Rare germline structural variants increase risk for pediatric solid tumors.

Pediatric solid tumors are rare malignancies that represent a leading cause of death by disease among children in developed countries. The early age-of-onset of these tumors suggests that germline genetic factors are involved, yet conventional germline testing for short coding variants in established predisposition genes only identifies pathogenic events in 10-15% of patients. Here, we examined the role of germline structural variants (SVs)-an underexplored form of germline variation-in pediatric extracranial solid tumors using germline genome sequencing of 1,766 affected children, their 943 unaffected relatives, and 6,665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and a four-fold increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we revealed burdens of ultra-rare SVs that cause loss-of-function of highly expressed, mutationally intolerant, neurodevelopmental genes, as well as noncoding SVs predicted to disrupt three-dimensional chromatin domains in neural crest-derived tissues. Collectively, our results implicate rare germline SVs as a predisposing factor to pediatric solid tumors that may guide future studies and clinical practice.

Cancer Type and Histology Influence Cutaneous Immunotherapy Toxicities: A Multi-Institutional Cohort Study.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) are the most common toxicities to occur in the setting of immune checkpoint inhibitor (ICI) therapy. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. OBJECTIVE: To investigate the influence of cancer type and histology on the development of cirAEs in the setting of ICI therapy and survival outcomes. METHODS: This retrospective cohort study included patients between December 1, 2011, and October 30, 2020. They received ICIs from 2011-2020 with follow-up of outcomes through October 2021. We identified 3,668 ICI recipients who were seen at Mass General Brigham and Dana-Farber. Of these, 669 developed cirAEs. Records that were incomplete or categories of insufficient sample size were excluded from the study cohort. Multivariate Cox proportional hazards models were utilized to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI initiation, and year of ICI initiation. Time-varying Cox proportional hazards modeling was utilized to examine the impact of cirAE development on mortality. RESULTS: Compared to other non-epithelial cancers (neuroendocrine, leukemia, lymphoma, myeloma, sarcoma, and central nervous system malignancies), cutaneous squamous cell carcinoma (cSCC) (HR = 3.57, p < 0.001), melanoma (HR = 2.09, p < 0.001), head and neck adenocarcinoma (HR = 2.13, p = 0.009), genitourinary transitional cell carcinoma (HR = 2.15, p < 0.001), and genitourinary adenocarcinoma (HR = 1.53, p = 0.037) were at significantly higher risk of cirAEs in multivariate analyses. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma (HR = 0.37, p < 0.001) and cSCC (HR = 0.51, p = 0.011). CONCLUSIONS: The highest rate of cirAEs and subsequent survival benefits were observed in cutaneous malignancies treated with ICIs. This study improves our understanding of patients who are at highest risk of developing cirAEs and would, therefore, benefit from appropriate counseling and closer monitoring by their oncologists and dermatologists throughout their ICI therapy. Limitations include its retrospective nature and cohort from one geography.

Lung cancer in patients who have never smoked - an emerging disease.

Lung cancer is the most common cause of cancer-related deaths globally. Although smoking-related lung cancers continue to account for the majority of diagnoses, smoking rates have been decreasing for several decades. Lung cancer in individuals who have never smoked (LCINS) is estimated to be the fifth most common cause of cancer-related deaths worldwide in 2023, preferentially occurring in women and Asian populations. As smoking rates continue to decline, understanding the aetiology and features of this disease, which necessitate unique diagnostic and treatment paradigms, will be imperative. New data have provided important insights into the molecular and genomic characteristics of LCINS, which are distinct from those of smoking-associated lung cancers and directly affect treatment decisions and outcomes. Herein, we review the emerging data regarding the aetiology and features of LCINS, particularly the genetic and environmental underpinnings of this disease as well as their implications for treatment. In addition, we outline the unique diagnostic and therapeutic paradigms of LCINS and discuss future directions in identifying individuals at high risk of this disease for potential screening efforts.

Obesity shapes selection for driver mutations in cancer.

Obesity is a leading risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. Here, we examined the relationship between obesity and tumor genotype in two large clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma, and cancers of unknown primary, independent of clinical covariates and genetic ancestry. Obesity is therefore a putative driver of etiologic heterogeneity across cancers.

A comprehensive analysis of clinical and polygenic germline influences on somatic mutational burden.

Tumor mutational burden (TMB), the total number of somatic mutations in the tumor, and copy number burden (CNB), the corresponding measure of aneuploidy, are established fundamental somatic features and emerging biomarkers for immunotherapy. However, the genetic and non-genetic influences on TMB/CNB and, critically, the manner by which they influence patient outcomes remain poorly understood. Here, we present a large germline-somatic study of TMB/CNB with >23,000 individuals across 17 cancer types, of which 12,000 also have extensive clinical, treatment, and overall survival (OS) measurements available. We report dozens of clinical associations with TMB/CNB, observing older age and male sex to have a strong effect on TMB and weaker impact on CNB. We additionally identified significant germline influences on TMB/CNB, including fine-scale European ancestry and germline polygenic risk scores (PRSs) for smoking, tanning, white blood cell counts, and educational attainment. We quantify the causal effect of exposures on somatic mutational processes using Mendelian randomization. Many of the identified features associated with TMB/CNB were additionally associated with OS for individuals treated at a single tertiary cancer center. For individuals receiving immunotherapy, we observed a complex relationship between PRSs for educational attainment, self-reported college attainment, TMB, and survival, suggesting that the influence of this biomarker may be substantially modified by socioeconomic status. While the accumulation of somatic alterations is a stochastic process, our work demonstrates that it can be shaped by host characteristics including germline genetics.

Development and validation of time-to-event models to predict metastatic recurrence of localized cutaneous melanoma.

BACKGROUND: The recent expansion of immunotherapy for stage IIB/IIC melanoma highlights a growing clinical need to identify patients at high risk of metastatic recurrence and, therefore, most likely to benefit from this therapeutic modality. OBJECTIVE: To develop time-to-event risk prediction models for melanoma metastatic recurrence. METHODS: Patients diagnosed with stage I/II primary cutaneous melanoma between 2000 and 2020 at Mass General Brigham and Dana-Farber Cancer Institute were included. Melanoma recurrence date and type were determined by chart review. Thirty clinicopathologic factors were extracted from electronic health records. Three types of time-to-event machine-learning models were evaluated internally and externally in the distant versus locoregional/nonrecurrence prediction. RESULTS: This study included 954 melanomas (155 distant, 163 locoregional, and 636 1:2 matched nonrecurrences). Distant recurrences were associated with worse survival compared to locoregional/nonrecurrences (HR: 6.21, P < .001) and to locoregional recurrences only (HR: 5.79, P < .001). The Gradient Boosting Survival model achieved the best performance (concordance index: 0.816; time-dependent AUC: 0.842; Brier score: 0.103) in the external validation. LIMITATIONS: Retrospective nature and cohort from one geography. CONCLUSIONS: These results suggest that time-to-event machine-learning models can reliably predict the metastatic recurrence from localized melanoma and help identify high-risk patients who are most likely to benefit from immunotherapy.

Prediction and stratification of longitudinal risk for chronic obstructive pulmonary disease across smoking behaviors.

Smoking is the leading risk factor for chronic obstructive pulmonary disease (COPD) worldwide, yet many people who never smoke develop COPD. We perform a longitudinal analysis of COPD in the UK Biobank to derive and validate the Socioeconomic and Environmental Risk Score which captures additive and cumulative environmental, behavioral, and socioeconomic exposure risks beyond tobacco smoking. The Socioeconomic and Environmental Risk Score is more predictive of COPD than smoking status and pack-years. Individuals in the highest decile of the risk score have a greater risk for incident COPD compared to the remaining population. Never smokers in the highest decile of exposure risk are more likely to develop COPD than previous and current smokers in the lowest decile. In general, the prediction accuracy of the Social and Environmental Risk Score is lower in non-European populations. While smoking status is often considered in screening COPD, our finding highlights the importance of other non-smoking environmental and socioeconomic variables.

Somatic mutations reveal hyperactive Notch signaling and racial disparities in prurigo nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin disease that disproportionately affects African Americans and is characterized by pruritic skin nodules of unknown etiology. Little is known about genetic alterations in PN pathogenesis, especially relating to somatic events which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 PN patients and 10 atopic dermatitis (AD) patients for comparison. Somatic mutational analysis revealed that PN lesional skin harbors pervasive somatic mutations in fibrotic, neurotropic, and cancer-associated genes. Nonsynonymous mutations were most frequent in NOTCH1 and the Notch signaling pathway, a regulator of cellular proliferation and tissue fibrosis, and NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, showed that recurrently deleted and downregulated genes in PN lesional skin are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, multi-center data revealed a significantly increased risk of NOTCH1-associated diseases in PN patients. In characterizing the somatic landscape of PN, we uncover novel insights into its pathophysiology and identify a role for dysregulated Notch signaling in PN.

Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance.

Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs T cell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of MTA-depleting enzymes reverses this immunosuppressive effect, increasing TILs and drastically impairing tumor growth and importantly, synergizes well with ICI therapy. As several studies have shown ICI resistance in 9p21/MTAP null/low patients, we propose that MTA degrading therapeutics may have substantial therapeutic benefit in these patients by enhancing ICI effectiveness.

A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus.

To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.

Collaborative privacy-preserving analysis of oncological data using multiparty homomorphic encryption.

Real-world healthcare data sharing is instrumental in constructing broader-based and larger clinical datasets that may improve clinical decision-making research and outcomes. Stakeholders are frequently reluctant to share their data without guaranteed patient privacy, proper protection of their datasets, and control over the usage of their data. Fully homomorphic encryption (FHE) is a cryptographic capability that can address these issues by enabling computation on encrypted data without intermediate decryptions, so the analytics results are obtained without revealing the raw data. This work presents a toolset for collaborative privacy-preserving analysis of oncological data using multiparty FHE. Our toolset supports survival analysis, logistic regression training, and several common descriptive statistics. We demonstrate using oncological datasets that the toolset achieves high accuracy and practical performance, which scales well to larger datasets. As part of this work, we propose a cryptographic protocol for interactive bootstrapping in multiparty FHE, which is of independent interest. The toolset we develop is general-purpose and can be applied to other collaborative medical and healthcare application domains.

Machine learning for genetics-based classification and treatment response prediction in cancer of unknown primary.

Cancer of unknown primary (CUP) is a type of cancer that cannot be traced back to its primary site and accounts for 3-5% of all cancers. Established targeted therapies are lacking for CUP, leading to generally poor outcomes. We developed OncoNPC, a machine-learning classifier trained on targeted next-generation sequencing (NGS) data from 36,445 tumors across 22 cancer types from three institutions. Oncology NGS-based primary cancer-type classifier (OncoNPC) achieved a weighted F1 score of 0.942 for high confidence predictions ([Formula: see text]) on held-out tumor samples, which made up 65.2% of all the held-out samples. When applied to 971 CUP tumors collected at the Dana-Farber Cancer Institute, OncoNPC predicted primary cancer types with high confidence in 41.2% of the tumors. OncoNPC also identified CUP subgroups with significantly higher polygenic germline risk for the predicted cancer types and with significantly different survival outcomes. Notably, patients with CUP who received first palliative intent treatments concordant with their OncoNPC-predicted cancers had significantly better outcomes (hazard ratio (HR) = 0.348; 95% confidence interval (CI) = 0.210-0.570; P = [Formula: see text]). Furthermore, OncoNPC enabled a 2.2-fold increase in patients with CUP who could have received genomically guided therapies. OncoNPC thus provides evidence of distinct CUP subgroups and offers the potential for clinical decision support for managing patients with CUP.

Germline mechanisms of immunotherapy toxicities in the era of genome-wide association studies.

Cancer immunotherapy has revolutionized the treatment of advanced cancers and is quickly becoming an option for early-stage disease. By reactivating the host immune system, immunotherapy harnesses patients' innate defenses to eradicate the tumor. By putatively similar mechanisms, immunotherapy can also substantially increase the risk of toxicities or immune-related adverse events (irAEs). Severe irAEs can lead to hospitalization, treatment discontinuation, lifelong immune complications, or even death. Many irAEs present with similar symptoms to heritable autoimmune diseases, suggesting that germline genetics may contribute to their onset. Recently, genome-wide association studies (GWAS) of irAEs have identified common germline associations and putative mechanisms, lending support to this hypothesis. A wide range of well-established GWAS methods can potentially be harnessed to understand the etiology of irAEs specifically and immunotherapy outcomes broadly. This review summarizes current findings regarding germline effects on immunotherapy outcomes and discusses opportunities and challenges for leveraging germline genetics to understand, predict, and treat irAEs.

Prediction and stratification of longitudinal risk for chronic obstructive pulmonary disease across smoking behaviors.

Smoking is the leading risk factor for chronic obstructive pulmonary disease (COPD) worldwide, yet many people who never smoke develop COPD. We hypothesize that considering other socioeconomic and environmental factors can better predict and stratify the risk of COPD in both non-smokers and smokers. We performed longitudinal analysis of COPD in the UK Biobank to develop the Socioeconomic and Environmental Risk Score (SERS) which captures additive and cumulative environmental, behavioral, and socioeconomic exposure risks beyond tobacco smoking. We tested the ability of SERS to predict and stratify the risk of COPD in current, previous, and never smokers of European and non-European ancestries in comparison to a composite genome-wide polygenic risk score (PGS). We tested associations using Cox regression models and assessed the predictive performance of models using Harrell's C index. SERS (C index = 0.770, 95% CI 0.756 to 0.784) was more predictive of COPD than smoking status (C index = 0.738, 95% CI 0.724 to 0.752), pack-years (C index = 0.742, 95% CI 0.727 to 0.756). Compared to the remaining population, individuals in the highest decile of the SERS had hazard ratios (HR) = 7.24 (95% CI 6.51 to 8.05, P < 0.0001) for incident COPD. Never smokers in the highest decile of exposure risk were more likely to develop COPD than previous and current smokers in the lowest decile with HR=4.95 (95% CI 1.56 to 15.69, P=6.65×10-3) and 2.92 (95%CI 1.51 to 5.61, P=1.38×10-3), respectively. In general, the prediction accuracy of SERS was lower in the non-European populations compared to the European evaluation set. In addition to genetic factors, socioeconomic and environmental factors beyond smoking can predict and stratify COPD risk for both non- and smoking individuals. Smoking status is often considered in screening; other non-smoking environmental and non-genetic variables should be evaluated prospectively for their clinical utility.

Germline Cancer Gene Expression Quantitative Trait Loci Are Associated with Local and Global Tumor Mutations.

Somatic mutations drive cancer development and are relevant to patient responses to treatment. Emerging evidence shows that variations in the somatic genome can be influenced by the germline genetic background. However, the mechanisms underlying these germline-somatic associations remain largely obscure. We hypothesized that germline variants can influence somatic mutations in a nearby cancer gene ("local impact") or a set of recurrently mutated cancer genes across the genome ("global impact") through their regulatory effect on gene expression. To test this hypothesis, tumor targeted sequencing data from 12,413 patients across 11 cancer types in the Dana-Farber Profile cohort were integrated with germline cancer gene expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression Project. Variants that upregulate ATM expression were associated with a decreased risk of somatic ATM mutations across 8 cancer types. GLI2, WRN, and CBFB eQTL were associated with global tumor mutational burden of cancer genes in ovarian cancer, glioma, and esophagogastric carcinoma, respectively. An EPHA5 eQTL was associated with mutations in cancer genes specific to colorectal cancer, and eQTL related to expression of APC, WRN, GLI1, FANCA, and TP53 were associated with mutations in genes specific to endometrial cancer. These findings provide evidence that germline-somatic associations are mediated through expression of specific cancer genes, opening new avenues for research on the underlying biological processes. SIGNIFICANCE: Analysis of associations between the germline genetic background and somatic mutations in patients with cancer suggests that germline variants can influence local and global tumor mutations by altering expression of cancer-related genes. See related commentary by Kar, p. 1165.

Graphene Oxide Nanosurface Reduces Apoptotic Death of HCT116 Colon Carcinoma Cells Induced by Zirconium Trisulfide Nanoribbons.

Due to their chemical, mechanical, and optical properties, 2D ultrathin nanomaterials have significant potential in biomedicine. However, the cytotoxicity of such materials, including their mutual increase or decrease, is still not well understood. We studied the effects that graphene oxide (GO) nanolayers (with dimensions 0.1-3 µm and average individual flake thickness less than 1 nm) and ZrS3 nanoribbons (length more than 10 µm, width 0.4-3 µm, and thickness 50-120 nm) have on the viability, cell cycle, and cell death of HCT116 colon carcinoma cells. We found that ZrS3 exhibited strong cytotoxicity by causing apoptotic cell death, which was in contrast to GO. When adding GO to ZrS3, ZrS3 was significantly less toxic, which may be because GO inhibits the effects of cytotoxic hydrogen sulfide produced by ZrS3. Thus, using zirconium trisulfide nanoribbons as an example, we have demonstrated the ability of graphene oxide to reduce the cytotoxicity of another nanomaterial, which may be of practical importance in biomedicine, including the development of biocompatible nanocoatings for scaffolds, theranostic nanostructures, and others.

Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: A multi-institutional cohort study.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) occur in up to 40% of immune checkpoint inhibitor (ICI) recipients. However, the association of cirAEs with survival remains unclear. OBJECTIVE: To investigate the association of cirAEs with survival among ICI recipients. METHODS: ICI recipients were identified from the Mass General Brigham healthcare system and Dana-Farber Cancer Institute. Patient charts were reviewed for cirAE development within 2 years after ICI initiation. Multivariate time-varying Cox proportional hazards models, adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, ICI type, cancer type, and year of ICI initiation were utilized to investigate the impact of cirAE development on overall survival. RESULTS: Of the 3731 ICI recipients, 18.1% developed a cirAE. Six-month landmark analysis and time-varying Cox proportional hazards models demonstrated that patients who developed cirAEs were associated with decreased mortality (hazardratio [HR] = 0.87, P = .027), particularly in patients with melanoma (HR = 0.67, P = .003). Among individual morphologies, lichenoid eruption (HR = 0.51, P < .001), psoriasiform eruption (HR = 0.52, P = .005), vitiligo (HR = 0.29, P = .007), isolated pruritus without visible manifestation of rash (HR = 0.71, P = .007), acneiform eruption (HR = 0.34, P = .025), and non-specific rash (HR = 0.68, P < .001) were significantly associated with better survival after multiple comparisons adjustment. LIMITATIONS: Retrospective design; single geography. CONCLUSION: CirAE development is associated with improved survival among ICI recipients, especially patients with melanoma.