Comprehensive cross cancer analyses reveal mutational signature cancer specificity

Mutational signatures refer to distinct patterns of DNA mutations that occur in a specific context or under certain conditions.It is a powerful tool to describe cancer etiology.We conducted a study to show cancer heterogeneity and cancer specificity from the aspect of mutational signatures through collinearity analysis and machine learning techniques.Through thorough training and independent validation,our results show that while the majority of the mutational signatures are distinct,similarities between certain mutational signature pairs can be observed through both mutation patterns and mutational signature abundance.The observation can potentially assist to determine the etiology of yet elusive mutational signatures.Further analysis using machine learning approaches demonstrated moderate mutational signature cancer specificity.Skin cancer among all cancer types demonstrated the strongest mutational signature specificity.

Modeling the relationship between gene expression and mutational signature

Background:Mutational signatures computed from somatic mutations,allow an in-depth understanding of tumorigenesis and may illuminate early prevention strategies.Many studies have shown the regulation effects between somatic mutation and gene expression dysregulation.Methods:We hypothesized that there are potential associations between mutational signature and gene expression.We capitalized upon RNA-seq data to model 49 established mutational signatures in 33 cancer types.Both accuracy and area under the curve were used as performance measures in five-fold cross-validation.Results:A total of 475 models using unconstrained genes,and 112 models using protein-coding genes were selected for future inference purposes.An independent gene expression dataset on lung cancer smoking status was used for validation which achieved over 80%for both accuracy and area under the curve.Conclusion:These results demonstrate that the associations between gene expression and somatic mutations can translate into the associations between gene expression and mutational signatures.

Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia

Postzygotic mutations are acquired in normal tissues throughout an individual’s lifetime and hold clues for identifying mutagenic factors.Here,we investigated postzygotic mutation spectra of healthy individuals using optimized ultra-deep exome sequencing of the time-series samples from the same volunteer as well as the samples from different individuals.In blood,sperm,and muscle cells,we resolved three common types of mutational signatures.Signatures A and B represent clocklike mutational processes,and the polymorphisms of epigenetic regulation genes influence the proportion of signature B in mutation profiles.Notably,signature C,characterized by C>T transitions at GpCpN sites,tends to be a feature of diverse normal tissues.Mutations of this type are likely to occur early during embryonic development,supported by their relatively high allelic frequencies,presence in multiple tissues,and decrease in occurrence with age.Almost none of the public datasets for tumors feature this signature,except for 19.6%of samples of clear cell renal cell carcinoma with increased activation of the hypoxia-inducible factor 1(HIF-1)signaling pathway.Moreover,the accumulation of signature C in the mutation profile was accelerated in a human embryonic stem cell line with drug-induced activation of HIF-1α.Thus,embryonic hypoxia may explain this novel signature across multiple normal tissues.Our study suggests that hypoxic condition in an early stage of embryonic development is a crucial factor inducing C>T transitions at GpCpN sites;and individuals’genetic background may also influence their postzygotic mutation profiles.

Favorable response to immunotherapy in a pancreatic neuroendocrine tumor with temozolomide-induced high tumor mutational burden

Neuroendocrine neoplasm of the pancreas is a rare tumor with limited treatment options.Among such tumors,treatment for pancreatic neuroendocrine tumor(PanNET)G3 is the most difficult.Temozolomide(TMZ)is commonly used to treat PanNET.However,TMZ may cause tumor gene alkylation,which induces drug resistance and rapid disease progression.Herein,we present a case of a female who was diagnosed with PanNET G3 and achieved a partial response to toripalimab,an anti-programmed cell death-ligand 1(anti-PD-L1)monoclonal antibody,after multiple cycles of TMZ treatment.Genomic profiling revealed that compared with the patient’s samples collected at baseline,the postTMZ-treatment samples had markedly higher levels of tumor mutational burden(TMB)associated with characteristic alkylating mutational signature representing a positive correlation with favorable response to anti-PD-1 treatment.In addition,we observed a germline truncating mutation of MUTYH(W156*)that was considered to be pathogenic and potentially conferred to genomic instability.This case suggests that anti-PD-1 therapy could be a treatment option for PanNET patients with increased TMB after TMZ-based treatment.

Aristolochic acids exposure was not the main cause of liver tumorigenesis in adulthood

Aristolochic acids(AAs) have long been considered as a potent carcinogen due to its nephrotoxicity. Aristolochic acid I(AAI) reacts with DNA to form covalent aristolactam(AL)-DNA adducts,leading to subsequent A to T transversion mutation, commonly referred as AA mutational signature. Previous research inferred that AAs were widely implicated in liver cancer throughout Asia. In this study, we explored whether AAs exposure was the main cause of liver cancer in the context of HBV infection in China's Mainland. Totally 1256 liver cancer samples were randomly retrieved from 3 medical centers and a refined bioanalytical method was used to detect AAI-DNA adducts. 5.10% of these samples could be identified as AAI positive exposure. Whole genome sequencing suggested 8.41% of 107 liver cancer patients exhibited the dominant AA mutational signature, indicating a relatively low overall AAI exposure rate. In animal models, long-term administration of AAI barely increased liver tumorigenesis in adult mice, opposite from its tumor-inducing role when subjected to infant mice. Furthermore, AAI induced dose-dependent accumulation of AA-DNA adduct in target organs in adult mice, with the most detected in kidney instead of liver. Taken together, our data indicate that AA exposure was not the major threat of liver cancer in adulthood.

Gene mutations of esophageal squamous cell carcinoma based on next-generation sequencing

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers without effective therapy. To explore potential molecular targets in ESCC, we quantified the mutation spectrum and explored the relationship between gene mutation and clinicopathological characteristics and programmed death-ligand 1 (PD-L1) expression.Methods: Between 2015 and 2019, 29 surgically resected ESCC tissues and adjacent normal tissues from the Fourth Hospital of Hebei Medical University were subjected to targeted next-generation sequencing. The expression levels of PD-L1 were detected by immunohistochemistry. Mutational signatures were extracted from the mutation count matrix by using non-negative matrix factorization. The relationship between detected genomic alterations and clinicopathological characteristics and PD-L1 expression was estimated by Spearman rank correlation analysis.Results: The most frequently mutated gene wasTP53 (96.6%, 28/29), followed byNOTCH1 (27.6%, 8/29),EP300 (17.2%, 5/29), andKMT2C (17.2%, 5/29). The most frequently copy number amplified and deleted genes wereCCND1/FGF3/FGF4/FGF19 (41.4%, 12/29) andCDKN2A/2B (10.3%, 3/29). By quantifying the contribution of the mutational signatures to the mutation spectrum, we found that the contribution of signature 1, signature 2, signature 10, signature 12, signature 13, and signature 17 was relatively high. Further analysis revealed genetic variants associated with cell cycle, chromatin modification, Notch, and Janus kinase-signal transducer and activator of transcription signaling pathways, which may be key pathways in the development and progression of ESCC. Evaluation of PD-L1 expression in samples showed that 13.8% (4/29) of samples had tumor proportion score ≥1%. 17.2% (5/29) of patients had tumor mutation burden (TMB) above 10 mut/Mb. All samples exhibited microsatellite stability. TMB was significantly associated with lymph node metastasis (r = 0.468,P = 0.010), but not significantly associated with PD-L1 expression (r = 0.246,P = 0.198). There was no significant correlation between PD-L1 expression and detected gene mutations (allP > 0.05).Conclusion: Our research initially constructed gene mutation profile related to surgically resected ESCC in high-incidence areas to explore the mechanism underlying ESCC development and potential therapeutic targets.

Host-specific asymmetric accumulation of mutation types reveals that the origin of SARS-CoV-2 is consistent with a natural process

The capacity of RNA viruses to adapt to new hosts and rapidly escape the host immune system is largely attributable to de novo genetic diversity that emerges through mutations in RNA.Although the molecular spectrum of de novo mutations—the relative rates at which various base substitutions occur—are widely recognized as informative toward understanding the evolution of a viral genome,little attention has been paid to the possibility of using molecular spectra to infer the host origins of a virus.Here,we characterize the molecular spectrum of de novo mutations for SARS-CoV-2 from transcriptomic data obtained from virus-infected cell lines,enabled by the use of sporadic junctions formed during discontinuous transcription as molecular barcodes.We find that de novo mutations are generated in a replication-independent manner,typically on the genomic strand,and highly dependent on mutagenic mechanisms specific to the host cellular environment.De novo mutations will then strongly influence the types of base substitutions accumulated during SARS-CoV-2 evolution,in an asymmetric manner favoring specific mutation types.Consequently,similarities between the mutation spectra of SARS-CoV-2 and the bat coronavirus RaTG13,which have accumulated since their divergence strongly suggest that SARS-CoV-2 evolved in a host cellular environment highly similar to that of bats before its zoonotic transfer into humans.Collectively,our findings provide data-driven support for the natural origin of SARS-CoV-2.

Pancreatic cancer: genetics, disease progression, therapeutic resistance and treatment strategies

Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States.It has a very low five-year survival rate(<5%)in the United States as well as in the world(about 9%).The current gemcitabine-based therapy soon becomes ineffective because treatment resistance and surgical resection also provides only selective benefit.Signature mutations in pancreatic cancer confer chemoresistance by deregulating the cell cycle and promoting anti-apoptotic mechanisms.The stroma-rich tumor microenvironment impairs drug delivery and promotes tumor-specific immune escape.All these factors render the current treatment incompetent and prompt an urgent need for new,improved therapy.In this review,we have discussed the genetics of pancreatic cancer and its role in tumor evolution and treatment resistance.We have also evaluated new treatment strategies for pancreatic cancer,like targeted therapy and immunotherapy.