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NGS-Cancer Panel Gene list

Gene mutation summary.

Summary of copy number data.

Mutation summary of individual tissue samples (Mutations with a frequency {greater than or equal to}1%)

Sample ID and Tissue Information.

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that remains poorly understood at the molecular level. Comprehensive tumor profiling was performed to understand clinically actionable alterations in IBC. Targeted next-generation sequencing (NGS) and IHC were performed to identify activated pathways in IBC tumor tissues. siRNA studies examined the impact of IBC genomic variants in cellular models. IBC tumor tissues were further characterized for immune infiltration and immune checkpoint expression by IHC. Genomic analysis identified recurrent alterations in core biologic pathways, including activating and targetable variants in HER/PI3K/mTOR signaling. High rates of activating HER3 point mutations were discovered in IBC tumors. Cell line studies confirmed a role for mutant HER3 in IBC cell proliferation. Immunologic analysis revealed a subset of IBC tumors associated with high CD8+/PD-L1+ lymphocyte infiltration. Immune infiltration positively correlated with an NGS-based estimate of neoantigen exposure derived from the somatic mutation rate and mutant allele frequency, iScore. Additionally, DNA mismatch repair alterations, which may contribute to higher iScores, occurred at greater frequency in tumors with higher immune infiltration. Our study identifies genomic alterations that mechanistically contribute to oncogenic signaling in IBC and provides a genetic basis for the selection of clinically relevant targeted and combination therapeutic strategies. Furthermore, an NGS-based estimate of neoantigen exposure developed in this study (iScore) may be a useful biomarker to predict immune infiltration in IBC and other cancers. The iScore may be associated with greater levels of response to immunotherapies, such as PD-L1/PD-1–targeted therapies. Mol Cancer Ther; 15(7); 1746–56. ©2016 AACR.

Ravi Varatharajalu,1 Kakuturu V Rao2 1The Department of Biochemistry and Molecular Medicine, The George Washington University, VA Medical Center, Washington, DC, 2American Molecular Laboratories, Vernon Hills, IL, USA Abstract: Strongyloides stercoralis is an intestinal nematode parasite with a global distribution. Most infected individuals have few or no symptoms. Strongyloidiasis is of primary medical importance, and fatal disease can occur in infected people who become immunosuppressed/immunocompromised through the administration of steroids or because of coinfection with human T-lymphotropic virus I. Often, misdiagnoses of strongyloidiasis in patients leads to expensive, nonspecific, invasive diagnostic techniques, including endoscopy, barium swallow, cancer biopsies, chest X-rays, and computerized tomography (CT) scans. Delayed treatment for strongyloidiasis brings in medical complications, such as vomiting, diarrhea, anemia, weight loss, pulmonary abnormalities, and septicemia. Chronic infection is difficult to diagnose by standard stool examination; hence, a reliable recombinant antigen-based serodiagnosis is important. Though albendazole and thiabendazole reduce the burden of the disease, they are not effective in an immunocompromised host. Ivermectin has the advantage of eradicating the disease, even in an immunocompromised host, with fewer side effects compared to albendazole. However, drug treatment is a temporary solution since reinfection can often occur. Thus, developing effective vaccine candidate antigens is imperative to stop the disease. Keywords: strongyloidiasis, hyperautoinfection, albendazole, thiabendazole septicemia, immunocompromised host, HTLV-1, ivermectin, gastrointestinal

Background Inflammatory breast Cancer (IBC) is a rare aggressive breast cancer in which cancer cells block the lymph vessels in the skin of the breast. IBC tumors have a high rate of ERBB2 positivity and response to ERBB2 targeted therapies. Due to the rarity of this cancer, the molecular etiology of this disease is poorly understood. Materials & Methods A 208 gene next-generation sequencing (NGS) panel was used to analyze 20 IBC patient tumor and matched normal samples. Tissues were stained for cell signaling proteins and immune-markers. Cell line studies were performed to understand the impact of genomic variants on therapeutic selection. Results Common pathway alterations reoccur among IBC samples that influence genome stability, PI3K signaling, and ERBB signaling. NGS revealed alterations in both the ERBB/PI3K pathways, including: ERBB2 amplification, ERBB3 mutations, and activating PI3K mutations. Immunohistochemistry (IHC) staining for pS6 and pERBB3 identified ERBB/PI3K pathway activity in IBC samples. Cell line studies using siRNA and neutralizing antibodies demonstrate that mutant ERBB3 signaling contributes to IBC proliferation. IBC tumors with high levels of CD8+ immune infiltrate have a significantly higher somatic mutation rate than other IBC tumors. A proposed score (iScore) based on the somatic mutation rate and the average mutant allele frequency, showed greater correlation with the level of CD8+ immune infiltration. Furthermore, tumors with high CD8+ infiltrating lymphocytes were associated with a higher frequency of alterations in DNA mismatch repair (MMR) genes. IHC revealed high levels of the immune checkpoint signaling molecule PD-L1 in the inflammatory infiltrate of IBC tumors. Conclusions This study identifies a higher level of ERBB3 mutations than reported in other cancers and an important role for ERBB3 mutation in IBC. ERBB3 targeted therapies in combination with ERBB/PI3K drugs may be important for IBC treatment. Furthermore, high somatic mutations rates in a subset of IBC tumors harboring MMR mutations lead to greater levels of PD-L1+ immune infiltrates, which suggests a possible benefit from immunotherapies such as anti-PD-L1 antibodies. iScore, a more predictive value of immune infiltration in tumors, may be indicative of the level of neoantigen exposure to the immune system. The utility of the newly proposed iScore is currently being investigated as a method to predict immune cell infiltrates and immunotherapy response in other tumor types. Citation Format: Diarmuid Moran, Christopher A. Hamm, Kakuturu Rao, Patricia Bacon-Trusk, Karen Pry, Victor Velculescu, Massimo Cristofanilli, Sarah S. Bacus. Genomic analysis identifies drug targetable pathways and predicts immune infiltration in inflammatory breast cancer tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3887. doi:10.1158/1538-7445.AM2015-3887