The Johns Hopkins University

Duke University

Amgen Inc.

Sian Jones

Bert Vogelstein

Kenneth W Kinzler

Victor E Velculescu

D Williams Parsons

Nickolas Papadopoulos

Jimmy Cheng-Ho Lin

Darell D Bigner

Hai Yan

Gregory J Riggins

Rebecca J Leary

Xiaosong Zhang

Chien-Tsun Kuan

Philipp Angenendt

Giovanni Parmigiani

Rachel Karchin

Tobias Sjoblom

Laura D Wood

Thomas Barber

Diana Mandelker

Sheng Cui

Liang Huang

Ying Chen

Krishnakumar Ranganathan

Kevin Crossley

Richard Crockett

Jeroen Bezemer

Asher Lower

Meng Li

Ralph Hruban

Scott E Kern

Michael Goggins

Manuel Medina Hidalgo

James R Eshleman

Donald Williams Parsons

Alison Klein

Jimmy Lin

Victor E Velculesu

Samuel Vincent Angiuoli

Luis Diaz

Williams Parsons

Kenneth Kinzler

Donald William Parsons

Jimmy Chang-Ho Lin

A method for preparing AMG 416, or a pharmaceutically acceptable salt thereof, is provided.

Method for preparing AMG 416 (etelcalcetide)

We found mutations of the R132 residue of isocitrate dehydrogenase 1 (IDH1) in the majority of grade II and III astrocytomas and oligodendrogliomas as well as in glioblastomas that develop from these lower grade lesions. Those tumors without mutations in IDH1 often had mutations at the analogous R172 residue of the closely related IDH2 gene. These findings have important implications for the pathogenesis and diagnosis of malignant gliomas.

Genetic alterations in isocitrate dehydrogenase and other genes in malignant glioma

We found mutations of the R132 residue of isocitrate dehydrogenase 1 (IDH1) in the majority of grade II and III astrocytomas and oligodendrogliomas as well as in gliblastomas that develop from these lower grade lesions. Those tumors without mutations in IDH1 often had mutations at the analogous R172 residue of the closely related IDH2 gene. These findings have important implications for the pathogenesis and diagnosis of malignant gliomas.

Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of &#x2dc;90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.

Consensus coding sequences of human breast and colorectal cancers

A method for preparing AMG 416, or a pharmaceutically acceptable salt thereof, is provided. AMG 416 is a synthetic, eight amino-acid selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with chronic kidney disease-mineral and bone disorder (CKD-MBD).

Method for preparing AMG 416

Two genes, ARID1A (AT-rich interactive domain-containing protein 1A) and PPP2R1A (protein-phosphatase 2, regulatory subunit 1, alpha), can be used in methods which are useful for detecting cancer, diagnosing cancer, contributing to a diagnosis of cancer, confirming a diagnosis of cancer, identifying appropriate treatments for cancer, monitoring treatment of cancer, and evaluating treatment protocols for cancer, including ovarian clear cell carcinoma, breast cancer, colon cancer, gastric cancer, lung cancer, medulloblastoma, pancreatic cancer, and prostate cancer.

ARID1A and PPP2R1A mutations in cancer

Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high density microarrays and sequenced all known protein-coding genes and miRNA genes using Sanger sequencing. We found that, on average, each tumor had 11 gene alterations, markedly fewer than in common adult cancers. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone H3K4 trimethylase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

Medulloblastoma genes as targets for diagnosis and therapeutics

The present invention provides a method for detecting mutations in the PALB2 gene in pancreatic cancer patients and in individuals having a family history of pancreatic cancer. Methods are also provided for diagnosing a predisposition to pancreatic cancer, for predicting a patient's response to pancreatic cancer therapies, and for treating pancreatic cancer, based on presence of a PALB2 mutation or abberant PALB2 gene expression in a patient.

Diagnostic method using PALB2

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Baltimore, MD, United States of America

Sian Jones