Common germline-somatic variant interactions in advanced urothelial cancer

Vosoughi, Aram; Zhang, Tuo; Shohdy, Kyrillus S.; Vlachostergios, Panagiotis J.; Wilkes, David; Bhinder, Bhavneet; Tagawa, Scott T.; Nanus, David M.; Molina, Ana M.; Beltran, Himisha; Sternberg, Cora N.; Motanagh, Samaneh; Robinson, Brian D.; Xiang, Jenny; Fan, Xiao; Chung, Wendy K.; Rubin, Mark A.; Elemento, Olivier; Sboner, Andrea; Mosquera, Juan Miguel; Faltas, Bishoy

doi:10.1038/s41467-020-19971-8

Cited by 24 publications

(19 citation statements)

References 77 publications

(140 reference statements)

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“…However, LOH at a few specific loci is different from generalized LOH produced by mitotic recombination, which entails a loss of complementation for thousands of genes distal to the site of crossing over, including numerous non-driver genes that are essential for the cell [ 62 , 63 , 64 ], and is more likely to be overall deleterious for cells. In tumors, gene expression is higher for genes conserved with unicellular organisms, which have generally systemic effects (such as housekeeping genes) than for genes of metazoan origin [ 65 , 66 ], especially in polyploid cancer cells [ 67 ]; therefore, the coordinated expression of interacting multicellularity and unicellularity processes is lost in cancer progression, and LOH may enhance this mismatch.…”

Section: Discussionmentioning

confidence: 99%

Polyploidy as an Adaptation against Loss of Heterozygosity in Cancer

Archetti

2022

IJMS

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Polyploidy is common in cancer cells and has implications for tumor progression and resistance to therapies, but it is unclear whether it is an adaptation of the tumor or the non-adaptive effect of genomic instability. I discuss the possibility that polyploidy reduces the deleterious effects of loss of heterozygosity, which arises as a consequence of mitotic recombination, and which in diploid cells leads instead to the rapid loss of complementation of recessive deleterious mutations. I use computational predictions of loss of heterozygosity to show that a population of diploid cells dividing by mitosis with recombination can be easily invaded by mutant polyploid cells or cells that divide by endomitosis, which reduces loss of complementation, or by mutant cells that occasionally fuse, which restores heterozygosity. A similar selective advantage of polyploidy has been shown for the evolution of different types of asexual reproduction in nature. This provides an adaptive explanation for cyclical ploidy, mitotic slippage and cell fusion in cancer cells.

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Section: Discussionmentioning

confidence: 99%

Polyploidy as an Adaptation against Loss of Heterozygosity in Cancer

Archetti

2022

IJMS

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“…Thus, in the 1000 Genomes Project, the ratio of variants by race was determined [ 55 ]. Associations between somatic and germline variants in several carcinomas have been confirmed using TCGA information [ 56 , 57 , 58 ]. This indicated the interaction of germline-somatic variants in tumorigenesis and assisted in understanding the mechanisms of cancer risk variants.…”

Section: Deposition Application and Indexing Of Genomic Variation Inf...mentioning

confidence: 99%

New Drug Development and Clinical Trial Design by Applying Genomic Information Management

Gim

2022

Pharmaceutics

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Depending on the patients’ genotype, the same drug may have different efficacies or side effects. With the cost of genomic analysis decreasing and reliability of analysis methods improving, vast amount of genomic information has been made available. Several studies in pharmacology have been based on genomic information to select the optimal drug, determine the dose, predict efficacy, and prevent side effects. This paper reviews the tissue specificity and genomic information of cancer. If the tissue specificity of cancer is low, cancer is induced in various organs based on a single gene mutation. Basket trials can be performed for carcinomas with low tissue specificity, confirming the efficacy of one drug for a single gene mutation in various carcinomas. Conversely, if the tissue specificity of cancer is high, cancer is induced in only one organ based on a single gene mutation. An umbrella trial can be performed for carcinomas with a high tissue specificity. Some drugs are effective for patients with a specific genotype. A companion diagnostic strategy that prescribes a specific drug for patients selected with a specific genotype is also reviewed. Genomic information is used in pharmacometrics to identify the relationship among pharmacokinetics, pharmacodynamics, and biomarkers of disease treatment effects. Utilizing genomic information, sophisticated clinical trials can be designed that will be better suited to the patients of specific genotypes. Genomic information also provides prospects for innovative drug development. Through proper genomic information management, factors relating to drug response and effects can be determined by selecting the appropriate data for analysis and by understanding the structure of the data. Selecting pre-processing and appropriate machine-learning libraries for use as machine-learning input features is also necessary. Professional curation of the output result is also required. Personalized medicine can be realized using a genome-based customized clinical trial design.

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“…Beyond the direct consequences of LOH on bona fide cancer genes, particularly tumor suppressor genes, numerous non-driver genes located nearby or distally on the same chromosome arm may also undergo LOH. The establishment of LOH maps by cytogenetics [24] or, more recently, by genome-wide copy number analyses and genome sequencing, have enabled identification of chromosomal regions lost in different tumor types [25][26][27][28]. A study of~10 5 LOH events in 363 glioblastoma and 513 ovarian cancer samples revealed that LOH selectively occurs in early replicating regions, especially near RNA pol II-bound transcription start sites [29].…”

Section: Loh Leads To Loss Of Non-driver Genes and Endows Cancer Cells With Unique Vulnerabilitiesmentioning

confidence: 99%

Targeting Loss of Heterozygosity: A Novel Paradigm for Cancer Therapy

Zhang

Sjöblom

2021

Pharmaceuticals

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Loss of heterozygosity (LOH) is a common genetic event in the development of cancer. In certain tumor types, LOH can affect more than 20% of the genome, entailing loss of allelic variation in thousands of genes. This reduction of heterozygosity creates genetic differences between tumor and normal cells, providing opportunities for development of novel cancer therapies. Here, we review and summarize (1) mutations associated with LOH on chromosomes which have been shown to be promising biomarkers of cancer risk or the prediction of clinical outcomes in certain types of tumors; (2) loci undergoing LOH that can be targeted for development of novel anticancer drugs as well as (3) LOH in tumors provides up-and-coming possibilities to understand the underlying mechanisms of cancer evolution and to discover novel cancer vulnerabilities which are worth a further investigation in the near future.

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Common germline-somatic variant interactions in advanced urothelial cancer

Cited by 24 publications

References 77 publications

Polyploidy as an Adaptation against Loss of Heterozygosity in Cancer

Polyploidy as an Adaptation against Loss of Heterozygosity in Cancer

New Drug Development and Clinical Trial Design by Applying Genomic Information Management

Targeting Loss of Heterozygosity: A Novel Paradigm for Cancer Therapy

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