HCMMCNVs: hierarchical clustering mixture model of copy number variants detection using whole exome sequencing technology

Abstract Summary In this article, we introduce a hierarchical clustering and Gaussian mixture model with expectation-maximization (EM) algorithm for detecting copy number variants (CNVs) using whole exome sequencing (WES) data. The R shiny package ‘HCMMCNVs’ is also developed for processing user-provided bam files, running CNVs detection algorithm and conducting visualization. Through applying our approach to 325 cancer cell lines in 22 tumor types from Cancer Cell Line Encyclopedia (CCLE), we show that our algorithm is competitive with other existing methods and feasible in using multiple cancer cell lines for CNVs estimation. In addition, by applying our approach to WES data of 120 oral squamous cell carcinoma (OSCC) samples, our algorithm, using the tumor sample only, exhibits more power in detecting CNVs as compared with the methods using both tumors and matched normal counterparts. Availability and implementation HCMMCNVs R shiny software is freely available at github repository https://github.com/lunching/HCMM_CNVs.and Zenodo https://doi.org/10.5281/zenodo.4593371. Supplementary information Supplementary data are available at Bioinformatics online.

Download Full-text

RefCNV: Identification of Gene-Based Copy Number Variants Using Whole Exome Sequencing

Cancer Informatics ◽

10.4137/cin.s36612 ◽

2016 ◽

Vol 15 ◽

pp. CIN.S36612 ◽

Cited By ~ 3

Author(s):

Lun-Ching Chang ◽

Biswajit Das ◽

Chih-Jian Lih ◽

Han Si ◽

Corinne E. Camalier ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Copy Number ◽

Copy Number Variants ◽

Estimation Methods ◽

Single Nucleotide Variants ◽

False Positive Error ◽

Reference Set ◽

Genome Wide ◽

Whole Exome

With rapid advances in DNA sequencing technologies, whole exome sequencing (WES) has become a popular approach for detecting somatic mutations in oncology studies. The initial intent of WES was to characterize single nucleotide variants, but it was observed that the number of sequencing reads that mapped to a genomic region correlated with the DNA copy number variants (CNVs). We propose a method RefCNV that uses a reference set to estimate the distribution of the coverage for each exon. The construction of the reference set includes an evaluation of the sources of variability in the coverage distribution. We observed that the processing steps had an impact on the coverage distribution. For each exon, we compared the observed coverage with the expected normal coverage. Thresholds for determining CNVs were selected to control the false-positive error rate. RefCNV prediction correlated significantly ( r = 0.96–0.86) with CNV measured by digital polymerase chain reaction for MET (7q31), EGFR (7p12), or ERBB2 (17q12) in 13 tumor cell lines. The genome-wide CNV analysis showed a good overall correlation (Spearman's coefficient = 0.82) between RefCNV estimation and publicly available CNV data in Cancer Cell Line Encyclopedia. RefCNV also showed better performance than three other CNV estimation methods in genome-wide CNV analysis.

Download Full-text

Whole exome sequencing is necessary to clarify ID/DD cases with de novo copy number variants of uncertain significance: Two proof-of-concept examples

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.37649 ◽

2016 ◽

Vol 170 (7) ◽

pp. 1772-1779 ◽

Cited By ~ 13

Author(s):

Elisa Giorgio ◽

Andrea Ciolfi ◽

Elisa Biamino ◽

Viviana Caputo ◽

Eleonora Di Gregorio ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Copy Number ◽

De Novo ◽

Copy Number Variants ◽

Proof Of Concept ◽

Variants Of Uncertain Significance ◽

Whole Exome ◽

Uncertain Significance

Download Full-text

Whole-exome sequencing study reveals common copy number variants in protocadherin genes associated with childhood obesity in Koreans

International Journal of Obesity ◽

10.1038/ijo.2017.12 ◽

2017 ◽

Vol 41 (4) ◽

pp. 660-663 ◽

Cited By ~ 6

Author(s):

S Moon ◽

M Y Hwang ◽

H B Jang ◽

S Han ◽

Y J Kim ◽

...

Keyword(s):

Childhood Obesity ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Copy Number ◽

Copy Number Variants ◽

Whole Exome

Download Full-text

Application of Whole-Exome Sequencing in Detecting Copy Number Variants in Patients with Developmental Delay and/or Multiple Congenital Malformations

Journal of Molecular Diagnostics ◽

10.1016/j.jmoldx.2020.05.007 ◽

2020 ◽

Vol 22 (8) ◽

pp. 1041-1049

Author(s):

Évelin A. Zanardo ◽

Fabíola P. Monteiro ◽

Samar N. Chehimi ◽

Yanca G. Oliveira ◽

Alexandre T. Dias ◽

...

Keyword(s):

Exome Sequencing ◽

Developmental Delay ◽

Whole Exome Sequencing ◽

Copy Number ◽

Congenital Malformations ◽

Copy Number Variants ◽

Whole Exome

Download Full-text

Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1911385116 ◽

2019 ◽

Vol 116 (45) ◽

pp. 22730-22736 ◽

Cited By ~ 6

Author(s):

Luca Zammataro ◽

Salvatore Lopez ◽

Stefania Bellone ◽

Francesca Pettinella ◽

Elena Bonazzoli ◽

...

Keyword(s):

Cervical Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Cell Lines ◽

Copy Number ◽

Mtor Pathway ◽

In Vivo Models ◽

Whole Exome

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.

Download Full-text