Multi-modal meta-analysis of 1494 hepatocellular carcinoma samples reveals vast impacts of consensus driver genes on phenotypes

AbstractAlthough driver genes in hepatocellular carcinoma (HCC) have been investigated in various previous genetic studies, prevalence of key driver genes among heterogeneous populations is unknown. Moreover, the phenotypic associations of these driver genes are poorly understood. This report aims to reveal the phenotypic impacts of a group of consensus driver genes in HCC. We used MutSigCV and OncodriveFM modules implemented in the IntOGen pipeline to identify consensus driver genes across six HCC cohorts comprising 1,494 samples in total. To access their global impacts, we used TCGA mutations and copy number variations to predict the transcriptomics data, under generalized linear models. We further investigated the associations of the consensus driver genes to patient survival, age, gender, race and risk factors. We identify 10 consensus driver genes across six HCC cohorts in total. Integrative analysis of driver mutations, copy number variations and transcriptomic data reveals that these consensus driver mutations and their copy number variations are associated with majority (62.5%) of the mRNA transcriptome, but only a small fraction (8.9%) of miRNAs. Genes associated withTP53, CTNNB1, andARID1Amutations contribute to the tripod of most densely connected pathway clusters. These driver genes are significantly associated with patients’ overall survival. Some driver genes are significantly linked to HCC gender (CTNNB1, ALB, TP53andAXIN1), race (TP53andCDKN2A), and age (RB1) disparities. This study prioritizes a group of consensus drivers in HCC, which collectively show vast impacts on the phenotypes. These driver genes may warrant as valuable therapeutic targets of HCC.

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Mutations of key driver genes in gastric cancer metastasis risk: a systematic review and meta-analysis

Expert Review of Molecular Diagnostics ◽

10.1080/14737159.2021.1946394 ◽

2021 ◽

pp. 1-10

Author(s):

Jin Wang ◽

Xinye Shao ◽

Yang Liu ◽

Ruichuan Shi ◽

Bowen Yang ◽

...

Keyword(s):

Gastric Cancer ◽

Systematic Review ◽

Cancer Metastasis ◽

Meta Analysis ◽

Driver Genes ◽

Key Driver

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Genome-wide copy number variations as molecular diagnostic tool for cutaneous intermediate melanocytic lesions: a systematic review and individual patient data meta-analysis

Virchows Archiv ◽

10.1007/s00428-021-03095-5 ◽

2021 ◽

Author(s):

Chiel F. Ebbelaar ◽

Anne M. L. Jansen ◽

Lourens T. Bloem ◽

Willeke A. M. Blokx

Keyword(s):

Systematic Review ◽

Sensitivity And Specificity ◽

Copy Number ◽

Individual Patient Data ◽

Meta Analysis ◽

Copy Number Variations ◽

Patient Data ◽

Melanocytic Lesions ◽

Genome Wide ◽

Malignant Lesions

AbstractCutaneous intermediate melanocytic neoplasms with ambiguous histopathological features are diagnostically challenging. Ancillary cytogenetic techniques to detect genome-wide copy number variations (CNVs) might provide a valuable tool to allow accurate classification as benign (nevus) or malignant (melanoma). However, the CNV cut-off value to distinguish intermediate lesions from melanoma is not well defined. We performed a systematic review and individual patient data meta-analysis to evaluate the use of CNVs to classify intermediate melanocytic lesions. A total of 31 studies and 431 individual lesions were included. The CNV number in intermediate lesions (median 1, interquartile range [IQR] 0–2) was significantly higher (p<0.001) compared to that in benign lesions (median 0, IQR 0–1) and lower (p<0.001) compared to that in malignant lesions (median 6, IQR 4–11). The CNV number displayed excellent ability to differentiate between intermediate and malignant lesions (0.90, 95% CI 0.86–0.94, p<0.001). Two CNV cut-off points demonstrated a sensitivity and specificity higher than 80%. A cut-off of ≥3 CNVs corresponded to 85% sensitivity and 84% specificity, and a cut-off of ≥4 CNVs corresponded to 81% sensitivity and 91% specificity, respectively. This individual patient data meta-analysis provides a comprehensive overview of CNVs in cutaneous intermediate melanocytic lesions, based on the largest pooled cohort of ambiguous melanocytic neoplasms to date. Our meta-analysis suggests that a cut-off of ≥3 CNVs might represent the optimal trade-off between sensitivity and specificity in clinical practice to differentiate intermediate lesions from melanoma.

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Genomic alterations caused by HPV integration in a cohort of Chinese endocervical adenocarcinomas

Cancer Gene Therapy ◽

10.1038/s41417-020-00283-4 ◽

2021 ◽

Author(s):

Wenhui Li ◽

Wanjun Lei ◽

Xiaopei Chao ◽

Xiaochen Song ◽

Yalan Bi ◽

...

Keyword(s):

Copy Number ◽

Somatic Mutations ◽

Hpv Infection ◽

Copy Number Variations ◽

Cervical Adenocarcinoma ◽

Structural Variations ◽

Driver Genes ◽

Genetic Changes ◽

Genomic Changes ◽

Whole Exome

AbstractThe association between human papillomavirus (HPV) integration and relevant genomic changes in uterine cervical adenocarcinoma is poorly understood. This study is to depict the genomic mutational landscape in a cohort of 20 patients. HPV+ and HPV− groups were defined as patients with and without HPV integration in the host genome. The genetic changes between these two groups were described and compared by whole-genome sequencing (WGS) and whole-exome sequencing (WES). WGS identified 2916 copy number variations and 743 structural variations. WES identified 6113 somatic mutations, with a mutational burden of 2.4 mutations/Mb. Six genes were predicted as driver genes: PIK3CA, KRAS, TRAPPC12, NDN, GOLGA6L4 and BAIAP3. PIK3CA, NDN, GOLGA6L4, and BAIAP3 were recognized as significantly mutated genes (SMGs). HPV was detected in 95% (19/20) of patients with cervical adenocarcinoma, 7 of whom (36.8%) had HPV integration (HPV+ group). In total, 1036 genes with somatic mutations were confirmed in the HPV+ group, while 289 genes with somatic mutations were confirmed in the group without HPV integration (HPV− group); only 2.1% were shared between the two groups. In the HPV+ group, GOLGA6L4 and BAIAP3 were confirmed as SMGs, while PIK3CA, NDN, KRAS, FUT1, and GOLGA6L64 were identified in the HPV− group. ZDHHC3, PKD1P1, and TGIF2 showed copy number amplifications after HPV integration. In addition, the HPV+ group had significantly more neoantigens. HPV integration rather than HPV infection results in different genomic changes in cervical adenocarcinoma.

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MBCL-08. INTEGRATIVE MOLECULAR ANALYSIS OF PATIENT-MATCHED DIAGNOSTIC AND RELAPSED MEDULLOBLASTOMAS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.484 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii389-iii389

Author(s):

Rahul Kumar ◽

Maximilian Deng ◽

Kyle Smith ◽

Anthony Liu ◽

Girish Dhall ◽

...

Keyword(s):

Molecular Analysis ◽

Copy Number ◽

Driver Mutations ◽

P Value ◽

Next Generation ◽

Driver Genes ◽

Methylation Array ◽

Primary Tumors ◽

Group 4 ◽

Group 3

Abstract INTRODUCTION The next generation of clinical trials for relapsed medulloblastoma demands a thorough understanding of the clinical behavior of relapsed tumors as well as the molecular relationship to their diagnostic counterparts. METHODS A multi-institutional molecular cohort of patient-matched (n=126 patients) diagnostic MBs and relapses/subsequent malignancies was profiled by DNA methylation array. Entity, subgroup classification, and genome-wide copy-number aberrations were assigned while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations. RESULTS Comprised of WNT (2%), SHH (41%), Group 3 (18%), Group 4 (39%), primary tumors retained subgroup affiliation at relapse with the notable exception of 10% of cases. The majority (8/13) of discrepant classifications were determined to be secondary glioblastomas. Additionally, rare (n=3) subgroup-switching events of Group 4 primary tumors to Group 3 relapses were identified coincident with MYC/MYCN pathway alterations. Amongst truly relapsing MBs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with Group 3 (55% of alterations shared) and Group 4 tumors (63% alterations shared) sharing a larger proportion of cytogenetic alterations compared to SHH tumors (42% alterations shared; Chi-square p-value < 0.001). Subgroup- and gene-specific patterns of conservation and divergence amongst putative driver genes were also observed. CONCLUSION Integrated molecular analysis of relapsed MB discloses potential mechanisms underlying treatment failure and disease recurrence while motivating rational implementation of relapse-specific therapies. The degree of genetic divergence between primary and relapsed MBs varied by subgroup but suggested considerably higher conservation than prior estimates.

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Systematic identification of mutations and copy number alterations associated with cancer patient prognosis

eLife ◽

10.7554/elife.39217 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 34

Author(s):

Joan C Smith ◽

Jason M Sheltzer

Keyword(s):

Copy Number ◽

Meta Analysis ◽

Gene Copy Number ◽

Gene Copy ◽

Driver Genes ◽

Cancer Driver ◽

Molecular Alterations ◽

Patient Prognosis ◽

Almost All ◽

Systematic Identification

Successful treatment decisions in cancer depend on the accurate assessment of patient risk. To improve our understanding of the molecular alterations that underlie deadly malignancies, we analyzed the genomic profiles of 17,879 tumors from patients with known outcomes. We find that mutations in almost all cancer driver genes contain remarkably little information on patient prognosis. However, CNAs in these same driver genes harbor significant prognostic power. Focal CNAs are associated with worse outcomes than broad alterations, and CNAs in many driver genes remain prognostic when controlling for stage, grade, TP53 status, and total aneuploidy. By performing a meta-analysis across independent patient cohorts, we identify robust prognostic biomarkers in specific cancer types, and we demonstrate that a subset of these alterations also confer specific therapeutic vulnerabilities. In total, our analysis establishes a comprehensive resource for cancer biomarker identification and underscores the importance of gene copy number profiling in assessing clinical risk.

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MON-LB48 The Genomic Landscape of Sporadic Thyrotrophinomas

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2282 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Angeline shen ◽

Paul Wang ◽

Sunita M C De Sousa ◽

David J Torpy ◽

Hamish Scott ◽

...

Keyword(s):

Cell Adhesion ◽

Rna Polymerase Ii ◽

Copy Number ◽

Large Scale ◽

Neutral Loss ◽

Copy Number Variations ◽

Driver Mutations ◽

Chromosomal Anomalies ◽

Tumour Type ◽

Genomic Landscape

Abstract Background: Thyrotrophinoma (TSHoma) is rare and knowledge on the genomic landscape of this tumour type is very limited. Aim: To perform whole-exome sequencing (WES) in a population of TSHomas to identify recurrent somatic genetic events Method: WES was performed on paired tumour and germline DNA of 7 patients with TSHomas. Three tissue samples were formalin-fixed paraffin-embedded and 4 fresh frozen tumour samples. Fresh blood samples were also collected from each patient. The average of mean depth of coverage amongst all samples was 129X, and 97% of target bases were covered ≥20X. Results:Four (57%) of the seven patients were male and median age at diagnosis was 52 years. (IQR 46, 60) Six patients (86%) had macroadenomas. Four patients (57%) had central thyrotoxicosis at diagnosis and three patients’ tumour stained positive for TSH on histology examination. Two patients (29%) had growth hormone co-secreting tumours. In total, 69 somatic variants were identified to be of potential interest, averaging 1.4 variants per million base-pair of DNA read. No variants were observed in more than one individual. According to the GTEx database, 9 of 69 genes (DRC3, HDAC5, KDM1A, POLR21, TCF25, THAP7, TTC13, UNC5D, UNC13A) were highly expressed in the pituitary (top 10%). Four of these genes appear to contribute to tumour development via epigenetic pathway. Specifically, three of these genes (HDAC5, KDM1A, THAP7) either interact with or form part of histone deacetylases whilst POLR21 encodes a subunit of RNA polymerase II which is responsible for mRNA synthesis. On the other hand, TCF25 gene is thought to act as transcriptional repressor and UNC5D plays a role in cell-cell adhesion. Large scale copy number variations involving gain or loss of whole chromosome or chromosome (chr) arm were observed in six (86%) tumour samples. Chr 5, 9, 13 and 19 were most commonly affected by chromosomal gains. Deletion of chr 1p was seen in two cases and mutations in KDM1A (p.Glu161fs/c.482_491delAGGAAGAAAA) and ADGRB2 gene (p.Leu1565Gln/c.4694T>A) were found in each of the remaining single copy of chr 1p. ADGRB2 gene is thought to be involved in cell adhesion and angiogenesis inhibition. Copy neutral loss-of-heterozygosity were present in two (29%) of the tumour samples (chr 2 and 12q). However, no somatic mutation was found in these regions. Gene level copy number analysis identified a potential deletion in TTI2 gene which encodes for a regulator in DNA damaging response as well as telomere length regulation. ConclusionOverall, the rate of somatic variant mutations in TSHomas is low, consistent with the relative benign nature of this tumour type. No classical driver mutations were identified by this study however, chromosomal anomalies and epigenetics may play an important part in TSHoma development.

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Patients with polyclonal hepatocellular carcinoma are at a high risk of early recurrence and have a poor recurrence-free survival period

10.21203/rs.3.rs-782031/v1 ◽

2021 ◽

Author(s):

Masaki Kaibori ◽

Kazuko Sakai ◽

Hideyuki Matsushima ◽

Hisashi Kosaka ◽

Kosuke Matsui ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

High Risk ◽

Copy Number ◽

Snp Array ◽

Early Recurrence ◽

Copy Number Variations ◽

Survival Period ◽

Recurrence Free Survival ◽

Free Survival ◽

A Genome

Abstract Background/purpose of the study Tumor heterogeneity based on copy number variations is associated with the evolution of cancer and its clinical grade. Clonal composition (CC) represents the number of clones based on the distribution of B-allele frequency (BAF) obtained from a genome-wide single nucleotide polymorphism (SNP) array. A higher CC number represents a high degree of heterogeneity. We hypothesized and evaluated that the CC number in hepatocellular carcinoma (HCC) tissues might be associated with the clinical outcomes of patients. Methods Somatic mutation, whole transcriptome, and copy number variations of 36 frozen tissue samples of operably resected HCC tissues by targeted deepsequencing, RNAseq and SNP array. Results The samples were classified the heterogeneous tumors as poly-CC (n = 26) and the homogeneous tumors as mono-CC (n = 8). The patients with poly-CC had a higher rate of early recurrence and a significantly shorter recurrence-free survival period than the mono-CC patients (7.0 vs. not reached, p = 0.0084). No differences in pathogenic non-synonymous mutations, such as TP53, were observed between the two groups when targeted deep sequencing was applied. A transcriptome analysis showed that cell cycle-related pathways were enriched in the poly-CC tumors, compared with the mono-CC tumors. poly-CC HCC is highly proliferative and has a high risk of early recurrence. Conclusion CC is a candidate biomarker for predicting the risk of early postoperative recurrence and warrants further investigation.

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The evolutionary history of 2,658 cancers

10.1101/161562 ◽

2017 ◽

Cited By ~ 30

Author(s):

Moritz Gerstung ◽

Clemency Jolly ◽

Ignaty Leshchiner ◽

Stefan C. Dentro ◽

Santiago Gonzalez ◽

...

Keyword(s):

Copy Number ◽

Timing Analysis ◽

Point Mutations ◽

Life History Evolution ◽

Driver Mutations ◽

Driver Genes ◽

Somatic Evolution ◽

History Of ◽

Small Set ◽

Trisomy 7

SummaryCancer develops through a process of somatic evolution. Here, we use whole-genome sequencing of 2,778 tumour samples from 2,658 donors to reconstruct the life history, evolution of mutational processes, and driver mutation sequences of 39 cancer types. The early phases of oncogenesis are driven by point mutations in a small set of driver genes, often including biallelic inactivation of tumour suppressors. Early oncogenesis is also characterised by specific copy number gains, such as trisomy 7 in glioblastoma or isochromosome 17q in medulloblastoma. By contrast, increased genomic instability, a nearly four-fold diversification of driver genes, and an acceleration of point mutation processes are features of later stages. Copy-number alterations often occur in mitotic crises leading to simultaneous gains of multiple chromosomal segments. Timing analysis suggests that driver mutations often precede diagnosis by many years, and in some cases decades, providing a window of opportunity for early cancer detection.

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