Overall Goal: To identify genes and pathways or mechanisms associated with patient reported outcomes (PRO) in an important area of symptom science: chemotherapy induced peripheral neuropathy (CIPN). Background: CIPN is the most important unmitigated toxicity of cancer treatments. As survivorship ranks grow, CIPN incidence continues to rise. 400,000 new cases occur yearly adding annual healthcare costs of $2.3 billion. Studies by us and others have associated CIPN susceptibility with single nucleotide variants (SNV) in several genes suggesting that CIPN is a complex genetic trait. Preliminary Data: CIPN phenotyping by adverse PRO provided statistical power equivalent to increasing the patient number (compared with prior designs) 5.1-fold. In a whole exam sequencing (WES) study we found that CIPN was associated with common SNV and rare deleterious mutations in genes shared with hereditary neuropathies. Through an exam-wide analysis, we identified the myelination pathway as a molecular mechanism linked to CIPN through genetic variants. Hypothesis: Rare and common genetic variants contribute to the hereditary basis of CIPN PRO. Statistical power considerations guide the Approach. WES has a record of successful implementation in small cohorts such as the NHLBI acute lung injury WES (n=88) and the NHLBI chronic P. aeruginosa infection WES (n=91). Our inaugural WES study on CIPN was also small, n=119, yet provided results with study-wide significance by prioritizing biologically informed hypotheses and by testing per-gene/pathway. The proposal aims to increase power further by larger cohorts; it also extends our studies to another class of chemotherapy drugs causing CIPN.
Aim 1. Determine rare coding mutations and common SNV by WES in 180 patients with extreme CIPN PRO phenotypes in the oxaliplatin trial N08CB; test HN genes for an association with CIPN due to rare mutations or common SNV; identify molecular mechanisms/pathways genetically associated with oxaliplatin-CIPN.
This aim will apply the methods from our paclitaxel WES study (preliminary data) to a new drug class (platinum's).
Aim 2. Test if increased genomic variation in regulatory (non-coding) regions of CIPN candidate genes is associated with the PRO phenotype.
This aim will apply a new method, whole genome sequencing (WGS), to patients previously analyzed by us with WES.
Aim 3. Analyze candidate genes nominated because of a role for QOL unrelated to peripheral nervous system (PNS) biology: forebrain- and immune system mechanisms.
Aim 4. Validate key results from Aims 1 and 2 by sequencing a newly designed CIPN custom gene panel in two independent cohorts with serial CIPN phenotyping (n=400 paclitaxel, n=400 oxaliplatin). Responsiveness to FOA 13-264: The proposal responds to the FOA by using WES and WGS as emerging technologies to predict individual susceptibility of patients to CIPN symptoms, which will be quantified with innovative methods based on serial PRO. Diverse information consisting of rare and common germ line genetic variants with coding and regulatory functions will be integrated.
Chemotherapy induced peripheral neuropathy (CIPN) is the most important unmitigated toxicity of cancer treatments. CIPN symptoms consist of chronic pain, loss of sensation, and autonomic dysfunction. More than 400,000 new cases occur yearly adding annual healthcare costs of $2.3 billion. Oxaliplatin and taxanes are the single most important cause of CIPN. The proposed study examines the genetic basis of oxaliplatin and paclitaxel -CIPN with dual long- term goals: First, to improve our ability to predict whether an individual patient is at risk and, second, to understand the molecular mechanisms under genetic control that underlie CIPN.
