Publications by authors named "Brendan Reardon"
Article Synopsis
- The introduction of immune checkpoint blockade (ICB) has greatly improved treatment outcomes for advanced melanoma, but many patients still become resistant to it due to unclear reasons.
- Although combining different ICB therapies has been shown to enhance response rates, it also comes with increased toxicity for patients.
- An analysis of tumor samples from ICB-naïve patients revealed that high genomic heterogeneity and low ploidy can identify those who are intrinsically resistant to aPD-1, leading to a predictive model that may help tailor treatment strategies.
Importance: Aggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition.
Objective: To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma.
Article Synopsis
- The study examines the variety of structural variants (SVs) in melanoma and their role in cancer development, revealing differences across melanoma subtypes, such as frequency, size, and types of SVs.
- The researchers found specific SVs associated with chromothripsis events and their effects on important cancer genes, particularly those influencing topologically associated domains (TADs).
- They also discovered loss-of-function SVs in genes MRE11 and NBN that correlate with a particular mutational profile and suggest a potential vulnerability of melanoma cells to PARP inhibitors due to these genetic alterations.
Background And Objective: Previous germline studies on renal cell carcinoma (RCC) have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification, which might have led to an inaccurate estimation of genetic risk. Here, we aim to analyze the major germline drivers of RCC risk and clinically relevant but underexplored germline variant types.
Methods: We first characterized germline pathogenic variants (PVs), cryptic splice variants, and copy number variants (CNVs) in 1436 unselected RCC patients.
Article Synopsis
- - Recent trials indicate that PD-1-directed immunotherapy, specifically pembrolizumab, may help some patients with anal squamous cell carcinoma, but there is a need for reliable biomarkers to predict who will respond to the treatment.
- - In a phase II clinical trial involving 32 patients, the objective response rate (ORR) to pembrolizumab was low at 9.4%, with a median progression-free survival of only 2.2 months, and most patients showed low levels of beneficial immune cells.
- - Some patients had long-term responses to pembrolizumab, with one patient lasting over 5 years, particularly those with HPV-positive tumors and no liver metastases, but challenges remain due to ongoing HPV infection
Importance: RCC encompasses a set of histologically distinct cancers with a high estimated genetic heritability, of which only a portion is currently explained. Previous rare germline variant studies in RCC have usually pooled clear and non-clear cell RCCs and have not adequately accounted for population stratification that may significantly impact the interpretation and discovery of certain candidate risk genes.
Objective: To evaluate the enrichment of germline PVs in established cancer-predisposing genes (CPGs) in clear cell and non-clear cell RCC patients compared to cancer-free controls using approaches that account for population stratification and to identify unconventional types of germline RCC risk variants that confer an increased risk of developing RCC.
Article Synopsis
- Tumor molecular profiling focuses on identifying key genetic changes ('first-order' alterations) in tumors, which can guide treatment options.
- There is a growing recognition that the interaction between these first-order changes and broader genetic information ('second-order' alterations) can influence patient outcomes, but these interactions haven't been included in clinical decision-making tools.
- The Molecular Oncology Almanac (MOAlmanac) is introduced as a tool that combines clinical interpretation and knowledge resources for analyzing complex genomic data, leading to more treatment recommendations and strategies for cancer patients in a clinical setting.
Article Synopsis
- Muscle-invasive bladder cancer (MIBC) can occur after radiation treatment for prostate cancer, known as radiation-associated MIBC (RA-MIBC), and poses unique management challenges due to prior radiation.
- The study aimed to analyze the genetic features of RA-MIBC tumors through whole exome sequencing and compare them to non-RA-MIBC tumors to understand if they have distinct genomic characteristics.
- While the frequency of mutations in common bladder cancer genes was similar in both groups, RA-MIBC showed a higher number of specific genetic alterations linked to previous radiation exposure, suggesting a unique mutational signature with implications for treatment strategies.
Article Synopsis
- Immune checkpoint inhibitors (ICIs) show limited effectiveness for treating hormone receptor-positive (HR+) breast cancer, as evidenced by final overall survival results from a trial involving 88 patients.
- The study compared eribulin with pembrolizumab, revealing no significant improvement in overall survival rates, despite some tumors showing immune response correlations.
- Key findings suggest that immune infiltration and antigen presentation are linked to positive responses, while tumor heterogeneity and estrogen signaling contribute to treatment resistance, indicating a need for further research and validation in clinical settings.
Several risk factors have been established for colorectal cancer, yet their direct mutagenic effects in patients' tumors remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 colorectal cancer cases that had occurred in three U.S.
View Article and Find Full Text PDFArticle Synopsis
- Small cell lung carcinoma (SCLC) has a high mutation rate but typically shows a low response to immune checkpoint blockade (ICB) treatments, meaning it's hard to treat effectively with current immunotherapies.
- Researchers discovered a specific group of SCLC cells that increase MHC I levels, which helps enhance the effectiveness of ICB, indicating a connection between loss of neuroendocrine traits and improved immune response.
- The study suggests that using EZH2 inhibitors to change cell characteristics, alongside STING agonists, could boost T-cell activity against SCLC, presenting new strategies for treatment based on the tumor's immune properties.
Purpose: Cohort-based germline variant characterization is the standard approach for pathogenic variant discovery in clinical and research samples. However, the impact of cohort size on the molecular diagnostic yield of joint genotyping is largely unknown.
Methods: Head-to-head comparison of the molecular diagnostic yield of joint genotyping in two cohorts of 239 cancer patients in the absence and then in the presence of 100 additional germline exomes.
Article Synopsis
- - We analyzed 1,048 melanoma samples and found significant differences in their genomic characteristics based on subtypes (BRAF, (N)RAS, NF1, triple wild-type (TWT)), identifying unique secondary driver genes and mutational processes for each subtype.
- - Each melanoma subtype showed distinct patterns of dysregulated pathways and co-mutation patterns that influence their response to immune checkpoint therapies, like increased TGF-β signaling in BRAF melanomas and disrupted SWI/SNF complex in (N)RAS melanomas.
- - The study also highlighted the TWT subtype's DNA-repair defects, offering new insights into potential therapeutic approaches based on genetic profiling for treating different melanoma patient groups.
Article Synopsis
- Less than 10% of cancer patients have detectable harmful genetic changes, which may be due to incomplete detection methods.
- The study aimed to assess whether deep learning can improve the identification of these genetic variants in cancer patients compared to standard methods.
- Results showed that deep learning techniques detected more patients with harmful variants in genes linked to cancer risk than traditional methods in cohorts of prostate and melanoma patients.
Article Synopsis
- * Most patients currently receive similar treatments (surgery, radiation, chemotherapy), which can lead to severe long-term side effects and do not always result in survival.
- * The study suggests a shift towards personalized therapy based on the unique characteristics of patients' tumors, showing that drug screening can reveal effective treatments that genomic analysis might miss, like actinomycin D for aggressive Group 3 medulloblastoma.
High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer with unpredictable outcome and poorly understood risk factors. Here, we examined the association of somatic mutation profiles with nonrecurrent disease (GO, good outcome), recurrence (R), or progression (PD) in a cohort of HGT1 patients. Exome sequencing was performed on 62 HGT1 and 15 matched normal tissue samples.
View Article and Find Full Text PDFBackground: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the authors performed a phase 2 study evaluating the efficacy of the pan-isoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC.
Methods: Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway-altered tumors.
Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003-2011) detects CHIP in 136/629 patients (21.
View Article and Find Full Text PDFMotivation: Large-scale sequencing studies have created a need to succinctly visualize genomic characteristics of patient cohorts linked to widely variable phenotypic information. This is often done by visualizing the co-occurrence of variants with comutation plots. Current tools lack the ability to create highly customizable and publication quality comutation plots from arbitrary user data.
View Article and Find Full Text PDFCancer genomes contain large numbers of somatic mutations but few of these mutations drive tumor development. Current approaches either identify driver genes on the basis of mutational recurrence or approximate the functional consequences of nonsynonymous mutations by using bioinformatic scores. Passenger mutations are enriched in characteristic nucleotide contexts, whereas driver mutations occur in functional positions, which are not necessarily surrounded by a particular nucleotide context.
View Article and Find Full Text PDFPurpose: Molecular properties associated with complete response or acquired resistance to concurrent chemotherapy and radiotherapy (CRT) are incompletely characterized. We performed integrated whole-exome/transcriptome sequencing and immune infiltrate analysis on rectal adenocarcinoma tumors prior to neoadjuvant CRT (pre-CRT) and at time of resection (post-CRT) in 17 patients [8 complete/partial responders, 9 nonresponders (NR)].
Results: CRT was not associated with increased tumor mutational burden or neoantigen load and did not alter the distribution of established somatic tumor mutations in rectal cancer.
Importance: Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs.
Objective: To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls.
Objectives: Secondary oral squamous cell carcinoma (OSCC) is a late complication in allogeneic hematopoietic stem cell transplantation (HSCT) patients, but little is known about long-term outcomes and prognostication. Additionally, molecular alterations and immunologic insights unique to this disease remain largely unexplored.
Methods: We present a cohort of 31 patients with post-HSCT OSCC and reported on clinicopathologic predictors of survival.