Liquid biopsy genotyping in lung cancer: ready for clinical utility?

Liquid biopsy is a blood test that detects evidence of cancer cells or tumor DNA in the circulation. Despite complicated collection methods and the requirement for technique-dependent platforms, it has generated substantial interest due, in part, to its potential to detect driver oncogenes such as epidermal growth factor receptor (EGFR) mutants in lung cancer. This technology is advancing rapidly and is being incorporated into numerous EGFR tyrosine kinase inhibitor (EGFR-TKI) development programs. It appears ready for integration into clinical care. Recent studies have demonstrated that biological fluids such as saliva and urine can also be used for detecting EGFR mutant DNA through application other user-friendly techniques. This review focuses on the clinical application of liquid biopsies to lung cancer genotyping, including EGFR and other targets of genotype-directed therapy and compares multiple platforms used for liquid biopsy

MuDelta: Delta-Oriented Mutation Testing at Commit Time

To effectively test program changes using mutation testing, one needs to use mutants that are relevant to the altered program behaviours. In view of this, we introduce MuDelta, an approach that identifies commit-relevant mutants; mutants that affect and are affected by the changed program behaviours. Our approach uses machine learning applied on a combined scheme of graph and vector-based representations of static code features. Our results, from 50 commits in 21 Coreutils programs, demonstrate a strong prediction ability of our approach; yielding 0.80 (ROC) and 0.50 (PR Curve) AUC values with 0.63 and 0.32 precision and recall values. These predictions are significantly higher than random guesses, 0.20 (PR-Curve) AUC, 0.21 and 0.21 precision and recall, and subsequently lead to strong relevant tests that kill 45%more relevant mutants than randomly sampled mutants (either sampled from those residing on the changed component(s) or from the changed lines). Our results also show that MuDelta selects mutants with 27% higher fault revealing ability in fault introducing commits. Taken together, our results corroborate the conclusion that commit-based mutation testing is suitable and promising for evolving software

EcoCyc: fusing model organism databases with systems biology.

EcoCyc (http://EcoCyc.org) is a model organism database built on the genome sequence of Escherichia coli K-12 MG1655. Expert manual curation of the functions of individual E. coli gene products in EcoCyc has been based on information found in the experimental literature for E. coli K-12-derived strains. Updates to EcoCyc content continue to improve the comprehensive picture of E. coli biology. The utility of EcoCyc is enhanced by new tools available on the EcoCyc web site, and the development of EcoCyc as a teaching tool is increasing the impact of the knowledge collected in EcoCyc

Selecting fault revealing mutants

Mutant selection refers to the problem of choosing, among a large number of mutants, the (few) ones that should be used by the testers. In view of this, we investigate the problem of selecting the fault revealing mutants, i.e., the mutants that are killable and lead to test cases that uncover unknown program faults. We formulate two variants of this problem: the fault revealing mutant selection and the fault revealing mutant prioritization. We argue and show that these problems can be tackled through a set of ‘static’ program features and propose a machine learning approach, named FaRM, that learns to select and rank killable and fault revealing mutants. Experimental results involving 1,692 real faults show the practical benefits of our approach in both examined problems. Our results show that FaRM achieves a good trade-off between application cost and effectiveness (measured in terms of faults revealed). We also show that FaRM outperforms all the existing mutant selection methods, i.e., the random mutant sampling, the selective mutation and defect prediction (mutating the code areas pointed by defect prediction). In particular, our results show that with respect to mutant selection, our approach reveals 23% to 34% more faults than any of the baseline methods, while, with respect to mutant prioritization, it achieves higher average percentage of revealed faults with a median difference between 4% and 9% (from the random mutant orderings)

Unique Molecular Features in High-Risk Histology Endometrial Cancers

Endometrial cancer is the most common gynecologic malignancy in the United States and the sixth most common cancer in women worldwide. Fortunately, most women who develop endometrial cancer have low-grade early-stage endometrioid carcinomas, and simple hysterectomy is curative. Unfortunately, 15% of women with endometrial cancer will develop high-risk histologic tumors including uterine carcinosarcoma or high-grade endometrioid, clear cell, or serous carcinomas. These high-risk histologic tumors account for more than 50% of deaths from this disease. In this review, we will highlight the biologic differences between low- and high-risk carcinomas with a focus on the cell of origin, early precursor lesions including atrophic and proliferative endometrium, and the potential role of stem cells. We will discuss treatment, including standard of care therapy, hormonal therapy, and precision medicine-based or targeted molecular therapies. We will also discuss the impact and need for model systems. The molecular underpinnings behind this high death to incidence ratio are important to understand and improve outcomes

Selecting fault revealing mutants

Mutant selection refers to the problem of choosing, among a large number of mutants, the (few) ones that should be used by the testers. In view of this, we investigate the problem of selecting the fault revealing mutants, i.e., the mutants that are killable and lead to test cases that uncover unknown program faults. We formulate two variants of this problem: the fault revealing mutant selection and the fault revealing mutant prioritization. We argue and show that these problems can be tackled through a set of ‘static’ program features and propose a machine learning approach, named FaRM, that learns to select and rank killable and fault revealing mutants. Experimental results involving 1,692 real faults show the practical benefits of our approach in both examined problems. Our results show that FaRM achieves a good trade-off between application cost and effectiveness (measured in terms of faults revealed). We also show that FaRM outperforms all the existing mutant selection methods, i.e., the random mutant sampling, the selective mutation and defect prediction (mutating the code areas pointed by defect prediction). In particular, our results show that with respect to mutant selection, our approach reveals 23% to 34% more faults than any of the baseline methods, while, with respect to mutant prioritization, it achieves higher average percentage of revealed faults with a median difference between 4% and 9% (from the random mutant orderings)

Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy.

Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization

Trivial compiler equivalence: A large scale empirical study of a simple, fast and effective equivalent mutant detection technique

Identifying equivalent mutants remains the largest impediment to the widespread uptake of mutation testing. Despite being researched for more than three decades, the problem remains. We propose Trivial Compiler Equivalence (TCE) a technique that exploits the use of readily available compiler technology to address this long-standing challenge. TCE is directly applicable to real-world programs and can imbue existing tools with the ability to detect equivalent mutants and a special form of useless mutants called duplicated mutants. We present a thorough empirical study using 6 large open source programs, several orders of magnitude larger than those used in previous work, and 18 benchmark programs with hand-analysis equivalent mutants. Our results reveal that, on large real-world programs, TCE can discard more than 7% and 21% of all the mutants as being equivalent and duplicated mutants respectively. A human- based equivalence verification reveals that TCE has the ability to detect approximately 30% of all the existing equivalent mutants

Detecting Trivial Mutant Equivalences via Compiler Optimisations

Mutation testing realises the idea of fault-based testing, i.e., using artificial defects to guide the testing process. It is used to evaluate the adequacy of test suites and to guide test case generation. It is a potentially powerful form of testing, but it is well-known that its effectiveness is inhibited by the presence of equivalent mutants. We recently studied Trivial Compiler Equivalence (TCE) as a simple, fast and readily applicable technique for identifying equivalent mutants for C programs. In the present work, we augment our findings with further results for the Java programming language. TCE can remove a large portion of all mutants because they are determined to be either equivalent or duplicates of other mutants. In particular, TCE equivalent mutants account for 7.4% and 5.7% of all C and Java mutants, while duplicated mutants account for a further 21% of all C mutants and 5.4% Java mutants, on average. With respect to a benchmark ground truth suite (of known equivalent mutants), approximately 30% (for C) and 54% (for Java) are TCE equivalent. It is unsurprising that results differ between languages, since mutation characteristics are language-dependent. In the case of Java, our new results suggest that TCE may be particularly effective, finding almost half of all equivalent mutants