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Somatic mutations and single nucleotide variants (SNVs) in paired tissue from cervical swabs, serum/plasma and urine from patient TG01

Mutational profile in Black HNSCC patients by anatomic site

Supplementary Figure 1

Supplementary Figure 4

Supplementary Figure 2

Differences in the frequency of somatic mutations observed in Non-Latino Whites and Black HNSCC patients.

The top differentially altered pathways revealed by Gene Ontology (GO) clustering when comparing Black and NLW HNSCC patients.

Legends for Supplementary Figures 1-4

Patient cohorts analyzed in this project.

Survival alleles at SNV level

Supplementary Figure 3

Aircraft Tracking Analogy that integrates Contextual, Bio-psychosocial and Molecular Determinants of Population Health in a Patient Centered Trajectory that can be used in Personalized Medicine workflows.

Methylation and mutation associations

Supplemental Methods, Figures and Tables

Molecular alterations that contribute to long-term (LT) and short-term (ST) survival in ovarian high-grade serous carcinoma (HGSC) may be used as precision medicine biomarkers. DNA promoter methylation is an early event in tumorigenesis, which can be detected in blood and urine, making it a feasible companion biomarker to somatic mutations for early detection and targeted treatment workflows. We compared the methylation profile in 12 HGSC tissue samples to 30 fallopian tube epithelium samples, using the Infinium Human Methylation 450K Array. We also used 450K methylation arrays to compare methylation among HGSCs long-term survivors (more than 5 years) and short-term survivors (less than 3 years). We verified the array results using bisulfite sequencing and methylation-specific PCR (qMSP). in another cohort of HGSC patient samples (n = 35). Immunoblot and clonogenic assays after pharmacologic unmasking show that HIST1H2BB and MAGI2 promoter methylation downregulates mRNA expression levels in ovarian cancer cells. We then used qMSP in paired tissue, ascites, plasma/serum, vaginal swabs, and urine from a third cohort of patients with HGSC cancer (n = 85) to test the clinical potential of HIST1H2BB and MAGI2 in precision medicine workflows. We also performed next-generation exome sequencing of 50 frequently mutated in human cancer genes, using the Ion AmpliSeqCancer Hotspot Panel, to show that the somatic mutation profile found in tissue and plasma can be quantified in paired urine samples from patients with HGSC. Our results suggest that HIST1H2BB and MAGI2 have growth-suppressing roles and can be used as HGSC precision medicine biomarkers.

Cox regression analysis of TCGA Head and Neck Squamous Cell Carcinoma patients (n=279).

Somatic mutations and single nucleotide variants (SNVs) in paired tissue from cervical swabs, serum/plasma and urine from patient TG05

To inform novel personalized medicine approaches for race and socioeconomic disparities in head and neck cancer, we examined germline and somatic mutations, immune signatures, and epigenetic alterations linked to neighborhood determinants of health in Black and non-Latino White (NLW) patients with head and neck cancer. Cox proportional hazards revealed that Black patients with squamous cell carcinoma of head and neck (HNSCC) with PAX5 (P = 0.06) and PAX1 (P = 0.017) promoter methylation had worse survival than NLW patients, after controlling for education, zipcode, and tumor–node–metastasis stage (n = 118). We also found that promoter methylation of PAX1 and PAX5 (n = 78), was correlated with neighborhood characteristics at the zip-code level (P < 0.05). Analyses also showed differences in the frequency of TP53 mutations (n = 32) and tumor-infiltrating lymphocyte (TIL) counts (n = 24), and the presence of a specific C → A germline mutation in JAK3, chr19:17954215 (protein P132T), in Black patients with HNSCC (n = 73; P < 0.05), when compared with NLW (n = 37) patients. TIL counts are associated (P = 0.035) with long-term (>5 years), when compared with short-term survival (

Molecular alterations that contribute to long-term (LT) and short-term (ST) survival in ovarian high-grade serous carcinoma (HGSC) may be used as precision medicine biomarkers. DNA promoter methylation is an early event in tumorigenesis, which can be detected in blood and urine, making it a feasible companion biomarker to somatic mutations for early detection and targeted treatment workflows. We compared the methylation profile in 12 HGSC tissue samples to 30 fallopian tube epithelium samples, using the Infinium Human Methylation 450K Array. We also used 450K methylation arrays to compare methylation among HGSCs long-term survivors (more than 5 years) and short-term survivors (less than 3 years). We verified the array results using bisulfite sequencing and methylation-specific PCR (qMSP). in another cohort of HGSC patient samples (n = 35). Immunoblot and clonogenic assays after pharmacologic unmasking show that HIST1H2BB and MAGI2 promoter methylation downregulates mRNA expression levels in ovarian cancer cells. We then used qMSP in paired tissue, ascites, plasma/serum, vaginal swabs, and urine from a third cohort of patients with HGSC cancer (n = 85) to test the clinical potential of HIST1H2BB and MAGI2 in precision medicine workflows. We also performed next-generation exome sequencing of 50 frequently mutated in human cancer genes, using the Ion AmpliSeqCancer Hotspot Panel, to show that the somatic mutation profile found in tissue and plasma can be quantified in paired urine samples from patients with HGSC. Our results suggest that HIST1H2BB and MAGI2 have growth-suppressing roles and can be used as HGSC precision medicine biomarkers.

OBJECTIVE Neurosurgical evacuation in elderly trauma patients is controversial. We analyzed impact of craniotomy for acute subdural hematoma on survival in octogenarians and nonagenarians. Methods The study population included all patients aged ≥ 80 years who presented with acute traumatic SDHs 09/01/15 - 01/01/20, with radiography indicating operative eligibility (i.e. MLS >5 mm and/or overall thickness >10 mm). Of 1054 TBIs aged ≥ 80 years, 104 (9.87%) were surgically indicated. Of these, 35 received craniotomy and 69 received supportive measures due to family/patient wishes or surgeon's professional decision. We analyzed these data using a Poisson regression adjusted for influence of covariates. RESULTS Of 35 craniotomies, 21 (60.00%) were deceased at 2 years of follow-up, compared to 48 (69.57%) deceased of 69 non-surgical patients. No significant demographic differences existed between these groups, other than age (craniotomy patients were younger; median age 84 vs 86; p

Single nucleotide polymorphisms associated with lipid metabolism and energy balance are implicated in the weight loss response caused by nutritional interventions. Diet‑induced weight loss is also associated with differential global DNA methylation. DNA methylation has been proposed as a predictive biomarker for weight loss response. Personalized biomarkers for successful weight loss may inform clinical decisions when deciding between behavioral and surgical weight loss interventions. The aim of the present study was to investigate the association between global DNA methylation, genetic variants associated with energy balance and lipid metabolism, and weight loss following a non‑surgical weight loss regimen. The present study included 105 obese participants that were enrolled in a personalized weight loss program based on their allelic composition of the following five energy balance and lipid metabolism‑associated loci: Near insulin‑induced gene 2 (INSIG2); melanocortin 4 receptor; adrenoceptor β2; apolipoprotein A5; and G‑protein subunit β3. The present study investigated the association between a global DNA methylation index (GDMI), the allelic composition of the five energy balance and lipid metabolism‑associated loci, and weight loss during a 12 month program, after controlling for age, sex and body mass index (BMI). The results demonstrated a significant association between the GDMI and near INSIG2 locus, after adjusting for BMI and weight loss, and significant trends were observed when stratifying by gender. In conclusion, a combination of genetic and epigenetic biomarkers may be used to design personalized weight loss interventions, enabling adherence and ensuring improved outcomes for obesity treatment programs. Precision weight loss programs designed based on molecular information may enable the creation of personalized interventions for patients, that use genomic biomarkers for treatment design and for treatment adherence monitoring, thus improving response to treatment.

// Francesca Pirini 1, * , Sassan Noazin 2, * , Martha H. Jahuira-Arias 3, 4, * , Sebastian Rodriguez-Torres 3 , Leah Friess 3 , Christina Michailidi 3 , Jaime Cok 5 , Juan Combe 6 , Gloria Vargas 7 , William Prado 8 , Ethan Soudry 3 , Jimena Perez 3 , Tikki Yudin 3 , Andrea Mancinelli 3 , Helen Unger 3 , Carmen Ili-Gangas 9, 10 , Priscilla Brebi-Mieville 9, 10 , Douglas E. Berg 11, 12 , Masamichi Hayashi 3, 13 , David Sidransky 3 , Robert H. Gilman 2, 4 , Rafael Guerrero-Preston 3, 14 1 Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 2 The Johns Hopkins University, Bloomberg School of Public Health, Department of International Health, Baltimore, MD, USA 3 The Johns Hopkins University, School of Medicine, Otolaryngology Department, Head and Neck Cancer Research Division, Baltimore, MD, USA 4 Universidad Peruana Cayetano Heredia, Lima, Peru 5 Hospital Nacional Cayetano Heredia, Pathology Department, Lima, Peru 6 Instituto Nacional de Enfermedades Neoplasicas, Gastroenterology Department, Lima, Peru 7 Hospital Nacional Arzobispo Loayza, Gastroenterology Department, Lima, Peru 8 Hospital Nacional Dos de Mayo, Gastroenterology Department, Lima, Peru 9 Laboratory of Molecular Pathology, Department of Pathological Anatomy, School of Medicine, Universidad de La Frontera, Temuco, Chile 10 Center of Excellence in Translational Medicine - Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco, Chile 11 Washington University Medical School, Department of Molecular Microbiology, St Louis, MO, USA 12 University of California San Diego, Department of Medicine, La Jolla, CA, USA 13 Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan 14 University of Puerto Rico School of Medicine, Department of Obstetrics and Gynecology, San Juan, Puerto Rico * These authors equally contributed to this work Correspondence to: Rafael Guerrero-Preston, email: rafael.guerrero@upr.edu Robert H. Gilman, email: rgilman1@jhmi.edu Keywords: translational epigenomics, global DNA methylation index, epigenome-wide DNA methylation analysis, IRF4, ELMO1 Received: January 09, 2017 Accepted: February 24, 2017 Published: March 16, 2017 ABSTRACT Clinically useful molecular tools to triage gastric cancer patients are not currently available. We aimed to develop a molecular tool to predict gastric cancer risk in endoscopy-driven biopsies obtained from high-risk gastric cancer clinics in low resource settings. We discovered and validated a DNA methylation biomarker panel in endoscopic samples obtained from 362 patients seen between 2004 and 2009 in three high-risk gastric cancer clinics in Lima, Peru, and validated it in 306 samples from the Cancer Genome Atlas project (“TCGA”). Global, epigenome wide and gene-specific DNA methylation analyses were used in a Phase I Biomarker Development Trial to identify a continuous biomarker panel that combines a Global DNA Methylation Index (GDMI) and promoter DNA methylation levels of IRF4, ELMO1, CLIP4 and MSC . We observed an inverse association between the GDMI and histological progression to gastric cancer, when comparing gastritis patients without metaplasia (mean = 5.74, 95% CI, 4.97−6.50), gastritis patients with metaplasia (mean = 4.81, 95% CI, 3.77−5.84), and gastric cancer cases (mean = 3.38, 95% CI, 2.82−3.94), respectively ( p 4 are useful molecular tools for gastric cancer risk stratification in endoscopic biopsies.

Clinically useful molecular tools to triage gastric cancer patients are not currently available. We aimed to develop a molecular tool to predict gastric cancer risk in endoscopy-driven biopsies obtained from high-risk gastric cancer clinics in low resource settings. We discovered and validated a DNA methylation biomarker panel in endoscopic samples obtained from 362 patients seen between 2004 and 2009 in three high-risk gastric cancer clinics in Lima, Perú, and validated it in 306 samples from the Cancer Genome Atlas project (“TCGA”). Global, genome wide and gene-specific DNA methylation analyses were used in a Phase I Biomarker Development Trial to identify a continuous biomarker panel that combines a Global DNA Methylation Index (GDMI) and promoter DNA methylation levels of IRF4, ELMO1, CLIP4 and MSC. We observed an inverse association between the GDMI and histological progression to gastric cancer, when comparing gastritis patients without metaplasia (mean= 5.74, 95% CI, 4.97-6.50), gastritis patients with metaplasia (mean= 4.81, 95% CI, 3.77-5.84), and gastric cancer cases (mean=3.38, 95% CI, 2.82-3.94), respectively (p 4, is a useful molecular tool for gastric cancer risk stratification in endoscopic biopsies. Citation Format: Francesca Pirini, Sassan Noazin, Martha Jahuira Arias, Sebastian Rodriguez-Torres, Leah Friess, Christina Michailidi, Jaime Cok, Juan Combe, Goria Vargas, William Prado, Ethan Soudry, Jimena Perez, Tikki Yudin, Andrea Mancinelli, Helen Unger, Carmen Ili, Priscilla Brebi, Douglas Berg, Masamichi Hayashi, David Sidransky, Robert Gilman, Rafael E. Guerrero-Preston. Early detection of gastric cancer using global and gene-specific promoter DNA methylation in endoscopic biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-247. doi:10.1158/1538-7445.AM2017-LB-247