Broad Institute

About: Broad Institute is a nonprofit organization based out in Cambridge, Massachusetts, United States. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 6584 authors who have published 11618 publications receiving 1522743 citations. The organization is also known as: Eli and Edythe L. Broad Institute of MIT and Harvard.

Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas

Abstract: Purpose: The genetic differences between human papilloma virus (HPV)–positive and –negative head and neck squamous cell carcinomas (HNSCC) remain largely unknown To identify differential biology and novel therapeutic targets for both entities, we determined mutations and copy-number aberrations in a large cohort of locoregionally advanced HNSCC Experimental Design: We performed massively parallel sequencing of 617 cancer-associated genes in 120 matched tumor/normal samples (425% HPV-positive) Mutations and copy-number aberrations were determined and results validated with a secondary method Results: The overall mutational burden in HPV-negative and HPV-positive HNSCC was similar with an average of 152 versus 144 somatic exonic mutations in the targeted cancer-associated genes HPV-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53 , CDKN2A , MLL2 , CUL3 , NSD1 , PIK3CA , and NOTCH genes HPV-positive tumors showed unique mutations in DDX3X , FGFR2 / 3 and aberrations in PIK3CA , KRAS , MLL2 / 3 , and NOTCH1 were enriched in HPV-positive tumors Currently targetable genomic alterations were identified in FGFR1 , DDR2 , EGFR , FGFR2/3 , EPHA2 , and PIK3CA EGFR , CCND1 , and FGFR1 amplifications occurred in HPV-negative tumors, whereas 176% of HPV-positive tumors harbored mutations in fibroblast growth factor receptor genes ( FGFR2 / 3 ), including six recurrent FGFR3 S249C mutations HPV-positive tumors showed a 58% incidence of KRAS mutations, and DNA-repair gene aberrations, including 78% BRCA1/2 mutations, were identified Conclusions: The mutational makeup of HPV-positive and HPV-negative HNSCC differs significantly, including targetable genes HNSCC harbors multiple therapeutically important genetic aberrations, including frequent aberrations in the FGFR and PI3K pathway genes Clin Cancer Res; 21(3); 632–41 ©2014 AACR See related commentary by Krigsfeld and Chung, p 495

A public genome-scale lentiviral expression library of human ORFs

Abstract: Functional characterization of the human genome requires tools for systematically modulating gene expression in both loss-of-function and gain-of-function experiments. We describe the production of a sequence-confirmed, clonal collection of over 16,100 human open-reading frames (ORFs) encoded in a versatile Gateway vector system. Using this ORFeome resource, we created a genome-scale expression collection in a lentiviral vector, thereby enabling both targeted experiments and high-throughput screens in diverse cell types.

Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block.

Abstract: Context Prolongation of the electrocardiographic PR interval, known as firstdegree atrioventricular block when the PR interval exceeds 200 milliseconds, is frequently encountered in clinical practice. Objective To determine the clinical significance of PR prolongation in ambulatory individuals. Design, Setting, and Participants Prospective, community-based cohort including 7575 individuals from the Framingham Heart Study (mean age, 47 years; 54% women) who underwent routine 12-lead electrocardiography. The study cohort underwent prospective follow-up through 2007 from baseline examinations in 19681974. Multivariable-adjusted Cox proportional hazards models were used to examine the associations of PR interval with the incidence of arrhythmic events and death. Main Outcome Measures Incident atrial fibrillation (AF), pacemaker implantation, and all-cause mortality. Results During follow-up, 481 participants developed AF, 124 required pacemaker implantation, and 1739 died. At the baseline examination, 124 individuals had PR intervals longer than 200 milliseconds. For those with PR intervals longer than 200 milliseconds compared with those with PR intervals of 200 milliseconds or shorter, incidence rates per 10000 person-years were 140 (95% confidence interval [CI], 95-208) vs 36 (95% CI, 32-39) for AF, 59 (95% CI, 40-87) vs 6 (95% CI, 5-7) for pacemaker implantation, and 334 (95% CI, 260-428) vs 129 (95% CI, 123-135) for all-cause mortality. Correspondingabsoluteriskincreaseswere1.04%(AF),0.53%(pacemakerimplantation),and2.05% (all-cause mortality) per year. In multivariable analyses, each 20-millisecond increment in PR was associated with an adjusted hazard ratio (HR) of 1.11 (95% CI, 1.02-1.22;P=.02) for AF, 1.22 (95% CI, 1.14-1.30; P.001) for pacemaker implantation, and 1.08 (95% CI, 1.02-1.13; P=.005) for all-cause mortality. Individuals with first-degree atrioventricular block had a 2-fold adjusted risk of AF (HR, 2.06; 95% CI, 1.36-3.12;P.001), 3-fold adjusted risk of pacemaker implantation (HR, 2.89; 95% CI, 1.83-4.57; P.001), and 1.4-fold adjusted risk of all-cause mortality (HR, 1.44, 95% CI, 1.09-1.91; P=.01). Conclusion Prolongation of the PR interval is associated with increased risks of AF, pacemaker implantation, and all-cause mortality.