Exploration of intermediate-sized INDELs by next-generation multigene panel testing in Han Chinese patients with breast cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Hata C
PROVIDER: S-EPMC6820797 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
Exploration of intermediate-sized INDELs by next-generation multigene panel testing in Han Chinese patients with breast cancer.
Hata Chihiro C Nakaoka Hirofumi H Xiang Yu Y Wang Dong D Yang Anping A Liu Dahai D Liu Fang F Zou Qingfeng Q Zheng Ke K Inoue Ituro I You Hua H
Human genome variation 20191029
Multigene panel testing via next-generation sequencing focuses on the detection of small-sized mutations, such as single nucleotide variants and short insertions and deletions (INDELs). However, intermediate-sized INDELs have not been fully explored due to technical difficulties. Here, we performed bioinformatics analyses to identify intermediate-sized INDELs in 54 cancer-related genes from 583 Han Chinese patients with breast cancer. We detected a novel deletion-insertion in a translational var ...[more]
Similar Datasets
Project description:BACKGROUND:High grade serous ovarian cancer is one of the poorly characterized malignancies. This study aimed to elucidate the mutational events in Malaysian patients with high grade serous ovarian cancer by performing targeted sequencing on 50 cancer hotspot genes. RESULTS:Nine high grade serous ovarian carcinoma samples and ten normal ovarian tissues were obtained from Universiti Kebangsaan Malaysia Medical Center (UKMMC) and the Kajang Hospital. The Ion AmpliSeq™ Cancer Hotspot Panel v2 targeting "mutation-hotspot region" in 50 most common cancer-associated genes was utilized. A total of 20 variants were identified in 12 genes. Eleven (55%) were silent alterations and nine (45%) were missense mutations. Six of the nine missense mutations were predicted to be deleterious while the other three have low or neutral protein impact. Eight genes were altered in both the tumor and normal groups (APC, EGFR, FGFR3, KDR, MET, PDGFRA, RET and SMO) while four genes (TP53, PIK3CA, STK11 and KIT) were exclusively altered in the tumor group. TP53 alterations were present in all the tumors but not in the normal group. Six deleterious mutations in TP53 (p.R175H, p.H193R, p.Y220C, p.Y163C, p.R282G and p.Y234H) were identified in eight serous ovarian carcinoma samples and none in the normal group. CONCLUSION:TP53 remains as the most frequently altered gene in high grade serous ovarian cancer and Ion Torrent Personal Genome Machine (PGM) in combination with Ion Ampliseq™ Cancer Hotspot Panel v2 were proven to be instrumental in identifying a wide range of genetic alterations simultaneously from a minute amount of DNA. However, larger series of validation targeting more genes are necessary in order to shed a light on the molecular events underlying pathogenesis of this cancer.
| S-EPMC4242548 | biostudies-literature
Project description:BackgroundThe discovery and mapping of genomic variants is an essential step in most analysis done using sequencing reads. There are a number of mature software packages and associated pipelines that can identify single nucleotide polymorphisms (SNPs) with a high degree of concordance. However, the same cannot be said for tools that are used to identify the other types of variants. Indels represent the second most frequent class of variants in the human genome, after single nucleotide polymorphisms. The reliable detection of indels is still a challenging problem, especially for variants that are longer than a few bases.ResultsWe have developed a set of algorithms and heuristics collectively called indelMINER to identify indels from whole genome resequencing datasets using paired-end reads. indelMINER uses a split-read approach to identify the precise breakpoints for indels of size less than a user specified threshold, and supplements that with a paired-end approach to identify larger variants that are frequently missed with the split-read approach. We use simulated and real datasets to show that an implementation of the algorithm performs favorably when compared to several existing tools.ConclusionsindelMINER can be used effectively to identify indels in whole-genome resequencing projects. The output is provided in the VCF format along with additional information about the variant, including information about its presence or absence in another sample. The source code and documentation for indelMINER can be freely downloaded from www.bx.psu.edu/miller_lab/indelMINER.tar.gz .
| S-EPMC4339746 | biostudies-literature
Project description:Neurofibromatosis (NF) is an autosomal genetic disorder for which early and definite clinical diagnoses are difficult. To identify the diagnosis, five affected probands with suspected NF from unrelated families were included in this study. Molecular analysis was performed using multigene panel testing and Sanger sequencing. Ultradeep sequencing was used to analyze the mutation rate in the tissues from the proband with mosaic mutations. Three different pathogenic variants of the NF1 gene were found in three probands who mainly complained of café-au-lait macules (CALMs), including one frameshift variant c.5072_5073insTATAACTGTAACTCCTGGGTCAGGGAGTACACCAA:p.Tyr1692Ilefs in exon 37, one missense variant c.3826C > T:p.Arg1276Ter in exon 28, and one splicing variant c.4110 + 1G > T at the first base downstream of the 3'-end of exon 30. One NF1 gene mosaic variant was found in a proband who complained of cutaneous neurofibroma with the frameshift variant c.495_498del:p.Thr165fs in exon 5, and ultradeep sequencing showed the highest mutation rate of 10.81% in cutaneous neurofibromas. A frameshift variant, c.36_39del:p.Ser12fs in exon 1 of the NF2 gene, was found in a proband who presented with skin plaques and intracranial neurogenic tumors. All of these pathogenic variants were heterozygous, one was not reported, and one not in Chinese before. This study expands the pathogenic variant spectrum of NF and demonstrates the clinical diagnosis.
| S-EPMC7985060 | biostudies-literature
Project description:Germline genetic testing is recommended for younger patients with idiopathic pancreatitis but there has been a lack of consensus in recommendations for those over age 35. We aimed to analyze the results of genetic testing among subjects of varying ages. Individuals who underwent germline multigene testing for pancreatitis susceptibility genes (CASR, CFTR, CPA1, CTRC, PRSS1, SPINK1) through a large commercial laboratory between 2017 and 2022 were included. Test results and information collected from test requisition forms were evaluated. Multivariable logistic regression models were performed to identify factors associated with a positive pancreatitis panel (pathogenic, likely pathogenic, and/or increased risk variants) in pancreatitis-related genes. Overall, 2,468 subjects with primary indication of acute pancreatitis (AP) (n = 401), chronic pancreatitis (CP) (n = 631), pancreatic cancer (n = 128), or other indications (n = 1,308) completed germline testing. Among patients with AP or CP, the prevalence of any positive result for those <35 versus ≥35 years of age was 32.1% and 24.5% (p = 0.007), and the prevalence of a clinically meaningful result was 10.8% and 5.4%, respectively (p = 0.001). Positive family history of pancreatitis was associated with increased odds ratio (OR) of 8.59 (95% confidence interval (CI) 2.92-25.25) for a clinically significant panel result while each 5-year increase in age at test completion had lower odds (OR 0.89, 95% CI 0.83-0.95). The highest prevalence of pathogenic variants is seen in younger individuals with a positive family history of pancreatitis. However, clinically meaningful results are identified in older subjects, suggesting that genetic counseling and testing should be considered for all age groups.
| S-EPMC11341018 | biostudies-literature
Project description:Introduction Colorectal cancer (CRC) is one of the leading causes of death and illness in the general population. Although the incidence of CRC is steadily decreasing worldwide, it is being diagnosed more in individuals under 50 years of age. Multiple disease-causing variants have been reported to be involved in the development of CRC. This study aimed to investigate the molecular and clinical characteristics of Thai patients with CRC. Methods NGS-based multigene cancer panel testing was performed on 21 unrelated patients. Target enrichment was performed using a custom-designed Ion AmpliSeq on-demand panel. Thirty-six genes associated with CRC and other cancer were analyzed for variant detection. Results Sixteen variants (five nonsense, eight missense, two deletions, and one duplication) in nine genes were identified in 12 patients. Eight (66.7%) patients harboring disease-causing deleterious variants in genes APC, ATM, BRCA2, MSH2, and MUTYH. One of the eight patients also carried additional heterozygous variants in genes ATM, BMPR1A, and MUTYH. In addition, four patients carried variants of uncertain significance in genes APC, MLH1, MSH2, STK11, and TP53. Among all detected genes, APC was the most frequent causative gene observed in CRC patients, which is consistent with previous reports. Conclusion This study demonstrated the comprehensive molecular and clinical characterization of CRC patients. These findings showed the benefits of using multigene cancer panel sequencing for pathogenic gene detection and showed the prevalence of genetic aberrations in Thai patients with CRC.
| S-EPMC10267666 | biostudies-literature
Project description:We aimed to investigate the prevalence and relative contributions of LS and non-LS mutations in patients with endometrial cancer in Korea. We retrospectively reviewed the medical records of 204 patients diagnosed with endometrial cancer who underwent a germline next generation sequencing multigene panel test covering MLH1, MSH2, MSH6, PMS2, and EPCAM at three tertiary centers. Thirty patients (14.7%) with pathogenic mutations (12 MLH1; 6 MSH2; 10 MSH6; 2 PMS2) and 20 patients (9.8%) with 22 unclassified variants (8 MLH1; 8 MSH2; 2 MSH6; 3 PMS2; 1 EPCAM) were identified. After excluding four close relatives of a proband, the prevalence of LS was 13.0% (26/200). Patients with LS were more likely than those with sporadic cancer to be younger at diagnosis (48 vs. 53 years, p = 0.045) and meet the Amsterdam II criteria (66.7 vs. 3.5%, p < 0.001). Non-endometrioid histology was more prevalent in patients with MSH6 or PMS2 mutations (41.7%) than those with MLH1 or MSH2 mutations (5.6%, p = 0.026). In this pre-selected cohort of endometrial cancer patients who underwent next generation sequencing, the prevalence of LS was 13%, thus supporting the use of gene panel testing for endometrial cancer patients.
| S-EPMC9316192 | biostudies-literature
Project description:BackgroundPathogenic germline mutations in BRCA1/2 constitute the majority of hereditary breast and/or ovarian cancers worldwide. Incidence and mortality rate of breast and ovarian cancers in Pakistani women is high. Thus, to establish the diagnosis for targeted therapy in Pakistan, we conducted Next-generation sequencing-based germline testing for the detection of BRCA1/2 oncogenic variants associated with breast and ovarian cancer subtype.MethodsPeripheral blood of 24 women, diagnosed with breast and epithelial ovarian cancers, was taken from the recruited cases with the consent of performing germline genetic testing. DNA was isolated from the peripheral blood and subjected to indexed BRCA Panel libraries. Targeted NGS was performed for all coding regions and splicing sites of BRCA1 and BRCA2 genes using AmpliSeq for Illumina BRCA Panel and Illumina MiSeq sequencer (placed at AFIP). Analysis of the sequencing results has been done by using Illumina bioinformatics tools.ResultsWe detected 421 variants having a quality score of 100 in all cases under study. The list of identified variants in BRCA1 and BRCA2 genes was narrowed down after filtering out those which did not pass q30 and those with a minor allele frequency (MAF) > 0.05 based on gnomAD browser. To classify these variants, clinical significance was predicted using external curated databases. As a result, we interpreted (n = 4) 16.7% pathogenic variants in BRCA1 and (n = 6) 25% variants of uncertain significance (VUS) in both genes. Descriptive statistics depicted that the age and BMI of BRCA positive cases are less than BRCA negative cases.ConclusionOur findings exhibit an initial report for the NGS based cancer genetic testing in Pakistan. This will enable us to pursue screening and diagnosis of hereditary BRCA mutation utilizing the latest state-of-the-art technique locally available in Pakistan ultimately resulting in targeted cancer therapy.
| S-EPMC8286662 | biostudies-literature
Project description:The management of melanoma has evolved owing to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next-generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-V600 (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent events in tumors with BRAFV600 and NRAS mutations. Melanomas with BRAFNon-V600mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAFV600 and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma.
| S-EPMC4289407 | biostudies-literature
Project description:Insertion and deletion polymorphisms (indels) are an important source of genomic variation in plant and animal genomes, but accurate genotyping from low-coverage and exome next-generation sequence data remains challenging. We introduce an efficient population clustering algorithm for diploids and polyploids which was tested on a dataset of 2000 exomes. Compared with existing methods, we report a 4-fold reduction in overall indel genotype error rates with a 9-fold reduction in low coverage regions.
| S-EPMC3562001 | biostudies-literature
Project description:Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2, RAD51C/RAD51D, BARD1, and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO.
| S-EPMC7226062 | biostudies-literature