scholarly journals A Prospective Analysis of the Genomic Landscape of Patients with Acute Myeloid Leukemia and Its Impact on Clinical Outcomes - Data from a Tertiary Care Center in India

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5163-5163
Author(s):  
Hamza Yusuf Dalal ◽  
Sharat Damodar ◽  
Vidya Harini Veldore ◽  
Coral Miriam K ◽  
Shilpa Prabhu ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Whole Genome Sequencing ◽  
Clinical Outcomes ◽  
Genome Sequencing ◽  
Myeloid Leukemia ◽  
Driver Mutations ◽  
Whole Genome ◽  
Intermediate Risk ◽  
Genomic Landscape ◽  
Acute Myeloid

BACKGROUND : Clinical Phenotype and outcomes of patients with Acute myeloid leukemia (AML) in the Indian subcontinent differs from published literature. A younger age at diagnosis and higher induction mortality complicate AML management in India(1). Metaphase Karyotyping represents the backbone of prognostication and risk stratification in AML. Optimal treatment strategies for the cohort of Cytogenetically normal AML are still under evaluation. Applications of Next generation Sequencing (NGS) techniques in AML have unravelled the genetic heterogeneity of this disease. Whole genome sequencing has identified many novel mutations leading to tremendous improvements in diagnosis and risk stratification. Development of therapies targeting these genetic alterations is enabling a gradual shift from non-specific approaches to personalised therapy tailored to an individual patient's genome. This will undoubtedly translate to better clinical outcomes for this disease, with otherwise poor prognosis. Whole genome sequencing is still in a nascent stage in Indian settings with no published literature on genomics in AML till date. We aimed to study the genomic landscape of AML in the Indian population and to co-relate this with clinical outcomes over the course of 1 year. METHODS: We recruited 34 newly diagnosed patients with AML who presented to our Centre (Mazumdar Shaw Medical Centre, Narayana Health City, Bangalore, India) between November 2017 and May 2018. Clinical and laboratory details of all patients were recorded. Bone marrow and paired peripheral blood samples were drawn before initiating therapy. Whole genome sequencing and Exome capture was done for each sample using Ilumina HiSeq platform. Patients were risk stratified as per ELN 2017 and treated as per NCCN guidelines. Patients were followed up prospectively for one year from initial diagnosis. Genetic results were stratified according to gene function and analysed with respect to predefined clinical outcomes (remission status post induction, relapse rates, progression free and overall survival). RESULTS: Amongst the 34 study participants, 5 patients failed QC during sequencing and were de-recruited. Hence 29 patients were available for final analysis. Median age of patients was 42 years with 13 patients (44.8%) less than 40 years of age.18 patients (60%) had normal cytogenetics at baseline.17 patients (58%) were classified as intermediate risk and 6 patients each as Standard and high risk, as per ELN 2017. 22 patients (79.3%) patients received standard Induction chemotherapy (3+7 regimen) while 6 patients received hypomethylating agents. Overall CR rate following induction at Day 28 was 50% and Induction mortality was 21.42%. 6 patients underwent an Allogenic Stem cell transplant. A total of 96 mutations (47 driver and 49 VUS mutations) in 123 genes were identified. The average number of Driver mutations was 1.48 per patient. IDH genes were the most frequently mutated Driver genes followed by FLT3 mutations. Frequency of NPM1 mutations was significantly low (17.25%). Highest frequency of VUS mutations was seen in the ETV6, ATM and CBLC genes. Highest frequency of somatic mutations were identified in the genes encoding for myeloid transcription factors and DNA methylation. Average driver mutations showed significant co-relation to Age (> 60 years) and high burden of Bone marrow blasts (>30%). An updated risk stratification incorporating mutation analysis findings resulted in re-stratification of 8 intermediate risk patients into high risk. 2 patients with detectable FLT3 ITD mutation by NGS were negative by PCR. Choice of consolidation therapy and Driver mutation status were found to show statistically significant association with both Event free survival and Overall survival at 1 year. Increased driver mutation burden was associated with increased refractoriness to chemotherapy and poor EFS and OS. Mutations in Tumour suppressor genes, were associated with suboptimal treatment outcomes and poor survival. CONCLUSIONS Genomic landscape of AML in Indian patients shows significant differences from published literature. This may hold clues to the differing biological characteristics of AML seen in this population. Genome based risk stratification and tailored therapy needs to be adapted into the management of AML. This data provides valuable insights into developing therapeutic strategies for Indian patients. Disclosures No relevant conflicts of interest to declare.

Whole Genome Sequencing of Therapy-Related Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 784-784
Author(s):  
Giridharan Ramsingh ◽  
Dong Shen ◽  
Tamara Lamprecht ◽  
Sharon Heath ◽  
Robert S. Fulton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
De Novo ◽  
Whole Genome ◽  
Hematopoietic Stem ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 784 Whole Genome Sequencing of Therapy-Related Acute Myeloid Leukemia Giridharan Ramsingh, Dong Shen, Tamara L. Lamprecht, Sharon E. Heath, Robert S. Fulton, Elaine Mardis, Li Ding, Peter Westervelt, John Welch, Matthew J. Walter, Timothy A. Graubert, John F. DiPersio, Timothy J. Ley, Richard K. Wilson, and Daniel C. Link. Therapy related therapy-related acute myeloid leukemia (t-AML) accounts for 10–20% of all new cases of AML, and its incidence is rising. A fundamental difference in the pathogenesis of de novo AML and t-AML is prior treatment with chemotherapy and/or radiotherapy. The exposure of hematopoietic stem/progenitors cells (HSPCs) to this genotoxic stress is hypothesized to alter the number and spectrum of mutations that arise in t-AML. Moreover, the genotoxic stress may exert selective pressure to expand those HSPC clones that are inherently resistant to chemotherapy, a common feature in t-AML. To test these hypotheses, we sequenced the genomes of 23 cases of t-AML and compared them to the genomes of 24 cases of de novo AML, which we recently reported (Welch et al., Cell, July 2012). We choose to focus our initial studies on the subset of t-AML with normal cytogenetics or simple balanced translocations. Specifically, MLL gene rearrangements were observed in 22% of cases, other balanced translocations in 22%, trisomy 8 in 22%, normal karyotype in 31%, and a complex karyotype in a single case. All patients had received prior alkylator chemotherapy (62%), topoisomerase inhibitor chemotherapy (65%), or radiotherapy (77%). To identify somatic mutations, whole genome sequencing was performed on leukemic bone marrow (average 65% blasts) and skin (normal) DNA. Average haploid coverage was 37.5X and 34.7X for the leukemia and skin genomes, respectively. All somatic mutations were verified using patient-specific custom NimbleGen capture arrays, followed by Illumina sequencing. Although the total number of somatic single nucleotide variants in older patients (>50 years) with t-AML was similar to that observed in de novo AML (484 ± 68 vs. 506 ± 45, respectively), significantly more mutations were present in younger (≤ 50 years) patients with t-AML (743 ± 228) compared with de novo AML (336 ± 179, P=0.04). Exposure to chemotherapy is associated with an increased rate of transversions in relapsed AML (Ding et al., Nature 2012). However, the percentage of somatic mutations that were transversions in t-AML (35.8 ± 1.91%) was similar to that seen in de novo AML (33.5 ± 0.93%), regardless of age. In the 23 t-AML genomes, we identified recurring mutations (present in at least 2 cases) in 20 genes. Many of these mutations were also observed in de novo AML genomes (Figure 1). The most commonly mutated gene in t-AML was TET2, which was mutated in 35% of cases. Of interest, missense mutations of the ABC transporter gene ABCG2 were significantly enriched in t-AML (2/23, 8.7%) compared with de novo AML (0 in 200 cases, P=0.01). ABCG2 (also known as breast cancer resistance protein, BCRP) has been implicated in chemotherapy resistance. ABCG2 is expressed at high levels in hematopoietic stem cells, where it is known to function as a key drug transporter. Studies are underway to define the frequency of ABCG2 mutations (and other ABC transporter genes) in a larger cohort of t-AML, including cases with alterations in chromosome 5 or 7 or with complex cytogenetic abnormalities. In summary, in younger patients with t-AML, the mutational burden is higher than that of de novo AML patients, possibly reflecting prior exposure to chemoradiotherapy, though no increase in transversions was observed. Mutations of ABCG2 may contribute to chemotherapy resistance in a subset of t-AML. Figure 1. Recurring mutations in t-AML (n = 23) compared with de novo AML (n = 24). Figure 1. Recurring mutations in t-AML (n = 23) compared with de novo AML (n = 24). Disclosures: Ley: Washington University: Patents & Royalties.

scholarly journals Genomic Landscape of Intramedullary Spinal Cord Tumors Suggests Distinct Genetic Origins Compared to Intracranial Histopathologic Counterparts

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Tej D Azad ◽  
Ming Zhang ◽  
Rajiv Iyer ◽  
Qing Wang ◽  
Tomas Garzon-Muvdi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Treatment Options ◽  
Driver Mutations ◽  
Whole Genome ◽  
Spinal Cord Tumors ◽  
Intramedullary Spinal Cord ◽  
Molecular Features ◽  
The Central Nervous System

Abstract INTRODUCTION Intramedullary spinal cord tumors (IMSCTs) are a rare, heterogeneous group of neoplasms with limited treatment options and high rates of morbidity and mortality. Next-generation sequencing has revealed opportunities for targeted therapies of the intracranial counterparts of IMSCT, but little is known about the molecular features of IMSCT. METHODS To better understand the genetic basis of these tumors we performed whole exome sequencing on fifty-one IMSCT and matched germline DNA, including 29 ependymomas, 16 astrocytomas, 4 gangliogliomas,1hemangioblastoma, and 1 oligodendroglioma. Whole-genome sequencing was further performed on 12 IMSCT to discover possible structural variants. RESULTS Though recurrent somatic mutations in IMSCTs were rare, we identified NF2 mutations in 15.7% of tumors (ependymoma, N = 7; astrocytoma, N = 1), RP1 mutations in 5.9% of tumors (ependymoma, N = 3), and ESX1 mutations in 5.9% of tumors (ependymoma, N = 3). We further identified copy number amplifications in CTU1 in 25% of myxopapillary ependymomas. Given the paucity of somatic driver mutations, we further performed whole-genome sequencing of 12 tumors (ependymoma, N = 9; astrocytoma, N = 3). Overall, we observed that IMSCTs with intracranial histologic counterparts did not harbor the canonical mutations associated with their intracranial counterparts (eg glioblastoma). CONCLUSION Our findings suggest that the origin of IMSCTs may be distinct from tumors arising within other compartments of the central nervous system and provides a framework to begin more biologically based therapeutic strategies.

scholarly journals Quantifying the influence of mutation detection on tumour subclonal reconstruction

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Lydia Y. Liu ◽  
Vinayak Bhandari ◽  
Adriana Salcedo ◽  
Shadrielle M. G. Espiritu ◽  
Quaid D. Morris ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Cancer Cells ◽  
Clinical Outcomes ◽  
Cancer Cell ◽  
Genome Sequencing ◽  
Somatic Mutations ◽  
Mutation Detection ◽  
Cell Populations ◽  
Whole Genome ◽  
Prostate Cancers

AbstractWhole-genome sequencing can be used to estimate subclonal populations in tumours and this intra-tumoural heterogeneity is linked to clinical outcomes. Many algorithms have been developed for subclonal reconstruction, but their variabilities and consistencies are largely unknown. We evaluate sixteen pipelines for reconstructing the evolutionary histories of 293 localized prostate cancers from single samples, and eighteen pipelines for the reconstruction of 10 tumours with multi-region sampling. We show that predictions of subclonal architecture and timing of somatic mutations vary extensively across pipelines. Pipelines show consistent types of biases, with those incorporating SomaticSniper and Battenberg preferentially predicting homogenous cancer cell populations and those using MuTect tending to predict multiple populations of cancer cells. Subclonal reconstructions using multi-region sampling confirm that single-sample reconstructions systematically underestimate intra-tumoural heterogeneity, predicting on average fewer than half of the cancer cell populations identified by multi-region sequencing. Overall, these biases suggest caution in interpreting specific architectures and subclonal variants.

scholarly journals The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients

Oncotarget ◽  
2015 ◽  
Vol 6 (2) ◽  
pp. 755-770 ◽  
Author(s):  
David G. Darcy ◽  
Rachel Chiaroni-Clarke ◽  
Jennifer M. Murphy ◽  
Joshua N. Honeyman ◽  
Umesh Bhanot ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Fibrolamellar Hepatocellular Carcinoma ◽  
Genomic Landscape

scholarly journals Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Felicity Newell ◽  
James S. Wilmott ◽  
Peter A. Johansson ◽  
Katia Nones ◽  
Venkateswar Addala ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genome Duplication ◽  
Structural Rearrangement ◽  
Whole Genome ◽  
Rare Form ◽  
Acral Melanoma ◽  
Mutational Signature ◽  
Genomic Complexity ◽  
Genomic Landscape

Abstract To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.

Sign in / Sign up

Export Citation Format

Share Document