The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets.
Using ...targeted exome sequencing (
= 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC.
and
mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes.
alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast,
and
mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%-58% vs. 4%; 9%-22% vs. 0; respectively). Among LG-NMIBC tumors,
mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (
= 0.001 and
< 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in
, and
correlated with worse overall survival in HG-UTUC and occurred concurrently.
Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC.
mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.
Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual ...variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10
) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10
; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10
; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10
, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.
Abstract The genome of a cell is continuously battered by a plethora of exogenous and endogenous processes that can lead to damaged DNA. Repair mechanisms correct this damage most of the time, but ...failure to do so leaves mutations. Mutations do not occur in random manner, but rather typically follow a more or less specific pattern due to known or imputed mutational processes. Mutational signature analysis is the process by which the predominant mutational process can be inferred for a cancer and can be used in several contexts to study both the genesis of cancer and its response to therapy. Recent pan-cancer genomic efforts such as “The Cancer Genome Atlas” have identified numerous mutational signatures that can be categorized into single base substitutions, doublet base substitutions, or small insertions/deletions. Understanding these mutational signatures as they occur in non-small lung cancer could improve efforts at prevention, predict treatment response to personalized treatments, and guide the development of therapies targeting tumor evolution. For non-small cell lung cancer, several mutational signatures have been identified that correlate with exposures such as tobacco smoking and radon and can also reflect endogenous processes such as aging, APOBEC activity, and loss of mismatch repair. Herein, we provide an overview of the current knowledge of mutational signatures in non-small lung cancer.
In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features ...associated with response to ICIs in mUC.
Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology.
Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01-1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01-0.43) and single-nucleotide variant (SNV) count < 10 (OR = 0.04, 95% CI, 0.006-0.27) were identified as independent predictors of NCB to ICI in multivariable analysis (c-statistic = 0.90). None of the 16 variables were associated with clinical benefit in the taxane cohort.
This three-factor model includes genomic (SNV count >9) and clinical (NLR <5, lack of visceral metastasis) variables predictive for benefit to ICI but not taxane therapy for mUC. External validation of these hypothesis-generating results is warranted to enable use in routine clinical care.
Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a ...highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).
Immune checkpoint inhibitors (ICI) have shown clinical benefit in many types of metastatic cancers with only a few predictive biomarkers identified so far.
is commonly altered in human cancers, but ...prior studies have provided conflicting evidence regarding the association between
genomic alterations (GA) and response to ICIs. Herein, we examined the impact of loss-of-function
alterations on response and survival in patients treated with ICIs.
We studied the association between loss-of-function
alterations and the response to ICIs in two independent cohorts of six different cancer types. Seven hundred and eighty-nine patients treated at Dana-Farber Cancer Institute (DFCI; Boston, MA) and 1,250 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY) were included in the final analysis. Patients' tumors were sequenced using Oncopanel or MSK-IMPACT. RNA sequencing data from The Cancer Genome Atlas and IMvigor210 were used to investigate differences in the tumor microenvironment.
In the DFCI cohort,
GAs were associated with poor response and survival in patients with urothelial carcinoma treated with ICIs, but not those treated with platinum-based therapy. Similarly,
GAs were associated with worse outcomes in the MSKCC urothelial carcinoma cohort treated with ICIs. There was no association of
status with ICI treatment outcome in five other cancers: esophagogastric, head and neck, non-small cell lung, renal cell carcinoma, and melanoma. Immuno-inflammatory pathways were significantly reduced in expression in
altered tumors.
Our data show that
GAs were associated with reduced benefit from ICI therapy in urothelial carcinoma as well as changes in the tumor-immune microenvironment.
Telomerase reverse transcriptase (TERT) gene promoter mutations have been explored, as biomarkers of improved survival for patients with cancer receiving immune checkpoint inhibitors. We sought to ...investigate their prevalence by race and sex across different cancer types to inform patient selection in clinical trials.
In this observational study, 31 925 patients with cancer underwent next-generation sequencing of their tumors with 88% (27 970) patients self-reported being Whites, 7.1% (2273) Asians, and 5.3% (1682) Blacks. Examining the distribution of TERT promoter mutations by race, White patients with melanoma harbored more TERT promoter mutations than Asian and Black patients (OR = 25.83; 95%CI, 6.84-217.42; P < .001). In contrast, Asian patients with head and neck cancer (HNC) harbored more TERT promoter mutations compared to White patients (OR = 2.47; 95%CI, 1.39-4.37; P = .004). In addition, the distribution of TERT promoter mutations differed by sex. Males were enriched for TERT gene promoter mutations compared to females with melanoma (OR = 1.82; 95%CI, 1.53-2.16; P < .001), cancer of unknown primary (OR = 1.96; 95%CI, 1.43-2.69; P < .001), hepatobiliary (OR = 3.89; 95%CI, 2.65-5.69; P < .001), and thyroid cancers (OR = 1.42; 95%CI, 1.10-1.84; P = .0087), while females were more enriched for TERT promoter mutations compared to males for HNC (OR = 0.56; 95%CI, 0.39-0.81; P = .0021).
The prevalence of TERT gene promoter mutations varies among patients with cancer based on race and sex. These findings inform our understanding of cancer biology and can assist in the design of future clinical trials that leverage drugs targeting TERT promoter dependencies.
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