Abstract Purpose Papillary renal cell carcinoma (PRCC) is the most common type of non-clear cell renal cell carcinoma (NCCRCC). Of PRCC, PRCC,type2(PRCC2) is known to have highly aggressiveness and relative drug resistance. In contrast of clear cell renal cell carcinoma (CCRCC), we poorly understand genetic alterations to drive PRCC2. Moreover, though many tyrosine kinase inhibitors (TKIs) are now available to treat PRCC, the predictive marker of TKIs is not in existence. Therefore, we aimed to analyze genetic alteration of PRCC2. Patients and Methods We performed whole-exome sequencing (WES) of DNA from 9 PRCC2 samples and matched normal tissue. In addition, whole-transcriptome sequencing (WTS) was conducted for 7 of these samples. We analyzed somatic mutations, copy number alterations, germ line mutations using WES data, pathway alterations and gene fusions through RNA expression data. We investigated the relationship between clinical prognosis and genetic alterations. Results Of nine samples, average non-silent mutation rate is 1.13 mutations per Mb (range, 0.49 to 2.14 mutations per Mbs). Forty-seven somatic mutations including SRRD(four), PKD1L2(three) and MX1(three) are discovered in more than 2 specimens. The genes associated to histone modification and ubiqutination are frequently altered. We found FH somatic mutation, a potent target of VEGFR TKI, in young female PRCC2 patient. Her tumor is extremely shrunk after 6cycles treatment and after that she received pazopanib for 52weeks maintaining effective response. Conclusion We suggest the possibility of translational research from sequencing data to real medical treatment of PRCC2. This pivotal study demonstrates that novel somatic FH mutation is the therapeutic target of VEGFR TKI. Therefore, further large scaled comprehensive genetic analysis of PRCC2 is required to propose personalized medicine for conquering papillary renal cell carcinoma, type 2. Note: This abstract was not presented at the meeting. Citation Format: Ji-Yeon Kim, Se-Hoon Lee, Soojin Cha, Kyung Chul Moon, Jong-Il Kim, Dae Seog Heo. Clinical applications of comprehensive genome analysis of papillary renal cell carcinoma, type II. [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 2994. doi:10.1158/1538-7445.AM2015-2994