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A portion of stage I non-small cell lung cancer (NSCLC) patients who have received R0 resection experience unexpected tumor recurrence during follow up. Some of them even recurred within 12 months after surgery, which is unable to predict by any clinical characteristics. Few study investigates the molecular features of such short-term recurrent tumors. Multiomics analysis were performed on 81 stage I NSCLC patients who had received R0 resection, based on deep whole-exome sequencing (average depth >500x) on multi-region 239 tumor tissue samples and 81 matched-adjacent normal specimens, as well as RNA sequencing and plasma targeted circulating tumor DNA detection. Dynamic dimension comparison of genomic alteration features between tumor recurrence and non-recurrence patients was made according to 60-months median time of follow up. Published WES datasets of Stage I NSCLCs of 131 East Asian (EAS LUADs), 62 European (TRACERx) and 277 American patients (TCGA) were extracted as validation. 60.5% patients were non-smokers. Lower chromosomal instability was found in our cohort characterized by less trunk CNVs and lower CNV coverage on genome as compared to the European cohort. Age-related signature mutations significantly accumulated in recurrence-free tumors. Somatic mutations occurred in DNA damage repair pathways were more likely to cause tumor recurrence (p=0.04), particularly in homologous recombination (HRR) (p=0.017) and translesion synthesis (TLS) (p=0.009) pathways. Dynamic analysis discovered the essential genes in Fanconi anemia (FA), TLS and HRR pathways that coordinate together for DNA interstrand crosslink (ICL) recognition and faithful repair of DNA double strand breaks (DSBs) during DNA replication stress frequently mutated in early tumor recurrence patients (n=7/11, 63%). Twenty-two focal CNV-driver genes, including cell proliferation-related RECQL4 (8q24.3), PIK3CA (3q26.32), BCL9 (1q21.2), TBL1XR1 (3q26.32) frequently amplified in recurrent tumors, as well as BCL3 and CBLC (19q13.31-32) in the early recurrent tumors. RNA-seq data demonstrated cell cycle pathway significantly up-regulated in recurrent tumors. More TMB, CNV fraction and genome doubling events in FA-TLS-HRR alteration patients verified genomic instability caused by dysfunction of cell cycle control and ICL-DSB repair contributing to early tumor recurrence. Integrative model cross clinical and molecular features stratified stage I patient prognosis in both our cohort and European cohort, in which and high risk patients were more detected by circulating tumor DNA. This is the first study to dynamically investigate the genomic features specifically in stage I lung NSCLC according to the precise tumor recurrence time, which provides important clues to postoperative treatment strategy and drug target research. Citation Format: Kezhong Chen, Airong Yang, Shuangxiu Wu, Yuntao Nie, Haifeng Shen, Jian Bai, Lin Wu, Fan Yang, Jun Wang. Spatio-temporal multiomics analysis reveals distinct molecular features in recurrent stage I non-small cell lung cancers after R0 tumor resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 618.

Colorectal cancer (CRC) is a serious malignancy with the third incidence and second mortality throughout the world. 5-Hydroxymethylcytosine (5hmC) signatures in circulating cell-free DNA (cfDNA) is an important epigenetic mark linked with human cancer pathogenesis. Here we explored the genome-wide 5-hydroxymethylcytosine profiling in the plasma cfDNA and tissue genomic DNA (gDNA) acquired from 101 samples (63 from plasma and 38 from tissues), collected from 21 CRC patients, 21 precancerous adenoma (AD) patients and 21 healthy control individuals (HC). 5hmC modifications exhibited distinct features in promoter and gene body regions in all 5 groups (3 groups from plasma and 2 groups from tissues), which offered a global overview of epigenetic changes of colon pathogenic statuses between early stage CRC and AD. Adenoma showed an independent property in the 5hmC profiles compared to cancer and healthy control. The 5hmC signatures in tumor were more comprehensive and could be divided into two clusters, one was similar to the healthy individuals and the other was similar to the AD patients. The results indicated that the candidate biomarkers to distinguish colorectal cancer from the blood-test population should be generated in two ways, one focused on the differential 5hmC features between CRC patients and healthy individuals; the other should detect the adenoma and tumor patients more extensive according to their precise pathological diagnosis and clinical information. Candidate cfDNA 5hmC biomarkers were further identified in the differential 5hmC modification regions between CRC and HC with a higher sensitivity than the classical CEA marker in non-invasive blood-based diagnosis. We suggested that the differentially enriched 5hmC regions in cfDNA were potential biomarkers to track colorectal cancer, even precancerous adenoma, with further large-scale follow-up studies. Citation Format: Zewen Xiao, Jiayan Wu, Chunlong Wu, Man Li, Fuming Sun, Lu Zheng, Gaojing Liu, Xiaoling Li, Zhiyuan Yun, Jiebing Tang, Yang Yu, Shengnan Luo, Wenji Sun, Xiaohong Feng, Qian Cheng, Xue Tao, Jian Bai, Lin Wu, Shuangxiu Wu, Ji Tao. 5-Hydroxymethylcytosine signatures in cell-free DNA as a potential biomarker for colorectal cancer andprecancerous adenoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4597.