Value of whole‐genome sequencing to Australian cancer patients and their first‐degree relatives participating in a genomic sequencing study

7062 Background: Cancer is a group of genetic diseases that result from changes in the genome of cells in the body, leading them to grow uncontrollably. Recent researches suggest Chromosome instability (CIN), which is defined as an increased rate of chromosome gains and losses, manifests as cell-to-cell karyotypic heterogeneity and drives cancer initiation and evolution. Methods: In the past two years, we initiated iStopCancer project, and characterized 4515 ‘best available’ minimal-invasive samples from cancer patients and 1501 plasma samples from non-tumor diseases by using low-pass whole genome sequencing. DNA from ‘best available’ minimal-invasive samples, including peripheral plasma, urines, pancreatic juice, bile and effusions were analyzed by low coverage whole genome sequencing followed by the UCAD Bioinformatics workflow to characterize the CINs. In total, 32T bp nucleotide (coverage =1.7X for each sample) were collected. All the data can be visualized on website: http://www.istopcancer.net/pgweb/cn/istopcancer.jsp . Results: 3748(83%) of tumors present detectable CIN (CIN score>1000) in minimal-invasive samples. The missed cancer patients were majorly from patients with either tumor size less than 2cm or less-aggressive cancers, including thyroid cancer, low-grade urothelial carcinoma, lung cancer in-situ, et al. Of the 1501 non-tumor individuals, 30(2.0%) present detectable CIN (|Z|>=3) at the time of sample collection, 24(80.0%) was diagnosed as tumor patient in 3-6 months follow-up. There were 9 (0.59%) of non-cancer individuals without detectable CIN were also reported as tumor patients during 6-month following up. In summary, the positive and negative prediction value is 80.0% and 99.4% respectively. The false alarms were majorly from patients with EBV activations, which indicates virus may interference chromosome stability and drove virus-associated carcinogenesis. For the patient with repeated detections, plasma cfDNA CIN dynamics predicted clinical responses and disease recurrences. Quick clearance of plasma cfDNA CIN in 2-3 weeks was found in 153 (83.6%) patients. Meanwhile, no quick clearance was found in majority of SDs/PDs (73/88=83.0%). Furthermore, cfDNA CIN predicts clinical response 2-8 weeks ahead of traditional biomarkers (CEA, CA15-3, CA199, AFP et al). Conclusions: Large-scale low coverage whole genome sequencing data provides useful information for cancer detection and managements.

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Whole genome sequencing of cell-free DNA yields genome-wide read distribution patterns to track tissue of origin in cancer patients

10.1101/772657 ◽

2019 ◽

Author(s):

Han Liang ◽

Fuqiang Li ◽

Sitan Qiao ◽

Xinlan Zhou ◽

Guoyun Xie ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Cancer Patients ◽

Genome Sequencing ◽

Somatic Mosaicism ◽

Distribution Patterns ◽

Whole Genome ◽

Cell Free Dna ◽

Free Dna ◽

Tissue Of Origin ◽

Read Distribution

AbstractSomatic mosaicism is widespread among tissues and could indicate distinct tissue origins of circulating cell-free DNA (cfDNA), DNA fragments released by lytic cells into the blood. By investigating the alignment patterns of whole genome sequencing reads with the genomic DNA of different tissues, we found that the read distributions formed type-specific patterns in some regions as a result of somatic mosaicism. We then utilized this information to construct a tissue-of-origin mapping model and evaluated its predictive performance on whole genome sequencing data from tissue and cfDNA samples. In total, 1,545 tissue samples associated with 13 cancer types were included, and identification of the tissue of origin achieved a specificity of 82% and a sensitivity of 80%. Furthermore, a total of 30 cfDNA samples from lung cancer and liver cancer patients and healthy controls were analyzed to predict their tissues of origin with a specificity of 87% and a sensitivity of 87%. Our results show that read distribution patterns from whole genome sequencing could be used to identify cfDNA tissues of origin with high accuracy, suggesting the potential application of our model to early cancer detection and diagnosis.

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The NSIGHT1 Randomized Controlled Trial: Rapid Whole Genome Sequencing for Accelerated Etiologic Diagnosis in Critically Ill Infants

10.1101/218255 ◽

2017 ◽

Cited By ~ 1

Author(s):

Josh E. Petrikin ◽

Julie A. Cakici ◽

Michelle M. Clark ◽

Laurel K. Willig ◽

Nathaly M. Sweeney ◽

...

Keyword(s):

Intensive Care ◽

Whole Genome Sequencing ◽

Intensive Care Units ◽

Genome Sequencing ◽

Genetic Diagnosis ◽

Pediatric Intensive Care ◽

Genomic Sequencing ◽

Whole Genome ◽

Randomized Controlled ◽

Standard Tests

AbstractImportanceGenetic disorders, including congenital anomalies, are a leading cause of morbidity and mortality in infants, especially in neonatal and pediatric intensive care units (NICU and PICU). While genomic sequencing is useful for diagnosis of genetic diseases, results are usually reported too late to guide inpatient management.ObjectiveTo test the hypothesis that rapid whole genome sequencing (rWGS) increases the proportion of infants in NICUs and PICUs receiving a genetic diagnosis within 28 days.DesignAn investigator-initiated, partially blinded, pragmatic, randomized controlled study with enrollment from October 2014 - June 2016, and follow up until December 2016.SettingA regional neonatal and pediatric intensive care unit in a tertiary referral childrens hospital.ParticipantsSixty five of 129 screened families with infants aged less than four months, in neonatal and pediatric intensive care units, and with illnesses of unknown etiology, completed the study.InterventionParent and infant trio rWGS.Main Outcome and MeasureThe hypothesis and end-points were formulated a priori. The primary end-point was rate of genetic diagnosis within 28 days of enrollment or first standard test order.ResultsTwenty six female proband infants, 37 male infants, and two infants of undetermined sex were randomized to receive rWGS plus standard tests (n=32, cases) or standard tests alone (n=33, controls). The study was terminated early due to loss of equipoise: 63% (21) controls received genomic sequencing as standard tests. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days to be higher in cases (31%, ten of 32) than controls (3%, one of 33; difference, 28% [95% CI, 10% to 46%]; p=0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, seven of 22) than controls (0%, zero of 23; difference, 32% [95% CI, 11% to 53%]; p=0.004). Age at diagnosis (median in cases 25 days, range 14-90 days vs median in controls 130 days, range 37-451) and time to diagnosis (median in cases thirteen days, range 1-84 days vs median in controls 107 days, range 21-429 days) were significantly less in cases than controls (p=0.04).CONCLUSIONSrWGS increased the proportion of infants in a regional NICU and PICU who received a timely diagnosis of a genetic disease. Additional, adequately powered studies are needed to determine whether accelerated diagnosis is associated with improved outcomes in this setting. ClinicalTrials.gov Identifier: NCT02225522.

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Detection of Chromosomal Alterations in the Circulation of Cancer Patients with Whole-Genome Sequencing

Science Translational Medicine ◽

10.1126/scitranslmed.3004742 ◽

2012 ◽

Vol 4 (162) ◽

pp. 162ra154-162ra154 ◽

Cited By ~ 390

Author(s):

R. J. Leary ◽

M. Sausen ◽

I. Kinde ◽

N. Papadopoulos ◽

J. D. Carpten ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Cancer Patients ◽

Genome Sequencing ◽

Whole Genome ◽

Chromosomal Alterations

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Whole genomic sequencing based genotyping reveals a specific X3 sublineage restricted to Mexico and related with multidrug resistance

Scientific Reports ◽

10.1038/s41598-020-80919-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ana Cristina Jiménez-Ruano ◽

Carlos Francisco Madrazo-Moya ◽

Irving Cancino-Muñoz ◽

Paulina M. Mejía-Ponce ◽

Cuauhtémoc Licona-Cassani ◽

...

Keyword(s):

Multidrug Resistance ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Multidrug Resistant ◽

Genomic Sequencing ◽

Whole Genome ◽

Drug Resistant ◽

The Past ◽

High Prevalence ◽

Genomic Cluster

AbstractWhole genome sequencing (WGS) has been shown to be superior to traditional procedures of genotyping in tuberculosis (TB), nevertheless, reports of its use in drug resistant TB (DR-TB) isolates circulating in Mexico, are practically unknown. Considering the above the main of this work was to identify and characterize the lineages and genomic transmission clusters present in 67 DR-TB isolates circulating in southeastern Mexico. The results show the presence of three major lineages: L1 (3%), L2 (3%) and L4 (94%), the last one included 16 sublineages. Sublineage 4.1.1.3 (X3) was predominant in 18 (27%) of the isolates, including one genomic cluster, formed by eleven multidrug resistant isolates and sharing the SIT 3278, which seems to be restricted to Mexico. By the use of WGS, it was possible to identify the high prevalence of L4 and a high number of sublineages circulating in the region, also was recognized the presence of a novel X3 sublineage, formed exclusively by multidrug resistant isolates and with restrictive circulation in Mexico for at least the past 17 years.

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