybridization with an 800-kilobase (kb) resolution. This strategy, combined with a newly developed statistical approach, enabled us to confirm previously reported genomic alterations such as loss of 1p, 6q, 11q, 13q and gain of 3q and 8q, but it also facilitated the detection of novel recurrent genomic imbalances, such as gain of 4p12-13 and loss of 20p12.1-12.3, 20q12-13.2, 22q12.1-12.3, and 22q13.31-13.32. Genomic hotspot detection allowed for the identification of small genomic intervals that are frequently affected (57%-93%), resulting in interesting positional candidate genes such as KITLG, GPC5, and ING1. Finally, by assessing multiple biopsies from the same patient, we show that seemingly stable genomes do show subtle genomic changes over time. The follow-up of multiple biopsies of patients with MCL by high-resolution genomic profiling is expected to provide us with new clues regarding the relation between clinical outcome and in vivo cytogenetic evolution.

Aged↗
PubMed2005

Biomarkers for neurodegenerative diseases.

PURPOSE OF REVIEW: A major goal of current clinical research in neurodegenerative diseases is to improve early detection of disease and presymptomatic detection of neuronal dysfunction. We also need better tools to assess disease progression in this group of disorders. Currently, many potential disease-modifying therapies are being developed and evaluated at the preclinical stage, and will lead to clinical trials in the near future for which biomarkers are urgently needed. This review summarizes the field of biomarker research in the major neurodegenerative diseases. RECENT FINDINGS: Many different approaches are being undertaken to identify biomarkers and include imaging, neurophysiological and cognitive testing in addition to newer technologies such as biochemical, proteomic, metabanomic and gene array profiling of tissue and biofluids from patients. Key recent findings in each of these areas are discussed. SUMMARY: The ideal biomarker needs to be easy to quantify and measure, reproducible, not subject to wide variation in the general population and unaffected by co-morbid factors. For evaluation of therapies the biomarker needs to change linearly with disease progression and closely correlate with established clinico-pathological parameters of the disease. It is unlikely that any one biomarker will fulfil all these characteristics, and it is likely that more than one biomarker will be needed for early diagnosis and similarly for evaluation of disease progression for therapeutic trials. For example, the combination of more detailed clinical assessments encompassing specific cognitive and neurophysiological testing, in addition to imaging, biochemical and genomic profiling, is likely to be needed.

Animals↗
PubMed2005

Multiple microalterations detected at high frequency in oral cancer.

The development of array comparative genomic hybridization (array CGH) at tiling-path resolution has enabled the detection of gene-sized segmental DNA copy number gains and losses. Here, we present the first application of whole genome tiling-path array CGH to archival clinical specimens for the detailed analysis of oral squamous cell carcinomas (OSCC). We describe the genomes of 20 OSCCs as well as a selection of matched normal DNA in unprecedented detail. Examination of their whole genome profiles enabled the identification of alterations ranging in size from whole-arm, segmental, to gene size alterations. Tiling-path resolution enabled the detection of many more alterations within each tumor than previously reported, many of which include narrow alterations found to be frequent events among the 20 OSCCs. We report the presence of several novel frequent submegabase alterations, such as the 0.58 Mb gain at 5p15.2 containing triple functional domain (TRIO), detected in 45% of cases. We also report the first coamplification of two gene clusters, by fine-mapping the precise base pair boundaries of the high-level amplification at 11q22.2-22.3 containing both matrix metalloproteinase and baculoviral IAP repeat-containing protein 2 (BIRC) gene clusters. These results show the large improvement in detection sensitivity and resolution compared with genome interval marker arrays and the utility of tiling resolution array CGH for the detection of both submegabase and single copy gains and losses in cancer gene discovery.

Carcinoma, Squamous Cell↗
PubMed2003

Plasminogen activator inhibitor-2: a molecular biomarker for head and neck cancer progression.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy in which the early diagnosis of premalignant lesions is known to directly correlate with increased survival. However, only a portion of biopsies showing dysplasia will progress to cancer, and there are no currently accepted criteria for predicting which lesions will progress. Therefore, diagnostic protocols that can identify the lesions that are likely to become HNSCC are required. RNA was isolated from normal keratinocytes, the immortalized but nontumorigenic HaCat cell line, and the tumor cell lines SCC-4, SCC-9, SCC-25, and OSCC-3. The RNA was then labeled and used to probe nylon microarray filters that contained a total of 9184 genes (5295 named and 3889 Expression Sequence Tags). Genes whose expression demonstrated a 3-fold or greater change were considered significant. Comparison of expression profiles from normal, HaCat, and four tumor cell lines revealed changes in gene expression in a total of 508 genes. Of these, 16 genes showed a consistent loss of expression when comparing normal to immortalized keratinocytes. In addition, 10 genes demonstrated a consistent loss of expression in the tumor cell lines only. In this latter group of genes, plasminogen activator inhibitor-2 (PAI-2), a gene whose expression has been linked to cell invasion, was additionally investigated. Altered expression of PAI-2 in the different cultured cells was validated via real-time quantitative-PCR. In addition, immunohistochemical evaluation of biopsy samples revealed a high expression of PAI-2 in both normal and dysplastic epithelium with a marked decrease of expression in areas of the biopsies containing HNSCC. These data demonstrate that genomic profiling can then be used to identify potential genotypic/phenotypic biomarkers that may predict which dysplastic lesions are most likely to progress to HNSCC.

Biomarkers, Tumor↗
PubMed2022

High early death rates, treatment resistance, and short survival of Black adolescents and young adults with AML.

Survival of patients with acute myeloid leukemia (AML) is inversely associated with age, but the impact of race on outcomes of adolescent and young adult (AYA; range, 18-39 years) patients is unknown. We compared survival of 89 non-Hispanic Black and 566 non-Hispanic White AYA patients with AML treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols. Samples of 327 patients (50 Black and 277 White) were analyzed via targeted sequencing. Integrated genomic profiling was performed on select longitudinal samples. Black patients had worse outcomes, especially those aged 18 to 29 years, who had a higher early death rate (16% vs 3%; P=.002), lower complete remission rate (66% vs 83%; P=.01), and decreased overall survival (OS; 5-year rates: 22% vs 51%; P<.001) compared with White patients. Survival disparities persisted across cytogenetic groups: Black patients aged 18 to 29 years with non-core-binding factor (CBF)-AML had worse OS than White patients (5-year rates: 12% vs 44%; P<.001), including patients with cytogenetically normal AML (13% vs 50%; P<.003). Genetic features differed, including lower frequencies of normal karyotypes and NPM1 and biallelic CEBPA mutations, and higher frequencies of CBF rearrangements and ASXL1, BCOR, and KRAS mutations in Black patients. Integrated genomic analysis identified both known and novel somatic variants, and relative clonal stability at relapse. Reduced response rates to induction chemotherapy and leukemic clone persistence suggest a need for different treatment intensities and/or modalities in Black AYA patients with AML. Higher early death rates suggest a delay in diagnosis and treatment, calling for systematic changes to patient care.

Adolescent↗
PubMed2024

Copy number variant scan in more than four thousand Holstein cows bred in Lombardy, Italy.

Copy Number Variants (CNV) are modifications affecting the genome sequence of DNA, for instance, they can be duplications or deletions of a considerable number of base pairs (i.e., greater than 1000 bp and up to millions of bp). Their impact on the variation of the phenotypic traits has been widely demonstrated. In addition, CNVs are a class of markers useful to identify the genetic biodiversity among populations related to adaptation to the environment. The aim of this study was to detect CNVs in more than four thousand Holstein cows, using information derived by a genotyping done with the GGP (GeneSeek Genomic Profiler) bovine 100K SNP chip. To detect CNV the SVS 8.9 software was used, then CNV regions (CNVRs) were detected. A total of 123,814 CNVs (4,150 non redundant) were called and aggregated into 1,397 CNVRs. The PCA results obtained using the CNVs information, showed that there is some variability among animals. For many genes annotated within the CNVRs, the role in immune response is well known, as well as their association with important and economic traits object of selection in Holstein, such as milk production and quality, udder conformation and body morphology. Comparison with reference revealed unique CNVRs of the Holstein breed, and others in common with Jersey and Brown. The information regarding CNVs represents a valuable resource to understand how this class of markers may improve the accuracy in prediction of genomic value, nowadays solely based on SNPs markers.

Cattle↗
PubMed2026

Next-Generation Sequencing Completion and Timeliness Using a Reflex Testing Protocol for Patients with Stage II to IV Nonsquamous Non-Small Cell Lung Cancer.

BACKGROUND: Next-generation Sequencing (NGS) is critical for providing treatment recommendations across multiple stages of non-small cell lung cancer (NSCLC). However, a substantial proportion of patients do not undergo testing. This study evaluated the completion rates and timeliness of NGS in patients with stage II to IV NSCLC at a single academic institution with a reflex NGS testing protocol. METHODS: Patients with stage II to IV nonsquamous NSCLC (ns-NSCLC) diagnosed between 2015 and 2022 were identified retrospectively. A reflex, tissue-based testing protocol was initiated in 2015 using in-house NGS. Pyrosequencing was performed if NGS failed. RESULTS: 501 patients were included: 75 (15.0%) with stage II, 82 (16.4%) with stage III, and 344 (68.6%) with stage IV ns-NSCLC. Tissue NGS was completed in 380 (75.8%) patients and 465 (92.8%) completed some tissue-based genomic testing when including pyrosequencing. Median time from biopsy to NGS was 17.0 days (range, 6-61 days). 61.0% of patients had NGS results prior to a first treatment of any type and 88.4% had tissue NGS results prior to systemic therapy. Among stage IV patients with completed NGS, median overall survival was 2.27 years for patients with NGS results prior to first treatment compared to 1.08 years for patients without NGS results prior to treatment initiation (P = .04). CONCLUSIONS: Implementation of an in-house, reflex NGS testing protocol enabled rapid genomic profiling in a high proportion of patients with stage II to IV ns-NSCLC. NGS completion prior to receiving first-line therapy was associated with improved survival compared to completion after first line treatment in stage IV patients.

Humans↗
PubMed1994

Efficient subtyping of pathogenic Yersinia enterocolitica strains by pulsed-field gel electrophoresis.

Yersinia enterocolitica is an enteropathogen that has recently and rapidly expanded over the world. There is a close correlation between the biotypes, serotypes, and phage types of the strains, making it virtually impossible to distinguish isolates of the same serotype with the classical phenotypic markers. In the present study, pulsed-field gel electrophoresis (PFGE) was used to compare the NotI genomic profile (i.e., pulsotype) of 20 strains each of serotypes O:3, O:9, and O:5. Eleven, 12, and 18 different pulsotypes were obtained, respectively, indicating that this technique is very efficient for subtyping pathogenic isolates of Y. enterocolitica. Within strains of serotype O:5, PFGE differentiated two subgroups that corresponded to two biotypes (biotypes 1A and 3). Comparison of the pulsotypes of three strains of biotype 3 and serotype O:3 (referred to as 3/O:3) with those of strains 4/O:3 and 3/O:5 suggested that the pulsotype is closer to the biotype than to the serotype. The pulsotypes of five pairs of strains isolated from the same patient or siblings were also analyzed. In four pairs, the two strains displayed identical pulsotypes, indicating that PFGE might be a powerful epidemiological tool. In the fifth pair, one restriction fragment differed, suggesting that genomic polymorphism may occur in vivo in Y. enterocolitica. Finally, the in vitro genomic stabilities of one strain each of Y. enterocolitica O:3, O:9, and O:5 were investigated. The pulsotypes of 10 isolated colonies were identical within each strain, indicating that in vitro, the genome of Y. enterocolitica is much more stable than that of Y. pestis.

Bacterial Typing Techniques↗
PubMed2025

Pangenome analysis of Lactobacillus mulieris strains reveals distinct subspecies clusters with defined ecological adaptations.

Lactobacillus mulieris is a recently described species, reportedly isolated from human urine, vagina, and gut. Previous genomic studies of L. mulieris highlighted significant genetic diversity among its strains. To gain a deeper understanding of this genomic diversity, we conducted a comprehensive genomic comparison of 70 L. mulieris strains from diverse sources. Phylogenomic and genome relatedness analysis identified three distinct clades, each representing a potential subspecies cluster. Pangenome analysis revealed distinct gene clusters shaping the functional characteristics and unique ecological adaptations of each clade. Clade 1 demonstrated a generalist lifestyle, with strains isolated from diverse sources and enriched in serine/threonine protein kinases, suggesting adaptive versatility. Clade 2, predominantly composed of urinary isolates, displayed enrichment in genes facilitating nutrient acquisition and osmotic regulation, enabling survival in the nutrient-limited and high osmolarity conditions of the urinary tract. Clade 3, exclusively composed of vaginal isolates, exhibited significant enrichment in genes supporting glycogen metabolism, carbohydrate transport, and capsular polysaccharide biosynthesis-features indicative of adaptation to the vaginal environment. Collectively, our findings provide essential genomic insights into the ecological specialization of L. mulieris, shedding light on their genetic variability and adaptive traits within their respective ecological niches.IMPORTANCERecognizing the genomic diversity within Lactobacillus mulieris is essential for understanding its ecological specialization and adaptation strategies across distinct human-associated environments. By identifying three distinct clades with unique functional traits, our study highlights the critical role of niche-specific genetic adaptations in microbial survival. The presence of specialized gene functions within each clade underscores how evolutionary pressures shape bacterial resilience in different environments. Despite their coexistence in overlapping environments, these clades exhibit distinct genomic profiles that may influence their colonization potential and interactions with the host and within the host-associated microbiota. Our findings emphasize the need for a classification framework that accounts for these genetic and functional differences and the necessity for further investigation to understand their distinct roles and impact on human health.

Humans↗
PubMed2006

Early-stage melanoma: staging criteria and prognostic modeling.

Accurate risk assessment is central to the process of making rational surgical and systemic treatment recommendations for melanoma patients and in establishing appropriate clinical trial stratification criteria. The current American Joint Commission on Cancer melanoma staging system incorporated relevant prognostic variables to provide a framework for the estimation of risk for recurrence; however, significant prognostic heterogeneity exists within the stage groupings. In the stage I/II group, survival rates range from 40% to 95% as defined by the combination of tumor thickness and ulceration. The use of novel prognostic factors, such as mitotic rate, sentinel node biopsy, and prognostic modeling using a variety of factors, can minimize this prognostic heterogeneity and provide a more accurate and individualized prognostic profile. Recent modifications in the stage III criteria include the number of positive nodes, whether the nodal disease is microscopic or clinically apparent, and the presence of an ulcerated primary. Through these factors, survival estimates can be provided, but like the stage I/II group, wide ranges in prognosis exist. The complexion of the stage III population is in evolution as a result of increasing numbers of patients being diagnosed as having microscopic sentinel node disease. Contemporary efforts are focused on defining the prognosis and natural history of this group. Through prognostic modeling using the number of nodes involved, ulceration status, and a measure of disease burden--disease in the sentinel node--relatively homogeneous subgroups can be identified. Long-term follow-up of patients staged with PCR molecular techniques on sentinel nodes shows conflicting value in assessing prognosis and therefore cannot be routinely used outside a clinical trial. The combination of genomic profiling using microarray analyses and the development of targeted therapy holds the future promise of individualizing prognosis and therapy.

Humans↗
PubMedDate not supplied

Rotaviruses as a cause of nosocomial, infantile diarrhoea in northern Brazil: pilot study.

Faecal samples were obtained from 190 children, aged 0 to 5 years, admitted to a public hospital in Belém, Pará, Brazil. These patients were placed in a pediatric ward with 40 beds distributed in six rooms. Cases were classified into three groups: (a) nosocomial: children who developed gastroenteritis 72 hr or later after admission; (b) community-acquired: patients admitted either with diarrhoea or who had diarrhoea within 72 hr following admission; (c) non-diarrhoeic: those children who had no diarrhoea three days before and three days after collection of formed faecal sample. Specimens were routinely processed for the presence of rotaviruses, bacteria and parasites. Rotaviruses were detected through enzyme-linked immunosorbent assay (ELISA) and subsequently serotyped/electrophoretyped. Rotaviruses were the most prevalent enteropathogens among nosocomial cases, accounting for 39% (9/23) of diarrhoeal episodes; on the other hand, rotaviruses occurred in 8.3% (11/133) and 9% (3/34) of community-acquired and non-diarrhoeic categories, respectively. Mixed infections involving rotavirus and Giardia intestinalis and rotavirus plus G. intestinalis and Entamoeba histolytica were detected in frequencies of 8.6 and 4.3%, respectively, in the nosocomial group. The absence of bacterial pathogens in this category, and the unusual low prevalence of these agents in the other two groups may reflect the early and routine administration of antibiotics following admission to this hospital. Rotavirus serotype 2 prevailed over the other types, accounting for 77.8% of isolates from nosocomial diarrhoeal episodes. In addition, at least five different genomic profiles could be observed, of which one displayed an unusual five-segment first RNA cluster. Dehydration was recorded in all cases of hospital-acquired, rotavirus-associated diarrhoea, whereas in only 57% of nosocomial cases of other aetiology. It was also noted that nosocomial, rotavirus-associated diarrhoeal episodes occur earlier (7 days), following admission, if compared with those hospital-acquired cases of other aetiology (14 days).

Brazil↗
PubMed2006

Establishment and characterization of xenografts and cancer cell cultures derived from BRCA1 -/- epithelial ovarian cancers.

The BRCA1 gene is responsible for a high number of hereditary breast and ovarian cancers that cluster in families with a strong genetic predisposition. Despite intense investigation, the accumulating findings on BRCA1 biological functions have not yet been translated into specific therapeutic approaches, also due to the lack of suitable experimental models. The purpose of this study was to establish and characterize cell cultures and xenografts from patients with BRCA1 -/- ovarian cancers. We derived two ovarian cancer cell lines, termed PD-OVCA1 and PD-OVCA2, both from patients previously treated with chemotherapy, that propagate in SCID mice as well as in vitro for a limited number of passages. Both cell lines expressed cytokeratins and the CA125 tumour marker. A detailed molecular characterization highlighted both constitutive and somatic genetic events that abrogate BRCA1 gene function. Both cell lines were shown to lose the wild type BRCA1 allele; intriguingly, these deletions were apparently accompanied by gain of one or more copies of the mutant alleles. Finally, a genomic profile of major chromosomal aberrations was obtained by the Multiplex Ligation-dependent Probe Amplification (MLPA) technique, which disclosed chromosomal imbalances targeting specific genes in each cell line. The PD-OVCA1 and PD-OVCA2 ovarian cancer cell lines will provide a valuable tool for new experimental models for the study of BRCA1-associated tumour biology.

Aged↗
PubMed2026

Whole genome and exome sequencing of pancreatic neuroendocrine tumour to investigate PRRT response.

Patients with pancreatic neuroendocrine tumours (PNETs) often have similar baseline clinical characteristics, including grade and molecular imaging phenotype, yet have highly variable responses to peptide receptor radionuclide therapy (PRRT). To identify genomic alterations and mutational patterns associated with PRRT treatment response and acquired somatic changes following PRRT exposure, whole genome or exome sequencing was applied to 40 PNET samples from 32 patients, including eight paired pre- or post-PRRT samples. The genomic profile of tumours reflected the known mutational landscape of PNET with MEN1 (34%), ATRX/DAXX (47%) alterations and a recurrent pattern of aneuploidy (38%) detected. A recurrent PSIP1::TBL1X fusion of unknown function was also identified in four tumours. The disease control rate following PRRT using RECIST1.1 and molecular imaging criteria was 88% (28/32). No mutational features were found to be statistically associated with progression-free survival. There was no significant increase in tumour mutational burden in the post-PRRT tumours, nor recurrent emergent mutational changes in cancer driver genes to explain progression to higher-grade disease, when observed. However, a small indel signature (ID8) previously associated with DNA damage repair by non-homologous end joining (NHEJ) was higher in PRRT-exposed compared with PRRT-naive samples (23.8 vs 4.8%, respectively; P < 0.001). Thus, comprehensive DNA analysis of pancreatic NETs did not identify biomarkers predictive of PRRT response nor evidence for high-level PRRT-induced genomic instability or hypermutation, yet mutation signature analysis supports NHEJ as being important for DNA repair and survival of neuroendocrine cells following exposure to beta-particle radiation.

Humans↗