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

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.

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

Oncotarget ◽

10.18632/oncotarget.2712 ◽

2015 ◽

Vol 6 (2) ◽

pp. 755-770 ◽

Cited By ~ 35

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

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Whole genome sequencing (WGS) to reveal the distinct genomic landscape of pulmonary lymphoepithelioma-like carcinoma (LELC).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.1530 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. 1530-1530 ◽

Cited By ~ 1

Author(s):

Shaodong Hong ◽

Kui Wu ◽

Dongbing Liu ◽

Wenfeng Fang ◽

Li Zhang

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

Genomic Landscape

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ICGC PedBrain - dissecting the genomic complexity underlying medulloblastoma using whole-genome sequencing

BMC Proceedings ◽

10.1186/1753-6561-6-s6-p43 ◽

2012 ◽

Vol 6 (S6) ◽

Cited By ~ 1

Author(s):

Natalie Jäger ◽

David TW Jones ◽

Marcel Kool ◽

Thomas Zichner ◽

Barbara Hutter ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome ◽

Genomic Complexity

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Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature

Cancers ◽

10.3390/cancers13040754 ◽

2021 ◽

Vol 13 (4) ◽

pp. 754

Author(s):

Helen R. Davies ◽

Kevin D. Broad ◽

Zerrin Onadim ◽

Elizabeth A. Price ◽

Xueqing Zou ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Driver Mutations ◽

Whole Genome ◽

Rb1 Gene ◽

Clinical Screening ◽

Genetic Changes ◽

Alternative Pathways ◽

Mutational Signature ◽

New Mutations

The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks.

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Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features

Nature Communications ◽

10.1038/s41467-020-20887-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Pauline A. J. Mendelaar ◽

Marcel Smid ◽

Job van Riet ◽

Lindsay Angus ◽

Mariette Labots ◽

...

Keyword(s):

Colorectal Cancer ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Fragile Sites ◽

Response To Treatment ◽

Whole Genome Sequencing Data ◽

Driver Gene ◽

Whole Genome ◽

Sequencing Data ◽

Genomic Landscape

AbstractIn contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.

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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 ◽

10.1182/blood-2019-130000 ◽

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.

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Whole-genome sequencing of 128 camels across Asia provides insights into origin and migration of domestic Bactrian camels

10.1101/656231 ◽

2019 ◽

Cited By ~ 1

Author(s):

Liang Ming ◽

Liyun Yuan ◽

Li Yi ◽

Guohui Ding ◽

Surong Hasi ◽

...

Keyword(s):

Genetic Distance ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Caspian Sea ◽

Whole Genome ◽

The Caspian Sea ◽

Genomic Landscape ◽

Bactrian Camels ◽

And Migration ◽

Basal Position

ABSTRACTThe domestic Bactrian camels were treated as the principal means of locomotion between the eastern and western cultures in history. To address the question of their origin, we performed whole-genome sequencing of 128 camels across Asia, including representative populations of domestic Bactrian camels from the Mongolian Plateau to the Caspian Sea, as well as the extant wild Bactrian camels and dromedaries. The domestic and wild Bactrian camels showed remarkable genetic divergence since they were split from dromedaries, confirming they were separated species. The wild Bactrian camels made also little contribution to the ancestry of domestic ones. Among the domestic Bactrian camels, those from Iran exhibited the largest genetic distance from others, and were the first population to separate in the phylogeny. Although evident admixture was observed between domestic Bactrian camels and dromedaries living around the Caspian Sea, the large genetic distance and basal position of Iranian Bactrian camels could not be explained by introgression alone. Taken together, our study favored the Iranian origin of domestic Bactrian camels, which were then immigrated eastward to Mongolia where the native wild Bactrian camels inhabited. This study illustrated the complex genomic landscape of migration underlying domestication in Bactrian camels.

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