Christopher Douville

AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O ([C@ H] 1C [C@@](O)(CC= 2C (O)= C3C (= O) C= 4C= CC= C (C= 4C (= O) C3= C (O) C= 21) OC) C (= O) CO)[C@ H] 1C [C@ H](N)[C@@ H](O)[C@ H](C) O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 6GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1= C (F) C (NC (= O) OCCCCC)= NC (= O) N1 [C@ H] 1 [C@ H](O)[C@ H](O)[C@@ H](C) O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 6

A method for classifying data using non-negative matrix factorization can include receiving a population of sample data, generating a first matrix of the amplicon counts per sample data, dividing the first matrix into a product of a second matrix and a third matrix, in the second matrix, determining whether each signature is a long or short fragment per each amplicon count, in the third matrix, determining intensities of each signature per the sample data, and classifying the sample data based on the intensities of each signature. The population can include amplicon counts per sample data. The second matrix can include signatures of short and long DNA fragments and the third matrix can include intensities of each signature of the short and long DNA fragments.

Background: The Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The five complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors. Results: Performance was particularly strong for clinical pathogenic variants, including some difficult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical effects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less definitive and indicates performance potentially suitable for auxiliary use in the clinic. Conclusions: Results show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead.Critical assessment of genome interpretation consortium. CAGI, the critical assessment of genome interpretation, establishes progress and pprospects for computational genetic variant interpretation methods/Jain, Shantanu; Bakolitsa, Constantina; E Brenner, Steven; Radivojac, Predrag; Moult, John; Repo, Susanna; A Hoskins, Roger; Andreoletti, Gaia; Barsky, Daniel; Chellapan, Ajithavalli; Chu, Hoyin; Dabbiru, Navya; K Kollipara, Naveen; Ly, Melissa; J Neumann, Andrew; R Pal, Lipika; Odell, Eric; Pandey, Gaurav; C Peters …

Serous tubal intraepithelial carcinoma (STIC) is the fallopian tube precursor lesion for most cases of pelvic high-grade serous carcinoma (HGSC). To date, the morphologic, molecular, and clinical heterogeneity of STIC and a less atypical putative precursor lesion, termed serous tubal intraepithelial lesion, has not been well characterized. Better understanding of precursor heterogeneity could impact the clinical management of women with incidental STICs (without concurrent carcinoma) identified in cases of prophylactic or opportunistic salpingectomy. This study analyzed morphologic and molecular features of 171 STICs and 21 serous tubal intraepithelial lesions. We assessed their histologic features, Ki-67 and p53 staining patterns, and genome-wide DNA copy number alterations. We classified all precursor lesions into 2 morphologic subtypes, one with a flat surface (Flat) and the other characterized by budding …

Background The Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The fve complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors. Results Performance was particularly strong for clinical pathogenic variants, including some difcult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical efects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less defnitive and indicates performance potentially suitable for auxiliary use in the clinic. Conclusions Results show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly la

Purpose Serous tubal intraepithelial carcinoma (STIC) is now recognized as the main precursor of ovarian high-grade serous carcinoma (HGSC). Other potential tubal lesions include p53 signatures and tubal intraepithelial lesions. We aimed to investigate the extent and pattern of aneuploidy in these epithelial lesions and HGSC to define the features that characterize stages of tumor initiation and progression. Experimental Design We applied RealSeqS to compare genome-wide aneuploidy patterns among the precursors, HGSC (cases, n = 85), and histologically unremarkable fallopian tube epithelium (HU-FTE; control, n = 65). On the basis of a discovery set (n = 67), we developed an aneuploidy-based algorithm, REAL-FAST (Repetitive Element AneupLoidy Sequencing Fallopian Tube Aneuploidy in STIC), to correlate the molecular data with pathology diagnoses. We …

The current approach to diagnosing and monitoring tumors of the central nervous system relies almost exclusively on radiographic imaging and neurosurgical procedures. Cerebrospinal fluid (CSF) is appealing for diagnosis because it is already part of the standard of care for the diagnosis or management of several types of CNS disease, including cancer, and the tumor DNA is more highly concentrated inside the blood brain barrier than in plasma or other bodily fluids. Even though cytology is widely used, sensitivity remains low ranging from 2% to 50%, depending on cancer type. We report an analytic technique that efficiently introduces identical molecular barcodes to both strands of CSF template DNA molecules for the identification of cancer specific somatic mutations and copy number alterations. We apply this approach to 126 CSF samples obtained from individuals with known primary or metastatic tumors …

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the …

Background: Plasma proteins, directly secreted from tumor cells or a result of the body’s response to a tumor, may have utility for early detection. We aimed to identify plasma protein combinations that predict prediagnostic cancers in a prospective study. Methods: We sampled from 8,186 ARIC study participants without a cancer diagnosis at blood draw and with 4,877 log2-transformed proteins measured by SomaScan. We selected as cases those diagnosed within 5 years after blood draw and were registry/medical record confirmed. We selected as controls those who never had a cancer history by 2015 and did not die of cancer. Participants with possible liver, kidney, or inflammatory conditions were excluded (eGFR-cr<30, top 1% of plasma AST, ALT, CRP). Highly correlated proteins (r>±0.75), abundant or known markers (albumin, CRP, PSA), and proteins with wide log2-transformed distributions (SD>1 and >10 …

12Background: Adjuvant chemotherapy (CT) following neoadjuvant chemoradiation and surgery for locally advanced rectal cancer (LARC) is widely adopted, despite uncertain survival benefit. Circulating tumor DNA (ctDNA) detection after surgery has been shown to be a strong prognostic marker in localized colorectal cancer and potentially could inform adjuvant treatment decision making. Methods: AGITG DYNAMIC-Rectal is a multi-centre randomized controlled phase II trial. Eligible patients (pts) had LARC (cT3-4 and/or cN+) treated with neoadjuvant chemoradiation, total mesorectal excision, and were fit for adjuvant CT. Pts were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician decision). A tumor-informed personalized ctDNA assay was used. For the ctDNA-guided group, a positive result at 4 and/or 7 weeks after surgery prompted 4 months of oxaliplatin-based or …

BackgroundThe aim of the Ascertaining Serial Cancer patients to Enable New Diagnostic 2 (ASCEND 2) case-control study is to develop a classifier algorithm for a refined version of a multi-analyte blood-based MCED test. Here, we report the study design, enrollment, and sample selection from this large, multi-center, prospective, case-control study of clinically characterized participants.MethodsThe ASCEND 2 study engaged 151 sites within the US and Europe for subject enrollment. Samples consisted of blood collected using LBgard® tubes for plasma and buffy samples. The study population includes male and female subjects≥ 50 years old with known cancer, suspicion of cancer, and controls without cancer. All subjects provided informed consent and were assessed for study participation eligibility.ResultsOver 11,000 subjects were enrolled in this study. A subset of 6361 samples was selected to develop and …

Patients with epithelial ovarian cancer (EOC) often relapse despite surgery and chemotherapy. Current prognosis estimates, based on FIGO staging molecular features lack precision. Standard of care for stage I III EOC is 6 cycles of adjuvant chemotherapy, which may include 3 cycles of neoadjuvant treatment. Many treated patients do not benefit from chemotherapy because they had no residual disease post operatively or because treatment did not eradicate disease that was present. Studies in multiple solid tumor types have demonstrated that after curative intent surgery detectable ctDNA a marker of minimal residual disease (MRD) predicts a very high risk of recurrence. Our primary aim was to explore the association between detectable ctDNA following debulking of primary EOC and recurrence free survival (RFS). Secondary aims included exploring the relationship between ctDNA and RFS at EOC diagnosis, following neoadjuvant therapy and post adjuvant chemotherapy. In a prospective cohort of patients with epithelial ovarian cancer analysed for ctDNA Neoadjuvant therapy cohort - ctDNA was detectable pre treatment in most patients. Most pre treatment ctDNA ve patients remained ctDNA ve despite chemotherapy. Post cancer cytoreduction surgery cohort - ctDNA was more likely to be detected in patients with stage III/IV disease, those with residual disease, and those without a BRCA mutation. ctDNA detection was associated with 2 year RFS. Post adjuvant chemotherapy cohort - ctDNA detection was associated with a trend to inferior 2 year RFS.

It is often challenging to distinguish cancerous from non-cancerous lesions in the brain using conventional diagnostic approaches. We introduce an analytic technique called Real-CSF (repetitive element aneuploidy sequencing in CSF) to detect cancers of the central nervous system from evaluation of DNA in the cerebrospinal fluid (CSF). Short interspersed nuclear elements (SINEs) are PCR amplified with a single primer pair, and the PCR products are evaluated by next-generation sequencing. Real-CSF assesses genome-wide copy-number alterations as well as focal amplifications of selected oncogenes. Real-CSF was applied to 280 CSF samples and correctly identified 67% of 184 cancerous and 96% of 96 non-cancerous brain lesions. CSF analysis was considerably more sensitive than standard-of-care cytology and plasma cell-free DNA analysis in the same patients. Real-CSF therefore has the capacity to …

3039Background: Recommended standard of care (SOC) early detection tests are solely available for four cancer types and fewer than 20% of incident cancers in the US are being diagnosed as a result of screening. Advances in detection of tumor-derived analytes in the blood are enabling the development of MCED tests that may expand early cancer detection. While MCED tests are being designed with high specificity, false positive (FP) results remain a concern for clinicians and patients alike, as no long-term outcomes of individuals with a FP MCED test have been reported. DETECT-A was the first prospective interventional clinical trial to evaluate an MCED blood test. The test used was an early version of CancerSEEK, evaluated in 9,911 women without history of cancer (Science, 369:6499, 2020). This prospectively planned analysis evaluates cancer incidence among DETECT-A participants with FP results …

Cell-free DNA (cfDNA) concentrations from patients with cancer are often elevated compared with those of healthy controls, but the sources of this extra cfDNA have never been determined. To address this issue, we assessed cfDNA methylation patterns in 178 patients with cancers of the colon, pancreas, lung, or ovary and 64 patients without cancer. Eighty-three of these individuals had cfDNA concentrations much greater than those generally observed in healthy subjects. The major contributor of cfDNA in all samples was leukocytes, accounting for ∼76% of cfDNA, with neutrophils predominating. This was true regardless of whether the samples were derived from patients with cancer or the total plasma cfDNA concentration. High levels of cfDNA observed in patients with cancer did not come from either neoplastic cells or surrounding normal epithelial cells from the tumor's tissue of origin. These …

3037Background: Less than 20% of cancers are diagnosed as a result of standard-of-care (SOC) screening in the US. MCED tests may expand screening to more cancers, but the long-term outcomes of MCED test-detected cancers are unknown. DETECT-A was the first large prospective interventional clinical trial to evaluate an MCED blood test. The test used was an early version of CancerSEEK and was evaluated in 9,911 women without history of cancer (Science 369:6499, 2020). CancerSEEK, coupled with diagnostic PET-CT, safely identified cancers including those not detected by SOC screening, the majority of which were localized or regional. This follow-up observational study evaluated longitudinal clinical outcomes of cancers diagnosed as a result of an abnormal CancerSEEK test with a median follow up of 4.4 (IQR:4.1-4.6) years from initial CancerSEEK testing. Methods: Nine cancer types were …

BackgroundMCED tests may improve early cancer detection, but the impact of MCED testing on anxiety and standard of care (SOC) screening adherence is unknown. The DETECT-A trial evaluated the CancerSEEK MCED test in 9,911 women without a cancer history (Science, 359: 6499, 2020). DETECT-A participants without a cancer diagnosis were invited to a follow-up observational study involving annual surveys. Here we report on participant satisfaction, anxiety, intent to adhere to SOC cancer screening, and adherence to breast cancer screening.MethodsThe survey, conducted approximately 3 years after DETECT-A enrollment, assessed: a) whether participants regretted DETECT-A participation or would participate again, b) how likely they were to adhere to routine cancer screenings, and c) how participation affected their anxiety. Adherence to biennial mammography screening was assessed at the month …

The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To further increase the sensitivity of such assays with limited amounts of sample, it would be useful to be able to evaluate the same template molecules for all these changes. Here, we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The epigenetic …

Background: Cigarette smoking is a leading causal risk factor for 13 cancers. Widely used self-reported smoking/packyears may not fully capture individualized risk of smoking-related cancer. Biomarkers (e.g., smoking-related proteins) may reflect biological effect of smoking and refine risk for personalized cancer screening recommendation. Methods: Protein levels were measured by SomaScan assay (log2 transformed) in Visit 3 plasma from ARIC. Participants were divided 50/50 into set-1 for protein selection and score building and set-2 for association analyses. In set-1, protein levels were evaluated in association with smoking status, packyears smoked, and time since quitting using linear regression. Proteins that passed the Bonferroni threshold were screened with elastic net regression to address correlation. For positively-related proteins, those with levels ≥median were assigned the weight of 1. For …

Malignant peripheral nerve sheath tumors (MPNST) are the deadliest cancer that arises in individuals diagnosed with neurofibromatosis and account for nearly 5% of the 15,000 soft tissue sarcomas diagnosed in the United States each year. Comprised of neoplastic Schwann cells, primary risk factors for developing MPNST include existing plexiform neurofibromas (PN), prior radiotherapy treatment, and expansive germline mutations involving the entire NF1 gene and surrounding genes. PN develop in nearly 30–50% of patients with neurofibromatosis type 1 (NF1) and most often grow rapidly in the first decade of life. One of the most important aspects of clinical care for NF1 patients is monitoring PN for signs of malignant transformation to MPNST that occurs in 10–15% of patients. We perform aneuploidy analysis on ctDNA from 883 ostensibly healthy individuals and 28 patients with neurofibromas, including 7 patients with benign neurofibroma, 9 patients with PN and 12 patients with MPNST. Overall sensitivity for detecting MPNST using genome wide aneuploidy scoring was 33%, and analysis of sub-chromosomal copy number alterations (CNAs) improved sensitivity to 50% while retaining a high specificity of 97%. In addition, we performed mutation analysis on plasma cfDNA for a subset of patients and identified mutations in NF1, NF2, RB1, TP53BP2, and GOLGA2. Given the high throughput and relatively low sequencing coverage required by our assay, liquid biopsy represents a promising technology to identify incipient MPNST.