Using ‘LOHGIC’ to Assess Inherited Cancer Mutations

Article ID: 688286

Released: 23-Jan-2018 8:00 AM EST

Source Newsroom: Rutgers Cancer Institute of New Jersey

Newswise — New Brunswick, N.J. – January 23, 2018 – Investigators at Rutgers Cancer Institute of New Jersey have developed a statistical method to identify patients with potential inherited, germline alterations in tumor suppressor genes while estimating gene loss in cancer cells through targeted genome sequencing. This work describes the therapeutic implications of inherited cancer mutations, and highlights the ongoing collaboration between computational biologists and physician-scientists involved in the Precision Medicine Program.

Shridar Ganesan, MD, PhD, associate director for translational science and chief of molecular oncology at Rutgers Cancer Institute, associate professor of medicine and pharmacology at Rutgers Robert Wood Johnson Medical School, and the Omar Boraie Chair in Genomic Science, along with Rutgers Cancer Institute research member Hossein Khiabanian, PhD, an assistant professor of pathology and laboratory medicine at Rutgers Robert Wood Johnson Medical School, are the co-corresponding authors on the work. Rutgers Cancer Institute medical oncologist Kim Hirshfield, MD, PhD, an assistant professor of medicine at Rutgers Robert Wood Johnson Medical School is also a lead author on this work. They share more about the research published in the January 19, 2018, online edition of JCO Precision Oncology (doi: 10.1200/PO.17.00148):

Q:  Why is this topic important to explore?

A: Inherited germline mutations contribute to five to ten percent of all cancers. Specifically, hereditary breast and ovarian cancer (HBOC) syndrome is among the most common familial cancer syndromes, with a prevalence of one in 400 to one in 500 in the general population. Identifying these patients and characterizing their mutations have important clinical implications. For instance, some drugs that target genomic instability in cancer cells are only approved for patients with germline BRCA1/2 mutations. Moreover, these patients are at risk of other cancers, and their relatives may also benefit from genetic testing to assess risk.  

In the era of precision medicine, high-quality DNA sequencing of patient tumors has become an integral part of clinical care. Pathogenic mutations in genes associated with hereditary cancer syndromes, such as BRCA1/2, can be routinely detected by these assays. The identification of BRCA1/2 variants in tumor-only data raises two important questions: 1) does a mutation exist in the germline or is it somatically acquired during disease evolution; and 2) has the un-mutated copy of the gene been lost, making the cancer cells susceptible to targeted therapy? The latter question, specifically, cannot be answered by routine germline testing. Therefore, there is a need for methods that allow early detection of these mutations and precise determination of their status to design effective therapeutic approaches.

Q:  How did you approach this work and what did you discover?

A:  The Precision Medicine Program at Rutgers Cancer Institute profiles the genomics of patients using the FoundationOne® assay. The allele frequency of detected mutations depends on the relative number of cancer cells compared to normal cells (tumor purity) in the specimen. In case of somatic mutations, the mutant allele is only found in tumor cells. The germline mutant allele is present in both normal and tumor cells, although in some patients the un-mutated allele may have been lost due to other genomic alterations. We developed an algorithm called LOHGIC to integrate tumor purity, observed allele frequency, and gene copy number, while including statistical uncertainties that are inherent to sequencing assays. LOHGIC infers the mutational status of detected variants and can identify patients with germline mutations. LOHGIC’s results were extremely accurate when they were compared to available genomic testing data for a subset of patients.

Q:  What are the implications of these findings?

A: LOHGIC has helped us understand the differences in the tumor spectrum associated with the BRCA1/2 mutations. Specifically, patients with germline BRCA1 mutations, whose tumors had lost the wild-type copy, were all women with HBOC or fallopian tube cancers. In contrast, tumors with germline BRCA2 mutations had a much wider spectrum of cancers and were seen in both sexes. The LOHGIC algorithm, which is also available online, is now implemented at Rutgers Cancer Institute to analyze DNA sequencing data to guide the evaluation and treatment of patients found to have unexpected pathogenic mutations in familial cancer genes.

The research was supported by the Functional Genomics and Biospecimen Repository Shared Resource(s) of Rutgers Cancer Institute (P30CA072720) and a generous gift to the Genetics Diagnostics to Cancer Treatment Program at Rutgers Cancer Institute and RUCDR Infinite Biologics.  Other support/acknowledgements can be found at http://ascopubs.org/doi/pdf/10.1200/PO.17.00148.  

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