Abstract 3689: Jak3 mutations in colorectal neoplasia- Preliminary data on a not so silent minority

As a tumorigenesis model, colorectal cancer is associated with multiple gene mutations accumulating progressively but also has mutations that may alter disease course and provide a therapeutic target. Good examples of this are EGFR and VEGF. In melanoma, PD-1 interactions involving the immunobiome are therapeutically important. We conducted a study to detect potential mutations that might enhance therapy in colorectal cancer guided by expression of p87, a product of innate immune system Paneth cells. Methods: Adnab-9 immunohistochemistry or ELISA was used to define significant p87 Adenoma-associated antigen field effects (FE) in 10 patients with u003e1cm large high grade dysplastic adenomas (LHiGDA) and 3 with smaller high grade dysplastic adenomas (SHiGDA). We postulated that SHiGDA are not immunologically recognized by host defenses leading to negative outcomes. We used Ion Torrent™ sequencing (ITS) to find mutations in DNA (QiaAmp kit) extracted from 4 normal-appearing colonic segments taken from 1 patient in each group. Novel mutations found on ITS would then be sought using PCR with appropriate primers and subsequent sequencing of the PCR product circulating DNA extracted from available serum samples. These samples were taken from the Large- and SHiGDA groups described above and from 17 patients undergoing colonoscopy for diverse indications. Results: p87 FE were found in 40% of 10 LHiGDA and 0% of 3 SHiGDA patients. The ITS in the 2 representative patients showed unique mutational fields in: KRAS, APC, p53 in the LHiGDA and Jak3, PIK3Ca, p53, APC in the SHiGDA patient, both of whom lacked p87 FE. PCR using the Jak3 primers used in the ITS and subsequent sequencing revealed the same non-synonymous mutation in the serum of a FAP patient after colonic resection and an additional colonic segment of the selected ShiGDA patient but not in his serum. Other Jak3 mutations were found in 1 of 8 LHiGDA, 1 (the selected patient) of 3 SHiGDA, 1 of 7 patients with FAP and 1 of 10 colonoscopy patients with a family history of colorectal cancer with a FE and an untoward outcome. The selected SHiGDA patient subsequently contracted and died of NSCLC adenocarcinoma. The positive LHiGDA and FAP patients had a severely dysplastic anal condyloma and severe pancreatitis, respectively. Overall, the non-synonymous mutation occurring in the non-FAP SHiGDA patient occurred in the absence of p87 FE. Conclusions: In this pilot study we demonstrate the presence of Jak3 mutations likely associated with the lack of p87 expression in patients with high grade dysplastic adenomas and 1 FAP patient. Most of these patients had a clinical course which may have differed from their group members suggesting an altered immune system milieu. If confirmed in SHiGDA and FAP, Jak 3 mutations, associated with the SCID and late onset combined immunodeficiency, may allow for intervention with currently available medications to potentially avert a deleterious clinical outcome. Citation Format: Martin Tobi, Xiaoping Zhao, Darshana Jhala, Rebecca Rodriguez, Fadi Antaki, Edi Levi, Paula Sochacki, John Lieb, MaryAnn Rambus, Tapan Ganguly, Martin Bluth, Michael J. Lawson. Jak3 mutations in colorectal neoplasia- Preliminary data on a not so silent minority [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3689. doi:10.1158/1538-7445.AM2017-3689