APOBEC mutagenesis

Our results and statistical framework were validated in independent cohorts of 23 non-metastatic UCs and 3,744 samples of 17 metastatic cancers, identifying cancer-type-specific drivers. Our study highlights the role of APOBEC in cancer development and may contribute to developing novel targeted therapy options for APOBEC-driven cancers.

Here we identify predictive markers of response, based on whole-genome DNA (n = 70) and RNA-sequencing (n = 41) of fresh metastatic biopsy samples, collected prior to treatment with pembrolizumab...The abundance of T cells and stromal cells, as reflected by the TSE score is confirmed by immunofluorescence in tumor tissue, and its good performance in two independent ICI-treated cohorts of patients with mUC (IMvigor210) and muscle-invasive UC (ABACUS) validate the predictive power of the TSE score. In conclusion, the TSE score represents a clinically applicable metric that potentially supports the prospective selection of patients with mUC for ICI treatment.

We show that the frequency of TP53 biallelic inactivation increases dramatically in early precancerous lesion stage while CNAs and APOBEC mutagenesis substantially increase at late stages. TP53 biallelic loss is the prerequisite for the development of CNAs of genes in cell cycle, DNA repair, and apoptosis pathways, suggesting it might be one of the earliest steps initiating malignant transformation.

APOBEC family was associated with genomic instability, DNA damage-related pathways, and cell cycle in LUAD. The AMES-related gene signature had a great potential to indicate the prognosis and guide immunotherapy/chemotherapy for patients suffering from LUAD.

We applied DLP to 7 MM patients obtaining 800-1600 single cell whole genomes per patient. All canonical IgH translocations identified by FISH were recovered in the scWGS data. Single cell copy number heterogeneity was observed in all but 1 patient, including heterogeneity affecting known drivers.

Tyrosine kinase inhibitors induce APOBEC3A, which promotes the emergence of drug-tolerant persister clones.

Functional screening identifies eight crucial drivers for androgen receptor (AR)-targeted therapy resistance in PCa that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3, and AR. These results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring AR-targeted therapy resistance in PCa.

Based on the relatively high rates of cure in HPV+ HNSCC, deintensification of therapy to reduce treatment-related morbidity is being studied at many institutions. Tumor subclassification based on oncogenic subtypes may help guide the selection of therapeutic intensity or modality for patients with HPV+ HNSCC.

Conclusively, HPV insertion/integration, APOBEC mutagenesis, and HLA polymorphisms are high-risk factors for cervical cancer and may be causes of genome instability and somatic mutations. This study provides experimental data for revealing the molecular mechanism of cervical cancer.

Conclusions An association between APOBEC mutagenesis and macrophages M1 infiltration was observed, suggesting that APOBEC processes may uniquely shape the TME in cancer. Going forward, we will investigate the impact of other mutagenesis processes, such as homologous recombination deficiency (HRD), on the TME, to gain a comprehensive understanding of the interplay between various mutational processes and the TME.

Among these, the presence of base excision repair deficiencies show remarkably poor prognosis in the cohort. In this work, we provide insights on the mutational aetiology and changes enabling the transition from pre-neoplastic to advanced oesophageal adenocarcinoma.

Lastly, we observed that the top identified driver genes, including NIRF-specific recurrently mutated genes, were selected based on a given mutational process, thus reflecting distinct natural disease histories.ConclusionOur results show that the NIRF OSCCs are likely driven by endogenous mutagenesis, with no apparent direct link to known exogenous exposures, and that these cancers have distinguishable disease histories. Our study provides a basis for more comprehensive future investigations of this emerging cancer subtype of unclear etiology and increasing incidence.

Simultaneously, A3A is associated with immunotherapy response which is predicted by TIDE algorithm, validated in a clinical cohort and further confirmed in mouse models. These findings systematically elucidate the clinical relevance, immunological characteristics, prognostic value for immunotherapy and underlying mechanisms of APOBEC mutagenesis in ESCC, which demonstrate great potential in clinical utility to facilitate clinical decisions.

Nonkeratinizing SCC and anaplastic carcinoma shared almost no somatic mutations, suggesting that each locally and independently arose in the MCT. We demonstrated that two MCT-SCCs with different histologic findings were highly heterogeneous tumors with clearly different clones associated with APOBEC-mediated mutagenesis, suggesting the importance of evaluating intratumor histological and genetic heterogeneity among multiple sites of MCT-SCC.

UHTMB MBC is a rare, yet clinically important subset of clinically advanced breast cancer driven by APOBEC mutagenesis, with high incidence of ER+ lobular histology and frequent alterations in CDH1 and PIK3CA. In addition to potential benefit from ICI based treatment, UHTMB MBC present with a high frequency of HER2-low status which may impact therapy decisions for this rare disease. >

In hepatocellular carcinoma, A3A has been shown to be the only APOBEC3 family member capable of driving tumor formation in the presence of p53 downregulation, while studies in breast cancer have suggested A3B as a driver of tamoxifen resistance...In silico data has shown differential roles for A3A and A3B as it relates to the tumor/immune environment; we hypothesize that this might result in subunit specific response and resistance to anti-PD-1 immunotherapy. Elucidation of the A3 specific driver of APOBEC mutagenesis in urothelial carcinoma will help identity a predictive and/or prognostic biomarker to anti-PD-1 checkpoint immune inhibition.

HAS tumors have slower clonal expansion and older age at onset compared to LAS, particularly in heavy smokers, consistent with high proportions of newly generated, unmutated cells in HAS. These findings show how heterogeneity in mutational burden across competing mutational processes and cell types contributes to tumor development, with important clinical implications.

Finally, contrary to conventional understanding, our study reveals that driver mutations in FOXA1 induced by APOBEC3B, not mutations in AR, evolutionarily outcompete other driver mutations and eventually dominate the resistant tumors. Collectively, these results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring targeted therapy resistance and could be the potential therapeutic targets to overcome resistance.

APOBEC+ HR+ HER2- patients had shorter TTD on first-line ET plus CDK4/6i relative to APOBEC- patients. Further research is needed to optimize the treatment of APOBEC+ HR+ HER2- BC and to investigate the efficacy of immunotherapeutic strategies in this population.

The etiology of SBS17 is as yet not established, but it has been proposed to be caused by reactive oxygen species. To conclude, ALL patients with multiple relapses showed an increased prevalence and large variety of interplaying mutational processes at diagnosis (36%) and final relapse (61%), with intrinsic or therapy induced origins.

UHTMB MBC is a rare but clinically important subset in breast cancer that could have high response rates to single agent pembrolizumab. This phenotype is driven by APOBEC mutagenesis, more often seen in ER+ lobular cancers, and have higher frequencies of MSI-high status and mutations in CDH1 and PIK3CA.

APOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.

We demonstrate that APOBEC effectively deaminates NFE2L2 at the locations that confer high cancer effect. Overall, we demonstrate that APOBEC activity can lead to mutations in NFE2L2 that have large contributions to cancer cell growth and survival, and that NFE2L2 is an attractive potential target for therapeutic intervention.

Furthermore, using machine learning approaches, a prognostic APOBEC mutagenesis-related model was established and validated in different BLCA cohorts. Our study illustrates the characterization of APOBECs and APOBEC mutagenesis in multiple cancer types and highlights its potential value as a promising biomarker for prognosis and immunotherapy in BLCA.

Multi-omic data may facilitate better prognostication and selection of therapeutic interventions in patients with G3pT1 NMIBC. These findings demonstrate the potential for improving the management of high-risk NMIBC patients and warrant further prospective validation.

Our results show that APOBEC mutagenesis recurrently targets various known drivers of BC initiation, progression, and endocrine resistance.

Approximately 60% of cells sequenced were annotated as T-cells and natural killer T-cells by SingleR. We treated mice bearing UPPA primary bladder tumors with anti-PD-1 antibody and observed significant tumor growth inhibition.

We demonstrate that matched pre-invasive and invasive lesions fall in two distinct phylogenetic evolutionary groups: those that have a shared somatic common ancestor and those that do not. SCA pre-invasive lesions exhibit elevated APOBEC mutagenesis and chromosomal instability, shedding some light on the process of malignant transformation.

Further, the relative risk of enriched APOBEC signature mutations was higher in endometriosis patients who were carriers of APOBEC3A/3B germline deletion, a common polymorphism in East Asians which involves the complete loss of APOBEC3B coding region. Our results illustrate the significance of APOBEC induced mutagenesis in driving the genomic heterogeneity of endometriosis.

In addition, APOBEC mutational process destroys DNA double-strand break repair pathway, and bladder cancer patients with high APOBEC activity, though with homologous recombination proficient, show a significantly longer overall survival with platinum regimens. These findings help to understand how mutational processes act on the genome to promote carcinogenesis, and further, presents novel insights for cancer prevention and treatment, as our results showing, APOBEC mutagenesis and HRD synergistically contributed to the clinical benefits of platinum-based treatment.

In human breast cancers, the relationship between APOBEC mutagenesis and immunogenicity varied by breast cancer subtype and the frequency of subclonal mutations. This work provides a mechanistic basis for the sensitivity of APOBEC tumors to checkpoint inhibitors and suggests a rationale for using APOBEC mutational signatures and clonality as biomarkers predicting immunotherapy response in HER2-positive breast cancers.

Evidence for APOBEC mutagenesis is present in >30% of metastatic breast cancers and associated with resistance to ET. Unlike ESR1 mutations, which are acquired as a late event in metastatic HR+ BCs, APOBEC mutagenesis is commonly present in paired primary and metastatic BCs, indicating its relatively early onset and potential role in driving the poor prognosis of these cancers.

APOBEC+ occurs in ~7% of BC and is more common in ILC and metastatic lesions. APOBEC+ HR+HER2- pts had shorter TTD and OS on SOC ET+CDK4/6i relative to APOBEC- pts. However, TTD on ICI tended to be longer in APOBEC+ pts, but our data is limited, and more research is needed.

High TMB alone does not strongly correlate with immune infiltrate or immune response gene signatures in MBC. Within TMB-H MBC, concurrent mutations in MSI-H and KMT2D are associated with an immune responsive TME while mutations in PIK3CA, CHEK2, CBFB, amplifications of CCND1, FGF19, FGF4, and MMLT6, and expression of IHC-AR are associated with an immune non-responsive TME. Co-occurring biomarkers within TMB-H breast cancer warrant evaluation in prospective cohorts for response or resistance to ICI to help develop composite biomarkers in breast cancer.

Using paired sequencing of host somatic exomes, transcriptomes, and viral genomes, we demonstrated for the first-time definitive evidence of concordance between tumor and viral APOBEC mutagenesis. This finding provides a missing link connecting APOBEC mutagenesis in host and virus and supports a common mechanism driving APOBEC dysregulation.

Using paired sequencing of somatic exomes, transcriptomes, and viral genomes of HPV+ HNSCC samples, here, we demonstrate for the first time concordance between tumor and viral APOBEC mutagenesis in HPV+ HNSCC, supporting existing hypotheses regarding the role of APOBEC in viral restriction and resultant off-target host-genome mutagenesis.

RB1&TP53 co-alterations are strongly associated with genomic biomarkers of response to ICIs in MIBCs.