ScalpelSig Designs Targeted Genomic Panels from Data to Detect Activity of Mutational Signatures.

Over the past decade, a promising line of cancer research has utilized machine learning to mine statistical patterns of mutations in cancer genomes for information. Recent work shows that these statistical patterns, commonly referred to as "mutational signatures," have diverse therapeutic potential as biomarkers for cancer therapies. However, translating this potential into reality is hindered by limited access to sequencing in the clinic. Almost all methods for mutational signature analysis (MSA) rely on whole genome or whole exome sequencing data, while sequencing in the clinic is typically limited to small gene panels. To improve clinical access to MSA, we considered the question of whether targeted panels could be designed for the purpose of mutational signature detection. Here we present ScalpelSig, to our knowledge the first algorithm that automatically designs genomic panels optimized for detection of a given mutational signature. The algorithm learns from data to identify genome regions that are particularly indicative of signature activity. Using a cohort of breast cancer genomes as training data, we show that ScalpelSig panels substantially improve accuracy of signature detection compared to baselines. We find that some ScalpelSig panels even approach the performance of whole exome sequencing, which observes over 10 × as much genomic material. We test our algorithm under a variety of conditions, showing that its performance generalizes to another dataset of breast cancers, to smaller panel sizes, and to lesser amounts of training data.

Deep Unfolding for Non-Negative Matrix Factorization with Application to Mutational Signature Analysis.

Non-negative matrix factorization (NMF) is a fundamental matrix decomposition technique that is used primarily for dimensionality reduction and is increasing in popularity in the biological domain. Although finding a unique NMF is generally not possible, there are various iterative algorithms for NMF optimization that converge to locally optimal solutions. Such techniques can also serve as a starting point for deep learning methods that unroll the algorithmic iterations into layers of a deep network. In this study, we develop unfolded deep networks for NMF and several regularized variants in both a supervised and an unsupervised setting. We apply our method to various mutation data sets to reconstruct their underlying mutational signatures and their exposures. We demonstrate the increased accuracy of our approach over standard formulations in analyzing simulated and real mutation data.

High Frequency of Juxtamembrane Domain ERBB2 Mutation in Gastric Cancer.

BACKGROUND/AIM: ERBB2 mutation is an emerging therapeutic target in solid tumors; its therapeutic responses depend on the location of mutation. In gastric cancer, the profiles of ERBB2 mutations and their relationship with human epidermal growth factor receptor 2 (HER2) overexpression remain unknown. We aimed to describe the details of ERBB2 mutations in gastric cancer. PATIENTS AND METHODS: Comprehensive panel sequencing was performed in 234 advanced gastric cancer patients. We investigated hotspots and clinicopathologic features of ERBB2 mutant gastric cancer in a single institute and evaluated the hotspots of ERBB2 mutation in a public database. RESULTS: Eighteen patients (7.7%) had ERBB2 mutations. The most frequent mutation was p.Arg678Gln (42.1%), which was located in the juxtamembrane domain and was the most common mutation in public databases (20.5%). All 18 ERBB2-mutant patients were negative for HER2 expression. Co-occurring genetic alterations included KRAS, PIK3CA, and ATM mutations. CONCLUSION: ERBB2 mutations were not associated with HER2 overexpression in gastric cancer patients. The most common mutation was located in the juxtamembrane domain of ERBB2.

Genetic Spectrum and Characteristics of Hereditary Optic Neuropathy in Taiwan.

Hereditary optic neuropathy (HON) is a group of genetically heterogeneous diseases that cause optic nerve atrophy and lead to substantial visual impairment. HON may present with optic nerve atrophy only or in association with various systemic abnormalities. Although a genetic survey is indispensable for diagnosing HON, conventional sequencing techniques could render its diagnosis challenging. In this study, we attempted to explore the genetic background of patients with HON in Taiwan through capture-based next-generation sequencing targeting 52 HON-related genes. In total, 57 patients from 48 families were recruited, with 6 patients diagnosed as having Leber hereditary optic neuropathy through initial screening for three common variants (m.3460G>A, m.11778G>A, m.14484T>C). Disease-causing genotypes were identified in 14 (33.3%) probands, and OPA1 variants were the most prevalent cause of autosomal HON. Exposure to medications such as ethambutol could trigger an attack of autosomal dominant optic atrophy. WFS1 variants were identified in three probands with variable clinical features in our cohort. Hearing impairment could occur in patients with OPA1 or WFS1 variants. This is the first comprehensive study investigating the genetic characteristics of HON in Taiwan, especially for autosomal HON. Our results could provide useful information for clinical diagnosis and genetic counseling in this field.

Early detection of duodenal cancer by upper gastrointestinal-endoscopy in Lynch syndrome.

Small bowel cancer (SBC) is the malignancy with the highest standardized incidence ratio in Lynch syndrome (LS) patients. Of all SBCs, about 50% are duodenal cancers (DCs), therefore being accessible by esophago-gastro-duodenoscopy (EGD) for surveillance. We asked whether early detection of DC is possible for LS patients undergoing surveillance by EGD and if surveillance should be limited to specific subgroups. Data for LS patients with DC were retrieved from the registry of the German Consortium for Familial Intestinal Cancer. Patients undergoing active surveillance by EGDs (surveillance group) were compared to those who did not (nonsurveillance group) regarding tumor stage at diagnosis. Union for International Cancer Control stages I-IIA were defined as early stage disease and IIB-IV as advanced stage disease. Statistical analysis was performed using Fisher's exact test. Among 2015 patients with pathogenic variants in any mismatch-repair-gene, 47 patients with 49 DCs were identified. In 10% of cases, patients were under 35 years at diagnosis; family and personal tumor history did not correlate with DC diagnosis. Pathogenic germline variants in MSH6, PMS2 or EPCAM were present in 10% of patients. Statistical analysis could be performed on 13 DC patients in the surveillance group and 14 in the nonsurveillance group. Early detection was possible for 71% of patients in the surveillance group and 29% of patients in the nonsurveillance group (P = .021). Early detection of DC by EGD in LS patients is feasible regardless of family history, mutational status and should start no later than 25 years of age.

De novo mutational signature discovery in tumor genomes using SparseSignatures.

Cancer is the result of mutagenic processes that can be inferred from tumor genomes by analyzing rate spectra of point mutations, or "mutational signatures". Here we present SparseSignatures, a novel framework to extract signatures from somatic point mutation data. Our approach incorporates a user-specified background signature, employs regularization to reduce noise in non-background signatures, uses cross-validation to identify the number of signatures, and is scalable to large datasets. We show that SparseSignatures outperforms current state-of-the-art methods on simulated data using a variety of standard metrics. We then apply SparseSignatures to whole genome sequences of pancreatic and breast tumors, discovering well-differentiated signatures that are linked to known mutagenic mechanisms and are strongly associated with patient clinical features.

Impact of molecular testing in advanced melanoma on outcomes in a tertiary cancer center and as reported in a publicly available database.

BACKGROUND: In patients with advanced melanoma (MM), genomic profiling may guide treatment decisions in the frontline setting and beyond as specific tumor mutations can be treated with targeted therapy (TT). The range of panel sizes used to identify targetable mutations (TM) can range from a few dozen to whole exome sequencing (WES). AIM: We investigated the impact of panel size and mutation status on first-line treatment selection and outcomes in MM. METHODS AND RESULTS: We analyzed data for 1109 MM patients from three cohorts: 169 patients at NYULH and profiled with the 50 gene Ion Torrent panel (IT), 195 patients at MSKCC, profiled with the 400-gene MSK-IMPACT panel (MSK-I) and 745 patients at seven different sites profiled with WES. Data for cohorts 2 and 3 were extrapolated from the publicly available cBioPortal. Treatment information was available for 100%, 25%, and 0% of patients in cohort 1, 2, and 3, respectively. BRAF and NRAS were among the top five most commonly mutated genes in the IT and MSK-I, whereas for WES only BRAF was a top five mutation. There was no significant difference in OS for BRAF MUT patients treated with immune checkpoint inhibitors (ICI) vs TT in cohort 1 (P = .19), nor for BRAF MUT patients from cohort 1 treated with ICI vs those from cohort 2 treated with TT (P = .762). CONCLUSION: Public datasets provide population-level data; however, the heterogeneity of reported clinical information limits their value and calls for data standardization. Without evidence of clear clinical benefit of a larger panel size, there is a rationale for adopting smaller, more cost effective panels in MM.

Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is a major cause of cancer death. In an effort to improve treatment strategies and outcomes, DNA damage repair (DDR) pathways have been introduced as a new target in PC and in other cancers, through the exploitation of synthetic lethality. Furthermore, genes involved in DDR are among the major determinants of cancer susceptibility. In addition to the well-known BRCA1 and BRCA2 genes, a plethora of other targets in the same pathways are now emerging. METHODS: We analyzed samples from 60 patients, affected by PC and already tested for BRCA, using a panel with 24 other cancer susceptibility genes. RESULTS: We detected 8 pathogenic or likely pathogenic mutations (13.3% of samples analyzed), 4 of which were found in non-BRCA genes (2 in ATM, 1 each in PALB2 and RAD50). Furthermore, 4 pathogenic or likely pathogenic mutations were found in patients without a personal or familial history of cancer. CONCLUSIONS: Our results suggest that genetic testing with a comprehensive gene panel should be perfomed in all patients with PC, in order to allow screening for PC and other gene-related cancers in all at risk family members and to assess patients' eligibility for emerging therapeutic options.

Achieving universal genetic assessment for women with ovarian cancer: Are we there yet? A systematic review and meta-analysis.

PURPOSE: Several professional organizations recommend universal genetic assessment for people with ovarian cancer as identifying pathogenic variants can affect treatment, prognosis, and all-cause mortality for patients and relatives. We sought to evaluate the literature on genetic assessment for women with ovarian cancer and determine if any interventions or patient characteristics drive utilization of services. METHODS: We searched key electronic databases to identify trials that evaluated genetic assessment for people with ovarian cancer. Trials with the primary aim to evaluate utilization of genetic assessment with or without interventions were included. Eligible trials were subjected to meta-analysis and the moderating influence of health interventions on rates of genetic assessment were examined. RESULTS: A total of 35 studies were included (19 report on utilization of genetic services without an intervention, 7 with an intervention, and 9 with both scenarios). Without an intervention, pooled estimates for referral to genetic counseling and completion of genetic testing were 39% [CI 27-53%] and 30% [CI 19-44%]. Clinician-facilitated interventions included: mainstreaming of genetic services (99% [CI 86-100%]), telemedicine (75% [CI 43-93%]), clinic-embedded genetic counselor (76% [CI 32-95%]), reflex tumor somatic genetic assessment (64% [CI 17-94%]), universal testing (57% [28-82%]), and referral forms (26% [CI 10-53%]). Random-effects pooled proportions demonstrated that Black vs. White race was associated with a lower rate of genetic testing (26%[CI 17-38%] vs. 40% [CI 25-57%]) as was being un-insured vs. insured (23% [CI 18-28%] vs. 38% [CI 26-53%]). CONCLUSIONS: Reported rates of genetic testing for people with ovarian cancer remain well below the goal of universal testing. Interventions such as mainstreaming can improve testing uptake. Strategies aimed at improving utilization of genetic services should consider existing disparities in race and insurance status.

Basal Cell Carcinoma Gene Mutations Differ Between Asian, Hispanic, and Caucasian Patients: A Pilot Study.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy worldwide. While most BCCs are treated surgically, advanced BCCs are often treated with gene-targeted therapies. While there has been a lot of research in BCC from Caucasian patients, research is lacking in patients with skin of color. OBJECTIVE: To identify potential variations in BCC gene mutations between Asian, Hispanic, and Caucasian patients. METHODS: A cohort study was performed from 2015 to 2017 with 23 patients treated for BCC at an urban academic hospital. Gene mutations were assessed using a targeted mutation panel for 76 cancer-associated genes from formalin-fixed paraffin-embedded (FFPE) samples. RESULTS: Groups studied comprised Asian (n=5), Hispanic (n=10), and Caucasian (n=8) patients. The Hispanic cohort had the highest number of mutations per patient on average (3.4 versus 2.8 for both Caucasian and Asian cohorts). GATA3 mutations were more prevalent in Hispanic patients (P=0.02, single factor ANOVA). ARID1A and PTEN mutations co-occurred in the Hispanic cohort (P<0.05). The most common mutation in the Asian cohort was TP53 (2/5). The Caucasian cohort had the highest percent of UVB mutations (68.4%). CONCLUSIONS: This study shows potential differences in the prevalence of somatic gene mutations for BCC patients of different races and ethnicities, which could inform the underlying pathogenesis, impact the efficacy of therapies in specific populations, and may also help identify novel therapeutic targets. J Drugs Dermatol. 20(5): doi:10.36849/JDD.5884.

Analysis of Common Driver Mutations in Philadelphia-Negative Myeloproliferative Neoplasms.

BACKGROUND: Philadelphia-negative myeloproliferative neoplasms (MPNs) are a group of hematopoietic stem cell disorders that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). This study examines the driver mutations among patients with MPNs in Kuwait. PATIENTS AND METHODS: This study was a retrospective review of 942 MPN cases with a driver mutation from July 2007 to June 2019 to examine their demographic, clinical, and laboratory attributes. RESULTS: The annual incidence of MPNs is 1.6 per 100,000 persons, and ET is the most common subtype. The median age of our cohort was 55 years, and the patients were predominantly male. We found that the most frequent gene mutation of MPNs in our cohort was the JAK2V617F mutation, which was present in 90% of cases, followed by the CALR exon 9, MPLW515L/K, and JAK2 exon 12 mutations. In our cohort, thrombotic events were observed in 18.7% of cases. CONCLUSION: Although Philadelphia-negative MPNs are rare hematologic malignancies, thrombosis is a relatively common initial presentation. The JAK2V617F mutation was the driver mutation in the majority of patients with MPN.

Histopathological characteristics and artificial intelligence for predicting tumor mutational burden-high colorectal cancer.

BACKGROUND: Tumor mutational burden-high (TMB-H), which is detected with gene panel testing, is a promising biomarker for immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC). However, in clinical practice, not every patient is tested for TMB-H using gene panel testing. We aimed to identify the histopathological characteristics of TMB-H CRC for efficient selection of patients who should undergo gene panel testing. Moreover, we attempted to develop a convolutional neural network (CNN)-based algorithm to predict TMB-H CRC directly from hematoxylin and eosin (H&E) slides. METHODS: We used two CRC cohorts tested for TMB-H, and whole-slide H&E digital images were obtained from the cohorts. The Japanese CRC (JP-CRC) cohort (N = 201) was evaluated to detect the histopathological characteristics of TMB-H using H&E slides. The JP-CRC cohort and The Cancer Genome Atlas (TCGA) CRC cohort (N = 77) were used to develop a CNN-based TMB-H prediction model from the H&E digital images. RESULTS: Tumor-infiltrating lymphocytes (TILs) were significantly associated with TMB-H CRC (P < 0.001). The area under the curve (AUC) for predicting TMB-H CRC was 0.910. We developed a CNN-based TMB-H prediction model. Validation tests were conducted 10 times using randomly selected slides, and the average AUC for predicting TMB-H slides was 0.934. CONCLUSIONS: TILs, a histopathological characteristic detected with H&E slides, are associated with TMB-H CRC. Our CNN-based model has the potential to predict TMB-H CRC directly from H&E slides, thereby reducing the burden on pathologists. These approaches will provide clinicians with important information about the applications of ICIs at low cost.

Characteristics and prognostic value of potential dependency genes in clear cell renal cell carcinoma based on a large-scale CRISPR-Cas9 and RNAi screening database DepMap.

BACKGROUND: Large-scale loss-of-function screening database such as Cancer Dependency Map (Depmap) provide abundant resources. Investigation of these potential dependency genes from human cancer cell lines in the real-world patients cohort would evaluate their prognostic value thus facilitate their clinical application and guide drug development. METHODS: A few genes were selected from top clear cell renal cell carcinoma (ccRCC) lineage preferential dependency candidates from Depmap. Their characteristic including expression levels both in normal and tumor tissues and correlations with methylation or copy number, genetic alterations, functional enrichment, immune-associated interactions, prognostic value were evaluated in KIRC cohort from TCGA, GTEx, and multiple other open databases and platforms. RESULTS: 16 genes were collected from 106 ccRCC preferential candidates and further analyzed including B4GALT4, BCL2L1, CDH2, COPG1, CRB3, FERMT2, GET4, GPX4, HNF1B, ITGAV, MDM2, NFE2L2, PAX8, RUVBL1, TFRC, and TNFSF10. The normalized gene effect scores of these genes varied from different ccRCC cell lines and principal component analysis (PCA) showed their tissue specificity expression profiles. Genetic alteration rates of them were low to moderate (0.7%-13%) in KIRC cohort. CDH2, MDM2, TNFSF10 showed a statistically significant higher level in tumors than normal tissues while PAX8 and FERMT2 were significantly downregulated. Moderate positive or negative correlations were observed in several genes between their expression and relative gene copy number or methylation levels, respectively. Based on the multivariable COX regression model adjusted by critical clinical variables revealed the expression of GET4 (p=0.002, HR=1.023 95%CI 1.009-1.038) and CRB3 (p<0.001, HR=0.969 95%CI 0.960-0.980) were independent predictive factors for overall survival in KIRC cohort. CONCLUSIONS: A dependency gene validated in cell lines didn't directly represent its role in corresponding patients with same histological type and their prognostic value might be determined by multiple factors including dependency driven types, genetic alteration rates and expression levels. GET4 and CRB3 were the independent prognostic factors for ccRCC patients. CRB3 seemed like a potential broad tumor suppressor gene while GET4 might be a ccRCC preferential dependency gene with a ligandable structure.

Analysis of FLT3-Activating Mutations in Patients With Acute Myelogenous Leukemia in Jordan: Association With FAB Subtypes and Identification of Subgroups With Poor Prognosis.

BACKGROUND: FLT3 mutations are common in acute myeloid leukemia (AML), particularly in French-American-British M2 subtype AML and in cytogenetically normal (CN) AML; however, its incidence in Jordan is poorly studied. An FLT3 mutation implies poor prognosis in AML patients. We aimed to assess the incidence and prognostic value of FLT3 mutations in AML in Jordan. PATIENTS AND METHODS: One hundred thirty-two newly diagnosed unselected AML patients were included. Patient data were collected, including demographics as well as morphologic, cytogenetic, and molecular testing results. FLT3 mutations were detected by real-time reverse transcriptase PCR, next-generation sequencing, or both. Survival analysis and comparisons of incidence, remission rate, relapse, and survival outcomes between FLT3-mutated and wild-type groups were done and prognostic factors identified. RESULTS: FLT3 mutation was detected in 40% of AML patients. The highest incidence was associated with M2 subtype AML (47%) and CN-AML (50%). There was a significant negative association between FLT3 mutations and overall survival (OS), as well as a trend toward improved relapse-free survival, with 3-year OS being 19.17% vs 34.16% (P < .0001) and 33.6% vs 71.0% (P = .085), respectively. Patients with FLT3 mutation had a significantly better complete remission rate after induction (67.9% vs 63.3%, P = .001). Also, OS improved in patients with complete remission (P = .0015) and who then continued to allogeneic hematopoietic cell transplantation compared to FLT3 wild-type patients (P < .001). CONCLUSION: FLT3 mutation is common in Jordanian AML patients, with the highest incidence occurring in patients with M2 or CN disease. It implies a poor prognosis, with poor OS and relapse-free survival, which may be abrogated by early allogeneic transplantation and/or peritransplantation provision of FLT3 inhibitors.

Tumor mutation burden as a biomarker in resected gastric cancer via its association with immune infiltration and hypoxia.

BACKGROUND: Tumor mutation burden (TMB) predicts immunotherapy efficacy in solid tumors. However, the biomarker role of TMB is still conflicting in resected tumors. We aimed to examine the association of TMB with prognosis and postoperative chemotherapy (CT) or radiochemotherapy (RCT) efficacy in resected gastric cancer (GC). METHODS: Whole-exome sequencing (WES) was performed in 73 resected GC specimens. Validation cohorts included 352 patients from The Cancer Genome Atlas (TCGA) and 222 patients from the Asian Cancer Research Group (ACRG). Immune infiltration and hypoxia were evaluated by transcriptome data and immunohistochemistry assay. RESULTS: TMB-high GC had favorable overall survival (OS) and disease-free survival (DFS), but the OS and DFS benefits with postoperative CT/RCT were more pronounced in TMB-low GC. These findings were consistent among all three cohorts and were maintained in the pooled cohort. Stratified by stages in the pooled cohort, stage III GC benefited from postoperative CT/RCT regardless of TMB level while stage Ib/II GC benefited from postoperative CT/RCT in TMB-low but not in TMB-high subgroup. TMB positively correlated with immune infiltration which was characterized by NK cell rather than CD8 + T cell enrichment. TMB-high GC was more hypoxic than TMB-low GC, and TMB-high stage Ib/II GC was the most hypoxic. CONCLUSIONS: High TMB may predict favorable prognosis in resected GC but poor response to postoperative CT/RCT in stage Ib/II subgroup, which may be determined by TMB-associated immune infiltration and hypoxia, respectively.

High mutation burden in the checkpoint and micro-RNA processing genes in myelodysplastic syndrome.

A number of sequencing studies identified the prognostic impact of somatic mutations in myelodysplastic syndrome (MDS). However the majority of them focused on methylation regulation, apoptosis and proliferation genes. Despite the number of experimental studies published on the role of micro-RNA processing and checkpoint genes in the development of MDS, the clinical data about mutational landscape in these genes is limited. We performed a pilot study which evaluated mutational burden in these genes and their association with common MDS mutations. High prevalence of mutations was observed in the genes studied: 54% had mutations in DICER1, 46% had mutations in LAG3, 20% in CTLA4, 23% in B7-H3, 17% in DROSHA, 14% in PD-1 and 3% in PD-1L. Cluster analysis that included these mutations along with mutations in ASXL1, DNMT3A, EZH2, IDH1, RUNX1, SF3B1, SRSF2, TET2 and TP53 effectively predicted overall survival in the study group (HR 4.2, 95%CI 1.3-13.6, p = 0.016). The study results create the rational for incorporating micro-RNA processing and checkpoint genes in the sequencing panels for MDS and evaluate their role in the multicenter studies.

An evaluation of RAS testing among metastatic colorectal cancer patients in the USA.

Background: Data on RAS testing practices prior to metastatic colorectal cancer (mCRC) treatment initiation are lacking in the USA. Materials & methods: Flatiron data were utilized for patients diagnosed with mCRC between 2011 and 2017. Flatiron is a longitudinal, demographically and geographically diverse database representing data from over 1.5 million active US patients treated at 255 community and hospital-affiliated oncology clinics. Results: Among 17,387 mCRC patients 69% were RAS tested and 31% were never tested. Timing of RAS testing was as follows: 23% were tested at the time of their initial CRC diagnosis, 60% following mCRC diagnosis but prior to first line of treatment, 3% prior to third line, the remaining 14% were tested following third line. Conclusion: A third (31%) of patients failed to receive RAS testing, therefore all treatment options were unavailable to them. These data highlight how universal testing has not been achieved.

Prevalence of Homologous Recombination Pathway Gene Mutations in Melanoma: Rationale for a New Targeted Therapeutic Approach.

Homologous recombination DNA damage repair (HR-DDR) deficient patients with various solid tumors have been treated with PARP inhibitors. However, the clinical characteristics of patients with melanoma who have HR-DDR gene mutations and the consequences of PARP inhibition are poorly understood. We compared the commercially available next-generation sequencing data from 84 patients with melanomas from our institution with a dataset of 1,986 patients as well as 1,088 patients profiled in cBioportal. In total, 21.4% of patients had ≥1 functional HR-DDR mutation, most commonly involving BRCA1, ARID1A, ATM, ATR, and FANCA. Concurrent NF1, BRAF, and NRAS mutations were found in 39%, 39%, and 22% of cases, respectively. HR-DDR gene mutation was associated with high tumor mutational burden and clinical response to checkpoint blockade. A higher prevalence of HR-DDR mutations was observed in the datasets from Foundation Medicine (Cambridge, CA) and those from the Cancer Genome Atlas. Treatment of HR-DDR‒mutated patient-derived xenograft models of melanoma with PARP inhibitor produced significant antitumor activity in vivo and was associated with increased apoptotic activity. RNA sequencing analysis of PARP inhibitor-treated tumors indicated alterations in the pathways involving extracellular matrix remodeling, cell adhesion, and cell-cycle progression. Melanomas with HR-DDR mutations represent a unique subset, which is more likely to benefit from checkpoint blockade and may be targeted with PARP inhibitor.

EGFR mutation testing and TKI treatment patterns among veterans with stage III and IV non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation testing is recommended in metastatic non-small cell lung cancer (NSCLC). The objective of this study was to assess changes in EGFR mutation testing patterns and tyrosine kinase inhibitor (TKI) use in US veterans with stage III-IV NSCLC between 2013 and 2017. PATIENTS AND METHODS: Retrospective study using linked data from Department of Veterans Affairs (VA) Cancer Registry System, Corporate Data Warehouse, commercial laboratories, and clinical notes. Generalized linear mixed models accounting for clustering by VA facility were used to determine factors associated with EGFR mutation testing. RESULTS: From 2013 to 2017, EGFR mutation testing increased from 29.5% to 38.4% among veterans with stage III-IV NSCLC and from 47.0% to 57.4% among veterans with stage IV non-squamous disease. Factors associated with increased odds of testing included being married, Medicare enrollment, and adenocarcinoma histology. Factors associated with decreased odds of testing included Medicaid eligibility, stage III disease, increasing age, being a current or former smoker, increasing Charlson-Deyo comorbidity score, and receiving cancer care in the South. Appropriate use of a TKI rose from 2013 to 2017 (17.2% to 74.1%). CONCLUSION: EGFR mutation testing rates increased to almost 60% in the stage IV non-squamous NSCLC population in 2017, with residual opportunity for further increase. Several sociodemographic characteristics, comorbidities, and geographic regions were associated with EGFR mutation testing suggestive of inequitable testing decisions. Appropriate use of TKI improved drastically from 2013 to 2017 demonstrating rapidly changing practice patterns through the adoption phase of new treatment options.

Effect of ACTN3 R577X Genotype on Injury Epidemiology in Elite Endurance Runners.

The p.R577X polymorphism (rs1815739) in the ACTN3 gene causes individuals with the ACTN3 XX genotype to be deficient in functional α-actinin-3. Previous investigations have found that XX athletes are more prone to suffer non-contact muscle injuries. This investigation aimed to determine the influence of the ACTN3 R577X polymorphism in the injury epidemiology of elite endurance athletes. Using a cross-sectional experiment, the epidemiology of running-related injuries was recorded for one season in a group of 89 Spanish elite endurance runners. ACTN3 R577X genotype was obtained for each athlete using genomic DNA samples. From the study sample, 42.7% of athletes had the RR genotype, 39.3% had the RX genotype, and 18.0% had the XX genotype. A total of 96 injuries were recorded in 57 athletes. Injury incidence was higher in RR runners (3.2 injuries/1000 h of running) than in RX (2.0 injuries/1000 h) and XX (2.2 injuries/1000 h; p = 0.030) runners. RR runners had a higher proportion of injuries located in the Achilles tendon, RX runners had a higher proportion of injuries located in the knee, and XX runners had a higher proportion of injuries located in the groin (p = 0.025). The ACTN3 genotype did not affect the mode of onset, the severity, or the type of injury. The ACTN3 genotype slightly affected the injury epidemiology of elite endurance athletes with a higher injury rate in RR athletes and differences in injury location. However, elite ACTN3 XX endurance runners were not more prone to muscle-type injuries.