Genomic analysis of liver cancer unveils novel driver genes and distinct prognostic features

AbstractWhile genomic analysis of tumors has stimulated major advances in cancer diagnosis, prognosis and treatment, current methods fail to identify a large fraction of somatic structural variants in tumors. We have applied a combination of whole genome sequencing and optical genome mapping to a number of adult and pediatric leukemia samples, which revealed in each of these samples a large number of structural variants not recognizable by current tools of genomic analyses. We developed computational methods to determine which of those variants likely arose as somatic mutations. The method identified 97% of the structural variants previously reported by karyotype analysis of these samples and revealed an additional fivefold more such somatic rearrangements. The method identified on average tens of previously unrecognizable inversions and duplications and hundreds of previously unrecognizable insertions and deletions. These structural variants recurrently affected a number of leukemia associated genes as well as cancer driver genes not previously associated with leukemia and genes not previously associated with cancer. A number of variants only affected intergenic regions but caused cis-acting alterations in expression of neighboring genes. Analysis of TCGA data indicates that the status of several of the recurrently mutated genes identified in this study significantly affect survival of AML patients. Our results suggest that current genomic analysis methods fail to identify a majority of structural variants in leukemia samples and this lacunae may hamper diagnostic and prognostic efforts.

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Genomic analysis of driver-negative lung adenocarcinoma (LA) in lifetime never smokers.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3571 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3571-3571

Author(s):

Aline Fusco Fares ◽

Sebastiao N. Martins-Filho ◽

Quan Li ◽

Andrew Seto ◽

Erin L. Stewart ◽

...

Keyword(s):

Rna Sequencing ◽

Genomic Analysis ◽

Base Substitution ◽

Negative Group ◽

Driver Genes ◽

Dna Mismatch ◽

Targeted Next Generation Sequencing ◽

Mutation Burden ◽

Biomarker Testing ◽

Never Smokers

3571 Background: Genomic events giving rise to driver negative LA in never smokers remain elusive. Here we report results of whole exome sequencing (WES) and targeted RNA sequencing in NS who had no mutation drivers found on routine clinical testing by targeted next generation sequencing (NGS). Methods: The cohort of never smokers with EGFR/ALK negative LA by clinical biomarker testing at Princess Margaret Cancer Centre, were first subjected to various clinical NGS profiling platforms (table). Where tissue was available, those negative for potential drivers in the clinical NGS then underwent WES (mean coverage > 200x) and Oncomine comprehensive v.3 RNA sequencing. We analyzed mutational signatures (MS) of the driver negative cohort based on the COSMIC catalog and assessed the median tumor mutation burden (mTMB mut/Mb -Megabase) in cases without a smoking MS, to avoid confounders. Results: Of 159 never smokers profiled with clinical NGS, potential drivers were found in 86 (54%): 75 (87%) with mutations in known LA driver genes and 11 (13%) with fusions. Among the remaining never smokers that tested negative by clinical NGS, 35 (48%) had available tissue for further testing. The Oncomine panel identified 9 cases (25%) with fusions or MET exon14 mutation (n = 7). Within the driver negative group, 24 (92%) underwent WES. Three tumors had WES base substitution patterns that were consistent with a smoking-related MS (MS4). Twenty-one patients exhibited signatures found common across all cancer types (MS 5), associated with DNA mismatch repair (MS 6, MS 20) or APOBEC over-activation (MS 2, MS13). In the driver-negative group, we identified 7 pts with somatic mutations in the KMT2 family (4 KMT2C, 4 KMT2A, 1 KMT2D), known for putative tumor suppressors and histone methyltransferases. mTMB on the driver negative group was 1.92, while one outlier with APOBEC MS and KMT2C/A mutations had a TMB of 16.8. Conclusions: Never smokers with driver negative LA are a heterogeneous group, with different MS and a wide TMB range. Mutations on KMT2 family are frequently found in driver negative LA in never smokers and warrant further investigations. [Table: see text]

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Genome-wide identification and analysis of prognostic features in human cancers

10.1101/2021.06.01.446243 ◽

2021 ◽

Author(s):

Joan Clara Smith ◽

Jason Meyer Sheltzer

Keyword(s):

Survival Data ◽

Drug Targets ◽

Cell Cycle Progression ◽

Housekeeping Genes ◽

Survival Models ◽

Survival Times ◽

Driver Genes ◽

Prognostic Features ◽

Genome Wide ◽

Biomarker Analysis

Clinical decisions in cancer rely on precisely assessing patient risk. To improve our ability to accurately identify the most aggressive malignancies, we constructed genome-wide survival models using gene expression, copy number, methylation, and mutation data from 10,884 patients with known clinical outcomes. We identified more than 100,000 significant prognostic biomarkers and demonstrate that these genomic features can predict patient outcomes in clinically-ambiguous situations. While adverse biomarkers are commonly believed to represent cancer driver genes and promising therapeutic targets, we show that cancer features associated with shorter survival times are not enriched for either oncogenes or for successful drug targets. Instead, the strongest adverse biomarkers represent widely-expressed housekeeping genes with roles in cell cycle progression, and, correspondingly, nearly all therapies directed against these features have failed in clinical trials. In total, our analysis establishes a rich resource for prognostic biomarker analysis and clarifies the use of patient survival data in preclinical cancer research and therapeutic development.

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Integrated genomic analysis-based identification of core pathways and driver genes associated with colorectal carcinoma

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2015.00619 ◽

2015 ◽

Vol 36 (6) ◽

pp. 619

Author(s):

Hua MIAO ◽

Fu-ao CAO ◽

Quan-quan ZHAO ◽

Zong-yuan MIAO ◽

Chun YE ◽

...

Keyword(s):

Colorectal Carcinoma ◽

Genomic Analysis ◽

Driver Genes

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Oncogenic driver genes and tumor microenvironment determine the type of liver cancer

Cell Death and Disease ◽

10.1038/s41419-020-2509-x ◽

2020 ◽

Vol 11 (5) ◽

Cited By ~ 5

Author(s):

Gang Wang ◽

Qian Wang ◽

Ning Liang ◽

Hongyuan Xue ◽

Tao Yang ◽

...

Keyword(s):

Tumor Microenvironment ◽

Liver Cancer ◽

Driver Genes ◽

Oncogenic Driver

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Exome sequencing identifies novel somatic variants in African American esophageal squamous cell carcinoma

Scientific Reports ◽

10.1038/s41598-021-94064-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hayriye Verda Erkizan ◽

Shrey Sukhadia ◽

Thanemozhi G. Natarajan ◽

Gustavo Marino ◽

Vicente Notario ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

African American ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Exome Sequencing ◽

Squamous Cell ◽

Somatic Mutations ◽

Mutational Analysis ◽

Genomic Analysis ◽

Driver Genes

AbstractEsophageal cancer has a strikingly low survival rate mainly due to the lack of diagnostic markers for early detection and effective therapies. In the U.S., 75% of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) are of African descent. African American ESCC (AA ESCC) is particularly aggressive, and its biological underpinnings remain poorly understood. We sought to identify the genomic abnormalities by conducting whole exome sequencing of 10 pairs of matched AA esophageal squamous cell tumor and control tissues. Genomic analysis revealed diverse somatic mutations, copy number alterations (SCNAs), and potential cancer driver genes. Exome variants created two subgroups carrying either a high or low tumor mutation burden. Somatic mutational analysis based on the Catalog of Somatic Mutations in Cancer (COSMIC) detected SBS16 as the prominent signature in the high mutation rate group suggesting increased DNA damage. SBS26 was also detected, suggesting possible defects in mismatch repair and microsatellite instability. We found SCNAs in multiple chromosome segments, encoding MYC on 8q24.21, PIK3CA and SOX2 on 3q26, CCND1, SHANK2, CTTN on 11q13.3, and KRAS on 12p12. Amplifications of EGFRvIII and EGFRvIVa mutants were observed in two patients, representing a novel finding in ESCC that has potential clinical relevance. This present exome sequencing, which to our knowledge, represents the first comprehensive exome analysis exclusively in AA ESCC, and highlights novel mutated loci that might explain the aggressive nature of AA ESCC and lead to the development of diagnostic and prognostic markers as well as therapeutic targets.

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Integrated genomic analysis for prediction of survival for patients with liver cancer using The Cancer Genome Atlas

World Journal of Gastroenterology ◽

10.3748/wjg.v24.i28.3145 ◽

2018 ◽

Vol 24 (28) ◽

pp. 3145-3154

Author(s):

Yan-Zhou Song ◽

Xu Li ◽

Wei Li ◽

Zhong Wang ◽

Kai Li ◽

...

Keyword(s):

Liver Cancer ◽

Genomic Analysis ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Prediction Of Survival ◽

Cancer Genome Atlas ◽

Genome Atlas

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Liver Resection and Surgical Strategies for Management of Primary Liver Cancer

Cancer Control ◽

10.1177/1073274817744621 ◽

2018 ◽

Vol 25 (1) ◽

pp. 107327481774462 ◽

Cited By ~ 18

Author(s):

Sonia T. Orcutt ◽

Daniel A. Anaya

Keyword(s):

Liver Resection ◽

Liver Cancer ◽

Liver Function ◽

Surgical Resection ◽

Primary Liver Cancer ◽

Curative Intent ◽

Surgical Strategies ◽

Prognostic Features ◽

Complex Anatomy ◽

Number Of Patients

Primary liver cancer—including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC)—incidence is increasing and is an important source of cancer-related mortality worldwide. Management of these cancers, even when localized, is challenging due to the association with underlying liver disease and the complex anatomy of the liver. Although for ICC, surgical resection provides the only potential cure, for HCC, the risks and benefits of the multiple curative intent options must be considered to individualize treatment based upon tumor factors, baseline liver function, and the functional status of the patient. The principles of surgical resection for both HCC and ICC include margin-negative resections with preservation of adequate function of the residual liver. As the safety of surgical resection has improved in recent years, the role of liver resection for HCC has expanded to include selected patients with preserved liver function and small tumors (ablation as an alternative), tumors within Milan criteria (transplant as an alternative), and patients with large (>5 cm) and giant (>10 cm) HCC or with poor prognostic features (for whom surgery is infrequently offered) due to a survival benefit with resection for selected patients. An important surgical consideration specifically for ICC includes the high risk of nodal metastasis, for which portal lymphadenectomy is recommended at the time of hepatectomy for staging. For both diseases, onco-surgical strategies including portal vein embolization and parenchymal-sparing resections have increased the number of patients eligible for curative liver resection by improving patient outcomes. Multidisciplinary evaluation is critical in the management of patients with primary liver cancer to provide and coordinate the best treatments possible for these patients.

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