Next Generation Sequencing-Based Tumor Genomic Profiling Aids in Detecting Hereditary Variants in Cancer Risk Genes

CHICAGO (May 20, 2015) — Cancer patients are increasingly having their tumors tested using comprehensive genomic profiling (CGP) to identify genetic mutations that can be targeted by precision therapies. A new study from investigators at Fox Chase Cancer Center in collaboration with Foundation Medicine has shown that 3-7% of patients receiving CGP could have a genetic mutation that they inherited from a parent that can also be identified using results from next generation sequencing (NGS)-based CGP.

NGS, also known as high-throughput sequencing, is the catch-all term used to describe a number of different modern sequencing technologies. These technologies have allowed the sequencing of DNA and RNA much more quickly and cheaply than previous sequencing techniques.

“NGS is an open-market, evolving field,” said Michael J. Hall, MD, MS, director of gastrointestinal risk assessment and associate professor of medicine at Fox Chase Cancer Center. “In the clinic, it is improving speed, access, and lowering the cost of genomics.” Dr. Hall will present the study results on May 31 at the 2015 American Society of Clinical Oncology Annual Meeting in Chicago.

In the study, germline, or hereditary variants, were predicted in data from 15,060 tumor samples that were analyzed by Foundation Medicine, a molecular information company based in Cambridge, MA. Analyses of variants focused on 20 hereditary cancer risk genes, determined by the American College of Medical Genetics and Genomics as “high priority for disclosure to patients if discovered by genomic testing.” The researchers assessed the pathogenicity of each variant and association with tumor histology via expert review of clinical evidence from multiple publically available variant annotation databases.

Among the tumors tested by the researchers, 30.8% had at least one germline variant in a cancer risk gene, with 521 total unique variants. A likely pathogenic variant was found in about 3.1% of tumors, and an additional 3.9% had a suspicious variant but conflicting pathogenicity data. Early-onset cancer was most strongly associated with pathogenic variants in BRCA1, a gene mostly associated with breast and ovarian cancers. Tumors for bladder cancer, squamous cell lung cancer, and kidney cancer had the most unexpected pathogenic variants, meaning these tumors were outside of the usual spectrum of cancers known to be associated with the particular gene and variant. However, data were insufficient to determine the pathogenicity for most of the variants identified.

The researchers noted some study limitations, which included the lack of data on race, family history, and controls, among others. Future short-term goals of the researchers include expanding the study to all hereditary cancer risk genes and to incorporate family history and healthy population variant rates. “More research is also needed to understand the impact that CGP has on patient behaviors,” Dr. Hall noted. “Our new genomic counseling pilot study is beginning to explore this in community-based colorectal cancer patients.”