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Background: Precision oncology highlights the individualization of diagnosis, prognosis and treatment based on molecular stratification of cancer patients (pts). Genetic patterns in many types of cancer vary among geographical regions, leading to variation in evidence-based recommendations for clinical management of pts. Genomic alterations (GAs) of solid tumors from Chinese pts have not been fully studied across all cancer types. Methods: Tumor tissues and matched blood from 5355 Chinese pts were collected and sequenced by a next generation sequencing based 450-gene panel assay. About 60% of the samples were FFPE tissues. In our study, 59% were males and 41% were females with a median age of 58 years old (range 1-92). The major cancer types were NSCLC (36%), CRC (8%), HCC (7%), gastric cancer (5%), pancreatic cancer (5%), and also cholangiocarcinoma, esophageal carcinoma, SCLC, gallbladder carcinoma, ovarian cancer, breast cancer, head and neck cancer, sarcoma, renal carcinoma, uterine neoplasms and others. 1% were pediatric patients . Single base substitutions, short and long insertions/deletions (indels), copy number alterations (CNA), fusions/rearrangements, TMB and MSI status were assessed by NGS. Results: On average, our study identified 7 mutations per patient. Gene rearrangements and long indels (50bp - 2k) were detected in 15% and 5% of the cancers. In total, 58% of pts harbored GAs in druggable genes defined as targets of FDA approved drugs. Highest mutation frequencies were found in TP53 (60%), EGFR (23%), KRAS (18%), CDKN2A (13%), TERT (12%), PIK3CA (11%), APC (11%), LRP1B (10%), ARID1A (9%), and RB1 (8%) across all tumor types. The frequency of other druggable genes included BRCA1/2 (5%), BRAF (3%), HER2 amplifications (3%), MET amplifications (2%), ALK fusions (2%), RET fusions (0.7%), ROS1 fusions (0.7%), FGFR fusions (0.7%), NTRK fusion (0.6%). Frequency of GAs in druggable genes varied among different tumor types. For instance, EGFR mutations occurred in 49% of NSCLC, 7% of SCLC, 2% of gastric cancer, and 2% of CRC. NTRK fusions enriched in sarcoma (4%), gastric cancer (2%) and CRC (1%). The median TMB of the whole cohort was 4.6 muts/Mb and 6% had TMB higher than 20 muts/Mb. Top 3 tumors with highest median TMB were SCLC, CRC and gastric cancer, while pancreatic cancer and sarcoma had low TMB. As a pan-cancer biomarker for immunotherapy, pts with MSI-H accounted for 1.3% of solid tumors, including 9% of uterine neoplasms, 8% of CRC, 6% of gastric cancer and 2% of ICC. Conclusions: In summary, we have constructed a large-scale data set including somatic mutations, CNAs, fusions/rearrangements, TMB and MSI status from 5355 Chinese pts with more than 19 tumor types, which provided an extensive understanding of disease-specific indicators, outcomes and therapeutic strategies for both targeted and immune therapies in Chinese pts. Citation Format: Ming Yao, Minghui Wang, Mingwu Chen, Tao Shou, Jingyu Cao, Hui Chen, Aodi Wang, Lijuan Chen, Jinwei Hu, Shuirong Zhang, Kai Wang. Landscape of genomic alterations across solid tumors based on a comprehensive clinical sequencing analysis of 5355 Chinese cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5134.

Introduction: The proofreading 3'-5' exonuclease activities of DNA polymerase-ϵ (POLE) and δ (POLD1) are critical for preventing mutations. POLE and POLD1 mutations can lead to high tumor mutational burdens (TMB), and predict responsiveness to immune checkpoint inhibitors (ICPI) in the absence of microsatellite instability (MSI). We therefore analyzed the genomic alterations of POLE and POLD1 in Chinese colorectal cancer (CRC) patients by comprehensive genome profiling (CGP). Method: A cohort of 123 Chinese CRC patients (pts) comprising 76 males and 47 females (median age of 60) with both FFPE tumor samples and matched peripheral blood normal control were analyzed. The majority (40%) of the patients were stage IV, 26% were stage III, 18% were stage I/II and the rest were unknown. CGP was performed with a 450-gene panel. In addition to the genomic alterations, TMB and MSI were calculated by next-generation sequencing-based algorithms. Result: CGP revealed a typical CRC mutation landscape with TP53 in 71%, APC in 70% and KRAS in 50% of the 123 Chinese pts. Fifteen percent of the pts (19/123) were MSI-H. Median TMB of all CRC pts was 11 muts/Mb, and the MSI-H subgroup had significantly higher TMB value compared to MSS subgroup (119 vs 10 muts/Mb, p-value is 1.5E-08). In total, 10% of the pts (12/123) harbored POLE and/or POLD1 known somatic mutations in the COSMIC database, including 10 POLE mutations in 8 pts and 7 POLD1 mutations in 7 pts. The 12 pts had a median age of 60 yrs (range 32-81), and 5/12 were females. Eight out of the 12 pts were associated with MSI-H. Additionally, 21 novel somatic short variants of uncertain significance (VUS) in 8 pts were detected (8/123=6.5%), and 5 pts were associated with MSI-H. Eight out of 123 Chinese CRC pts (6.5%) had POLE known mutations, which is significantly higher than 0.7% in Western population (p=9e-9). Four pts had loss-of-function (LOF) mutations. Two cases were POLE V411L associated with younger ages and the other two were truncations. All four CRC patients possess very high TMB compared to the whole cohort (305 vs 11 muts/Mb) while three of them are microsatellite stable (MSS) at stage III and IV. Conclusion: Our small cohort suggests a higher incidence of known POLE and POLD1 mutations in Chinese CRC patients and warrants further study. Our results highlight the clinical utility of comprehensive genome profiling in identifying likely responders to immune checkpoint inhibitors. Citation Format: Yinbo Chen, Sen Zhang, Wei Huang, Jun Guo, Weidong Guo, Fabo Qiu, Meihai Deng, Jingyu Cao, Samuel J. Klempner, Shun Yao, Jicheng Yao, Shou Mu, Ming Yao, Kai Wang, Weifeng Wang. High incidence of POLE and POLD1 mutations in Chinese colorectal cancer patients identified by comprehensive genomic profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4335.

Background: Intrahepatic cholangiocarcinoma (ICC) is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis. Targeted and immune-therapy have yielded promising therapeutic effects in various solid tumor patients (pts). Thus the understanding of ICC genomic profiling, especially which of Chinese pts, seems to be necessary for the treatment strategy for ICC. Methods: Comprehensive genomic profiling of molecular alterations and predictive biomarkers to personalized treatment genes were performed on Formalin Fixed Paraffin Embedded (FFPE) samples and matched blood samples of 69 Chinese ICC pts. Genomic alterations (GAs) including substitutions, short and long insertion/deletions (indels), copy number variations and gene rearrangements were assessed. Tumor mutation burden (TMB) of total somatic substitutions and indels per megabase after filtering known driver mutations was calculated. Microsatellite instability (MSI) status was determined by identifying and scoring multiple mono-nucleotide repeats loci. Results: Median age of the 69 ICC pts was 58 years (range: 38-88), and male vs female was approximately 3:1. Average of 3.7 GAs /sample and 0.9 actionable GAs/sample were detected. The most widespread genomic alterations among the pts were revealed as TP53 (44.9%), ARIDIA (23.2%), KRAS (18.8%), BAP1 (14.5%), IDH1/2 (14.5%), PIK3CA (11.6%), FGFR2/3 (10.1%), MLC1 (8.7%), CDKN2A/B (8.7%), BRAF (7.2%), TERT (7.2%), PBRM1 (7.2%). The actionable mutations of the PI3K/mTOR pathway were found in 18.8% of the pts. In total, pts with one or more actionable GAs were 62.3%. Pts presented MSI-high were 7.2% of the total. Proportion was 10.1% for the pts with TMB value higher than 20 mut/Mb, and 32.8% for those higher than 10 mut/Mb. The TMB range of the 69 pts was 1.1 to 58.4 mut/Mb, and median was 7.4 mut/Mb. Conclusions: In our study, 62.3% of Chinese ICC pts were detected to have actionable GAs which could potentially guide and influence their personalized treatments. The identification of more frequent high TMB level than the published western populations indicated that Chinese ICC pts may more likely derive therapeutic benefits from immune checkpoint inhibitors. Citation Format: Jingyu Cao, Bo Jiang, Zimin Liu, Weibin Shu, Lei Li, Han Yang, Hua Li, Zhiyu Xiao, Maolin Yan, Jie Lin, Siqin Liu, Peng Zhang, Milind Javle, Ming Yao, Kai Wang, Haitao Zhao. Genomic alterations, mutation burden, and microsatellite instability status of Chinese intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3437.