Abstract 4493: Germline findings in targeted tumor sequencing using matched normal DNA
Authors: Krishnan Subha , Basu Gargi D. , Gonzalez-Malerva Laura , Royce Thomas , White Tracey , Lobello Janine R. , King Amy , Lau Kevin , Kurdoglu Ahmet , Halbert Matthew , Kiefer Jeff , Cherni Irene , Aldrich Jessica , Izatt Tyler , Russell Megan , Nasser Sara , Carpten John D. , Craig David W. , Trent Jeffrey , Demeure Michael J. 
Published: July 2016

Background: The promise of precision medicine is vast and efforts are needed to increase utilization of precision oncology tests. Studies have suggested that mutations in cancer predisposition are more common than previously thought. Herein, we investigated germline alterations in cancer patients undergoing tumor profiling to identify the potential genetic predisposing factors as well as therapeutically relevant germline variants.

Methods: Comprehensive genomic profiling was performed on tumor samples from 67 patients from 24 cancer types with ages ranging 23-77 years. We performed targeted exome sequencing of 562 genes in tumor and paired normal DNA which included 116 genes that have been associated with cancer predisposition syndromes. In addition to identifying the somatic changes, we characterized germline mutations in select 116 genes using public databases (ClinVar, Ensembl).

Results: Pathogenic germline mutations were found in 17.91% (12/67) of cases, which included 10 unique variants in 8 genes, the majority of which included DNA repair genes (ATM, BRCA2, ERCC4, NBN, PSM2, MUTYH, XPC and AR). Likely pathogenic mutations were found in 23% (16/67) of the cases and 12% (8/67) were predicted pathogenic by SIFT/PolyPhen. In select cases we found existence of a 2nd hit which may have an impact on certain targeted therapeutics such as PARP inhibitors. All of the cases profiled carried either benign or variants of unknown significance (VUS) mutations. Germline findings in cancer susceptibility genes that were concordant with the individual's cancer type included ATM (R2227C) in HER2+ breast cancer patient; BRCA2 missense mutation (K944X) in peritoneal cancer and HER2+ breast cancer; BRCA2 (W1692MfsX3, I2588YfsX60) in patients with pancreatic and breast cancer respectively and PMS2(L729QfsX6) in colorectal cancer (CRC). Germline pathogenic findings in cancer susceptibility genes that were dis-concordant with the individual's cancer type included ERCC4 (R799W) in endometrial cancer; XPC (P334H) in CRC; MUTYH (G393D) in esophageal and CRC; NBN (K219NfsX16) in HER2+ breast cancer and AR (A646D) mutation in CRC. Interestingly, FLT4 (R1324L) mutation which is associated with decreased response and toxicity to sunitinib in renal cell cancer was found across several tumor types including lung adenocarcinoma (n = 3), pancreatic cancer (n = 3), HER2+ breast cancer (n = 2), CRC (n = 2) and n = 1 in gallbladder carcinoma, cholangiocarcinoma and endometrial adenocarcinoma. The comparison of somatic to germline mutation will be presented.

Conclusion: Germline data analysis of a small cohort of advanced cancer patients revealed that unselected cancer patients may benefit from germline evaluation which may influence the evaluation and care of the patient or the patient's family members. Even though majority of germline mutations were VUS, several mutations were identified which may be amenable to targeted therapeutic strategies.

Citation Format: Subha Krishnan, Gargi D. Basu, Laura Gonzalez-Malerva, Thomas Royce, Tracey White, Janine R. Lobello, Amy King, Kevin Lau, Ahmet Kurdoglu, Matthew Halbert, Jeff Kiefer, Irene Cherni, Jessica Aldrich, Tyler Izatt, Megan Russell, Sara Nasser, John D. Carpten, David W. Craig, Jeffrey Trent, Michael J. Demeure. Germline findings in targeted tumor sequencing using matched normal DNA. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4493.