A Rapid and Comprehensive Approach for Clinical Genomic Profiling in Lung Cancer

点击翻译按钮获取中文摘要

ABSTRACT The long-term goal of this project is to advance precision medicine by developing a simple, rapid, and comprehensive approach to molecular diagnostic testing that can be easily performed on any cancer subtype. In lung adenocarcinoma and many other solid tumor types, optimal treatment relies on the identification of specific genomic alterations. These include single nucleotide variants and small insertions and deletions, as well as larger copy number alterations and chromosomal translocations. Currently, clinical testing for these mutations requires multiple assays and significant amounts of tissue so that both DNA and RNA can be obtained for analysis. As a result, many samples fail or simply cannot be tested. At our cancer center 38% of lung cancer patient biopsies sent for comprehensive molecular evaluation either fail or result in incomplete results. More robust and streamlined diagnostic methods are therefore needed to provide truly comprehensive mutational profiling for all cancer patients. We have developed a novel approach for whole-genome sequencing (ChromoSeq) that provides rapid, unbiased evaluation of all mutation types in a single assay. ChromoSeq leverages recent advances in high-throughput sequencing methods to deliver a complete genomic profile in as little as 3 days using minimal DNA input. We have previously shown that ChromoSeq can provide rapid comprehensive genomic profiles from blood or marrow of patients with myeloid malignancies and that ChromoSeq has increased sensitivity to detect clinically significant genomic alterations compared to conventional methods. However, obtaining similar performance from solid tumors with limited amounts of degraded DNA typically obtained from formalin-fixed paraffin-embedded (FFPE) tissue biopsies is challenging. We hypothesize that with substantial methodologic pre-analytic improvements and rigorous clinical validation testing, ChromoSeq can also be used for the comprehensive genomic profiling of solid tumors. In this application, we propose to measure and optimize DNA changes that occur during pre-analytic tissue processing of routine clinical biopsies (Aim 1) and then establish the clinical performance of the assay using retrospectively and prospectively collected patient samples (Aim 2). These Aims will be performed in a CLIA-licensed, CAP- accredited laboratory with the overall objective of producing a CLIA-compliant assay for future use in clinical studies and to improve the diagnosis and treatment of patients with lung cancer. Tools and protocols developed in this application will enable other laboratories to benefit from this simplified approach to cancer genomic profiling.