Genomic profiling reveals high frequency of DNA repair genetic aberrations in gallbladder cancer
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ABSTRACT:
SUBMITTER: Abdel-Wahab R
PROVIDER: S-EPMC7745036 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Canine hemangiosarcoma is a highly aggressive vascular neoplasm associated with extensive clinical and anatomical heterogeneity and a grave prognosis. Comprehensive molecular characterization of hemangiosarcoma may identify novel therapeutic targets and advanced clinical management strategies, but there are no published reports of tumor-associated genome instability and disrupted gene dosage in this cancer. We performed genome-wide microarray-based somatic DNA copy number profiling of 75 primary intra-abdominal hemangiosarcomas from five popular dog breeds that are highly predisposed to this disease. The cohort exhibited limited global genomic instability, compared to other canine sarcomas studied to date, and DNA copy number aberrations (CNAs) were predominantly of low amplitude. Recurrent imbalances of several key cancer-associated genes were evident; however, the global penetrance of any single CNA was low and no distinct hallmark aberrations were evident. Copy number gains of dog chromosomes 13, 24, and 31, and loss of chromosome 16, were the most recurrent CNAs involving large chromosome regions, but their relative distribution within and between cases suggests they most likely represent passenger aberrations. CNAs involving CDKN2A, VEGFA, and the SKI oncogene were identified as potential driver aberrations of hemangiosarcoma development, highlighting potential targets for therapeutic modulation. CNA profiles were broadly conserved between the five breeds, although subregional variation was evident, including a near twofold lower incidence of VEGFA gain in Golden Retrievers versus other breeds (22 versus 40 %). These observations support prior transcriptional studies suggesting that the clinical heterogeneity of this cancer may reflect the existence of multiple, molecularly distinct subtypes of canine hemangiosarcoma.
| S-EPMC5518683 | biostudies-literature
Project description:Array-CGH is a powerful tool for the detection of chromosomal aberrations. The introduction of high-density SNP genotyping technology to genomic profiling, termed SNP-CGH, represents a further advance, since simultaneous measurement of both signal intensity variations and changes in allelic composition makes it possible to detect both copy number changes and copy-neutral loss-of-heterozygosity (LOH) events. We demonstrate the utility of SNP-CGH with two Infinium whole-genome genotyping BeadChips, assaying 109,000 and 317,000 SNP loci, to detect chromosomal aberrations in samples bearing constitutional aberrations as well tumor samples at sub-100 kb effective resolution. Detected aberrations include homozygous deletions, hemizygous deletions, copy-neutral LOH, duplications, and amplifications. The statistical ability to detect common aberrations was modeled by analysis of an X chromosome titration model system, and sensitivity was modeled by titration of gDNA from a tumor cell with that of its paired normal cell line. Analysis was facilitated by using a genome browser that plots log ratios of normalized intensities and allelic ratios along the chromosomes. We developed two modes of SNP-CGH analysis, a single sample and a paired sample mode. The single sample mode computes log intensity ratios and allelic ratios by referencing to canonical genotype clusters generated from approximately 120 reference samples, whereas the paired sample mode uses a paired normal reference sample from the same individual. Finally, the two analysis modes are compared and contrasted for their utility in analyzing different types of input gDNA: low input amounts, fragmented gDNA, and Phi29 whole-genome pre-amplified DNA.
| S-EPMC1557768 | biostudies-literature
Project description:BackgroundDNA mismatch repair (MMR) deficiency is a major pathway of genomic instability in cancer. It leads to the accumulation of numerous mutations predominantly at microsatellite sequences, a phenotype known as microsatellite instability (MSI). MSI tumors have a distinct clinical behavior and commonly respond well to immune checkpoint blockade, irrespective of their origin. Data about the prevalence of MSI among gallbladder cancer (GBC) have been conflicting. We here analyzed a well-characterized cohort of 69 Western-world GBCs.MethodsWe analyzed the mononucleotide MSI marker panel consisting of BAT25, BAT26, and CAT25 to determine the prevalence of MMR deficiency-induced MSI.ResultsMSI was detected in 1/69 (1.4%) of analyzed GBCs. The detected MSI GBC had a classical histomorphology, i.e. of acinar/tubular/glandular pancreatobiliary phenotype, and showed nuclear expression of all four MMR proteins MLH1, MSH2, MSH6, and PMS2. The MSI GBC patient showed a prolonged overall survival, despite having a high tumor stage at diagnosis. The patient had no known background or family history indicative of Lynch syndrome.ConclusionsEven though the overall number of MSI tumors is low in GBC, the potentially therapeutic benefit of checkpoint blockade in the respective patients may justify MSI analysis of GBC.
| S-EPMC6506936 | biostudies-literature
Project description:Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 (BRCA2) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non-BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.
| S-EPMC8471942 | biostudies-literature
Project description:Single-nucleotide polymorphism arrays allow for genome-wide profiling of copy-number alterations and copy-neutral runs of homozygosity at high resolution. To identify novel genetic lesions in myeloproliferative neoplasms, a large series of 151 clinically well characterized patients was analyzed in our study. Copy-number alterations were rare in essential thrombocythemia and polycythemia vera. In contrast, approximately one third of myelofibrosis patients exhibited small genomic losses (less than 5 Mb). In 2 secondary myelofibrosis cases the tumor suppressor gene NF1 in 17q11.2 was affected. Sequencing analyses revealed a mutation in the remaining NF1 allele of one patient. In terms of copy-neutral aberrations, no chromosomes other than 9p were recurrently affected. In conclusion, novel genomic aberrations were identified in our study, in particular in patients with myelofibrosis. Further analyses on single-gene level are necessary to uncover the mechanisms that are involved in the pathogenesis of myeloproliferative neoplasms.
| S-EPMC2857198 | biostudies-literature
Project description:Over the past years, several studies have demonstrated that defects in DNA damage response and repair (DDR) genes are present in a significant proportion of patients with prostate cancer. These alterations, particularly mutations in BRCA2, are known to be associated with an increased risk of developing prostate cancer and more aggressive forms of the disease. There is growing evidence that certain DDR gene aberrations confer sensitivity to poly-(ADP ribose) polymerase inhibitors and/or platinum chemotherapy, while other defects might identify cases that are more likely to benefit from immune checkpoint inhibition. The potential prognostic impact and relevance for treatment selection together with the decreasing costs and broader accessibility to next-generation sequencing have already resulted in the increased frequency of genetic profiling of prostate tumours. Remarkably, almost half of all DDR genetic defects can occur in the germline, and prostate cancer patients identified as mutation carriers, as well as their families, will require appropriate genetic counselling. In this review, we summarise the current knowledge regarding the biology and clinical implications of DDR defects in prostate cancer, and outline how this evidence is prompting a change in the treatment landscape of the disease.
| S-EPMC7851123 | biostudies-literature
Project description:BackgroundThe genetics of advanced biliary tract cancers (BTC), which encompass intra- and extra-hepatic cholangiocarcinomas as well as gallbladder carcinomas, are heterogeneous and remain to be fully defined.MethodsTo better characterize mutations in established known oncogenes and tumor suppressor genes we tested a mass spectrometric based platform to interrogate common cancer associated mutations across a panel of 77 formalin fixed paraffin embedded archived BTC cases.ResultsMutations among three genes, KRAS, NRAS and PIK3CA were confirmed in this cohort. Activating mutations in PIK3CA were identified exclusively in GBC (4/32, 12.5%). KRAS mutations were identified in 3 (13%) intra-hepatic cholangiocarcinomas and 1 (33%) perihillar cholangiocarcinoma but were not identified in gallbladder carcinomas and extra-hepatic cholangiocarcinoma.ConclusionsThe presence of activating mutations in PIK3CA specifically in GBC has clinical implications in both the diagnosis of this cancer type, as well as the potential utility of targeted therapies such as PI3 kinase inhibitors.
| S-EPMC3045359 | biostudies-literature
Project description:BackgroundCervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. In China, it is the most common cancer in the female genital tract. However, the genomic profiles of Chinese cervical cancer patients remain unclear.Materials and methodsA total of 129 cervical cancer patients were enrolled in this study (113 squamous, 12 adenocarcinoma, 2 adenosquamous, and 2 neuroendocrine carcinoma). To classify the clinical features and molecular characteristics of cervical cancer, the genomic alterations of 618 selected genes were analyzed in the samples of these patients, utilizing target next-generation sequencing (NGS) technology. Furthermore, the findings from the Chinese cohort were then compared with the data of Western patients downloaded from The Cancer Genome Atlas (TCGA) database, in terms of gene expression files, mutation data, and clinical information.ResultsAll studied patients had valid somatic gene alterations, and the most frequently altered genes were PIK3C, TP53, FBXW7, ARID1A, ERBB2, and PTEN. Comparison of genomic profiling showed significantly different prevalence of genes, including TP53, KMT2C, and RET, between the Chinese and the TCGA cohorts. Moreover, 57 patients (44.19%) with 83 actionable alterations were identified in our cohort, especially in PI3K and DNA damage repair (DDR) pathways. After an in-depth analysis of cervical cancer data from the TCGA cohort, DDR alteration was found to be associated with extremely higher tumor mutation burden (TMB) (median mutation count: 149.5 vs 66, p <0.0001), and advanced stages (p <0.05). Additionally, DDR alteration, regardless of its function, was positively correlated with hypoxia feature and score. Moreover, patients with a high hypoxia score were positively correlated with a high abundance of mast cell resting, but lower abundance of CD8+ T cells and activated mast cell. Finally, CDHR5 was identified as the hub gene to be involved in the DDR-hypoxia network, which was negatively correlated with both the DDR alteration and hypoxia score.ConclusionsOverall, a unique genomic profiling of Chinese patients with cervical cancer was uncovered. Besides, the prevalent actionable variants, especially in PI3K and DDR pathways, would help promote the clinical management. Moreover, DDR alteration exerted the significant influence on the tumor microenvironment in cervical cancer, which could guide the clinical decisions for the treatment. CDHR5 was the first identified hub gene to be negatively correlated with DDR or hypoxia in cervical cancer, which had potential effects on the treatment of immune checkpoint inhibitors (ICIs).
| S-EPMC8782566 | biostudies-literature
Project description:Male and female germ cells can transmit genetic defects that lead to pregnancy loss, infant mortality, birth defects, and genetic diseases in offspring; however, the parental origins of transmitted defects are not random, with de novo mutations and chromosomal structural aberrations transmitted predominantly by sperm. We tested the hypotheses that paternal mutagenic exposure during late spermatogenesis can induce damage that persists in the fertilizing sperm and that the risk of embryos with paternally transmitted chromosomal aberrations depends on the efficiency of maternal DNA repair during the first cycle after fertilization. We show that female mice with defective DNA double-strand break repair had significantly increased frequencies of zygotes with sperm-derived chromosomal aberrations after matings with wild-type males irradiated 7 days earlier with 4 Gy of ionizing radiation. These findings demonstrate that mutagenic exposures during late spermatogenesis can induce damage that persists for at least 7 days in the fertilizing sperm and that maternal genotype plays a major role in determining the risks for pregnancy loss and frequencies of offspring with chromosomal defects of paternal origin.
| S-EPMC2077046 | biostudies-literature
Project description:DNA damage and unrepaired or insufficiently repaired DNA double-strand breaks as well as telomere shortening contribute to the formation of structural chromosomal aberrations (CAs). Non-specific CAs have been used in the monitoring of individuals exposed to potential carcinogenic chemicals and radiation. The frequency of CAs in peripheral blood lymphocytes (PBLs) has been associated with cancer risk and the association has also been found in incident cancer patients. CAs include chromosome-type aberrations (CSAs) and chromatid-type aberrations (CTAs) and their sum CAtot. In the present study, we used data from our published genome-wide association studies (GWASs) and extracted the results for 153 DNA repair genes for 607 persons who had occupational exposure to diverse harmful substances/radiation and/or personal exposure to tobacco smoking. The analyses were conducted using linear and logistic regression models to study the association of DNA repair gene polymorphisms with CAs. Considering an arbitrary cutoff level of 5 × 10-3, 14 loci passed the threshold, and included 7 repair pathways for CTA, 4 for CSA, and 3 for CAtot; 10 SNPs were eQTLs influencing the expression of the target repair gene. For the base excision repair pathway, the implicated genes PARP1 and PARP2 encode poly(ADP-ribosyl) transferases with multiple regulatory functions. PARP1 and PARP2 have an important role in maintaining genome stability through diverse mechanisms. Other candidate genes with known roles for CSAs included GTF2H (general transcription factor IIH subunits 4 and 5), Fanconi anemia pathway genes, and PMS2, a mismatch repair gene. The present results suggest pathways with mechanistic rationale for the formation of CAs and emphasize the need to further develop techniques for measuring individual sensitivity to genotoxic exposure.
| S-EPMC8242355 | biostudies-literature