Presentation Authors: Xuesong Li*, Huan Lu, Bao Guan, Liqun Zhou, Juan Li, Zhengzheng Xu, Qun He, Ding Peng, Weimin Ci, Yue Shi, Beijing, China, People's Republic of
Introduction: To characterize the genomic landscape of UTUC from China and provide insights into its biological diversity between patients treated in China and the US.
Methods: Tumour DNA from 90 patients with UTUC from China were analysed using whole-genome sequencing. Consensus mutation calls from two independent pipelines were used to filter tumour variants. Using nonnegative matrix factorization, we measured the contribution of each mutational signature to carcinogenesis. Subtypes were defined by mutational signatures and copy number alterations using unsupervised consensus hierarchical clustering.
Results: Comparison of UTUC in China and US revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in Chinese UTUC than in US UTUC included CDC27 (32% vs. 0%, respectively; p=0.001). Genes less frequently mutated in Chinese patients than in US patients included FGFR3 (1% vs. 74%, respectively; p < 0.001). Predominant mutational signatures clustered UTUC into 3 major subtypes with following clinicopathologic and genomic characteristics. SIG1: the typical aristolochic acid (AA) mutational signature, P53 mutations (56%), KMT2D mutations (62%), hypermutation, favourable CSS (cancer-specific survival); SIG2: signatures with deficiencies in DNA damage repair, intermediate mutation burden, CDC27 and/or ANAPC10 mutations (76%), better CSS; SIG3: an age-related signature, TBC1D3B mutations (30%), lowest mutation burden, poor CSS. Integrating analyses revealed 3 genomic subtypes with distinct copy number profile. The SIG3 subtype is significantly enriched in UTUC patients with fewer or no copy number variations.
Conclusions: UTUC mutations occur at different frequencies across patients from different geographic distributions. The high prevalence of featured genomic alterations, SNVs and CNVs within signature subtypes provide an important reference for developing strategies for the prognosis and management of UTUC in China.
Source of Funding: This work was supported by CAS Strategic Priority Research Program (XDA16010102 to W.C.), the National Key R&D Program of China (2016YFC0900303 to W.C.), CAS (QYZDB-SSW-SMC039 and KJZD-EW-L14 to W.C.), the National Natural Science Foundation of China (814