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Cancer Driver Discovery Program

Lung cancer cells driven by the KRAS oncogene, which is highlighted in purple.

Credit: National Cancer Institute

Cancer Driver Discovery Program (CDDP) aims to identify driver mutations in as few as 2% of patients. Further elucidation of the molecular causes of cancer through deeper characterization of tumors is expected to yield insights into tumor biology, leading to better treatment options. Although a large number of driver mutations have been identified through the efforts of The Cancer Genome Atlas (TCGA), some tumor types have not been characterized deeply enough to reach that level of discovery. By sequencing larger numbers of cases, CDDP will have the statistical power to discover recurrent mutations in genes that may drive the oncogenic process.

CDDP selected cancers to be analyzed based on statistical models that suggest additional driver mutations remain to be discovered, while also considering the public health impact of further research into these cancers. As a pilot project, CDDP will analyze samples from lung, colon, and ovarian cancers, and all data will be shared through the Genomic Data Commons (GDC).

TRACERx Lung Cancer Study

CCG is partnering with Cancer Research UK’s TRACERx (Tracking Cancer Evolution through Treatment) study to better understand lung cancer outcomes through genomics. Launched in 2013, TRACERx, tracks the disease of 850 patients with lung adenocarcinoma over the course of their treatment, including when some patients tragically relapse following treatment. The goals of the study are to understand how intratumoral heterogeneity, meaning diversity within a tumor, affects clinical outcomes, and to establish the impact of particular lung cancer treatments on tumors.

TRACERx collaborators in the UK are analyzing the exomes, the areas of the genome that encode proteins, of the 850 patients at a deep enough level to measure intratumoral heterogeneity. Other collaborators in the UK will analyze the involvement of immune cells in the tumors as well as circulating cells and DNA in blood samples. CCG will contribute whole genome sequencing and total RNA sequencing to the TRACERx study. By providing information about the areas of the genome that do not code for proteins but impact cells in other ways, and the sequence and expression of RNA, CCG’s data will provide a clearer portrait of the cancer genomes and help TRACERx realize its goals.

Target Lung Cancer Project

CCG is characterizing the genomes of patients who donated tissues to the St. James’s Hospital Foundation Lung Cancer Biobank as part of the Target Lung Cancer project. Established in 2004, St. James’s Hospital Biobank collects and maintains tumor tissues and associated follow-up information, including patients’ treatments and long-term survival. St. James’s Hospital is providing 600 tissue samples that each have at least three years of follow-up data, and CCG will perform a suite of genomic analyses, including DNA sequencing of whole genomes as well as exomes, the areas of the genome that encode proteins, and total RNA sequencing. CCG will combine this comprehensive genomic characterization with clinical information to identify rare driver events and better understand patient responses.

Testing Cetuximab in the Treatment of Colon Cancer

An NCI-funded clinical trial comparing combination chemotherapy regimens with or without cetuximab, run by the North Central Cancer Treatment Group, will provide CCG with 1,400 biospecimens from its Phase III trial testing the addition of cetuximab to the treatment of patients with Stage III Colon Cancer. The trial randomly assigned qualifying patients to one of two treatment arms: a modified version of a chemotherapy regimen called FOLFOX, or the same FOLFOX regimen plus cetuximab, an antibody that binds to epidermal growth factor receptor (EGFR) to mitigate abnormal growth.

The trial’s aim to evaluate the effectiveness of cetuximab in combination with chemotherapy will be extended to a deeper understanding of the patient outcomes and a broader study of cancer genomics by CCG’s Genome Characterization Pipeline. CCG will provide information on DNA sequence, RNA sequence and expression, variations in the number of copies of genes, chemical markers added to DNA called methylation, and proteins, the molecular machines of the cell. Characterizing all of these genomic modalities within the context of clinical trial N0147 will allow CCG to identify molecular attributes associated with patient responses and contribute to a greater understanding of colon cancer.

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