Comprehensive profiling of 1015 patients’ exomes reveals genomic-clinical associations in colorectal cancer

Zhao, Qi; Wang, Feng; Chen, Yan‐Xing; Chen, Shifu; Yao, Yonghong; Zeng, Zhao-Lei; Jiang, Teng-Jia; Wang, Yingnan; Wu, Chen‐Yi; Jing, Ying; Huang, Ying; Zhang, Jing; Wang, Zi‐Xian; He, Ming-Ming; Pu, Heng‐Ying; Mai, Zong-Jiong; Wu, Qi‐Nian; Long, Rodney; Zhang, Xiaoni; Huang, Tanxiao; Xu, Mingyan; Qiu, Miao‐Zhen; Luo, Hongyu; Li, Yuhong; Zhang, Dong-Shen; Jia, Wei‐Hua; Chen, Gong; Ding, Pei-Rong; Li, Liren; Lu, Zheng-Hai; Pan, Zhizhong; Xu, Rui‐Hua

doi:10.1038/s41467-022-30062-8

Cited by 29 publications

(26 citation statements)

References 72 publications

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“…Using our panel of 95 cancerassociated genes, we found that the mutational burden varied greatly among patients (0-237 mutations), with an average of 7 mutations per patient. This data is consistent with the reported wide range of tumor mutational burden in CRC and also suggested that some hypermutated cases in our cohort could have microsatellite instability (23).…”

Section: Discussionsupporting

confidence: 93%

Tumor genomic profiling and personalized tracking of circulating tumor DNA in Vietnamese colorectal cancer patients

Nguyen

Nguyen²,

Hoang³

et al. 2022

Front. Oncol.

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BackgroundColorectal cancer (CRC) is the fifth most common cancer with rising prevalence in Vietnam. However, there is no data about the mutational landscape and actionable alterations in the Vietnamese patients. During post-operative surveillance, clinical tools are limited to stratify risk of recurrence and detect residual disease.MethodIn this prospective multi-center study, 103 CRC patients eligible for curative-intent surgery were recruited. Genomic DNA from tumor tissue and paired white blood cells were sequenced to profile all tumor-derived somatic mutations in 95 cancer-associated genes. Our bioinformatic algorithm identified top mutations unique for individual patient, which were then used to monitor the presence of circulating tumor DNA (ctDNA) in serial plasma samples.ResultsThe top mutated genes in our cohort were APC, TP53 and KRAS. 41.7% of the patients harbored KRAS and NRAS mutations predictive of resistance to Cetuximab and Panitumumab respectively; 41.7% had mutations targeted by either approved or experimental drugs. Using a personalized subset of top ranked mutations, we detected ctDNA in 90.5% of the pre-operative plasma samples, whereas carcinoembryonic antigen (CEA) was elevated in only 41.3% of them. Interim analysis after 16-month follow-up revealed post-operative detection of ctDNA in two patients that had recurrence, with the lead time of 4-10.5 months ahead of clinical diagnosis. CEA failed to predict recurrence in both cases.ConclusionOur assay showed promising dual clinical utilities in residual cancer surveillance and actionable mutation profiling for targeted therapies in CRC patients. This could lay foundation to empower precision cancer medicine in Vietnam and other developing countries.

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Section: Discussionsupporting

confidence: 93%

Tumor genomic profiling and personalized tracking of circulating tumor DNA in Vietnamese colorectal cancer patients

Nguyen

Nguyen²,

Hoang³

et al. 2022

Front. Oncol.

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“…Here, we found that genomic alterations overall provided inferior performance compared to the panel of methylation markers, and importantly, our attempt to integrate the mutation profile with the methylation markers showed marginal enhancement. The mutational landscape of human genome identified in stool DNA was highly consistent with what has been known for Chinese CRC patients 52 , which suggests that these mutant genomes indeed came from malignant colorectal epithelial cells and mutational profile of fecal DNA may be used effectively as non-invasive markers for CRC. Nevertheless, our results showed that mutational status as diagnostic markers provided high specificity (near 100%) but sensitivity was suboptimal.…”

Section: Discussionsupporting

confidence: 70%

Identification of multi-omic biomarkers from Fecal DNA for improved Detection of Colorectal Cancer and precancerous lesions

Peng

et al. 2022

Preprint

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Background: Timely diagnosis and intervention of colorectal cancer (CRC) at curable stages is essential for improving patient survival. Stool samples carry exfoliation of intestinal epithelium, therefore providing excellent opportunity for non-invasive diagnosis of CRC as well as precancerous lesions. In this study, we aimed to conduct multi-dimensional analysis of fecal DNA and investigate the utility of different types of biomarkers for CRC detection. Method: In this case-control study, we performed comprehensive analyses of the genomic, epigenomic, and metagenomic features of fecal DNA from CRC patients, individuals with advanced precancerous lesions (APLs) and controls. DNA methylation markers were identified by whole genome bisulfite sequencing of paired colorectal cancer and normal tissues. A multi-gene fecal DNA methylation test was then developed based on three marker genes (SDC2, ADHFE1 and PPP2R5C) using quantitative methylation-specific PCR (qMSP), and validated on fecal DNA samples. Genomic mutation profiles as well as microbiome signatures of fecal DNA were analyzed using high-throughput sequencing. Results: The methylation-based fecal DNA test demonstrated an overall sensitivity of 88% for CRC and 46.2% for APL respectively, and a specificity of 91.8% for controls. On the other hand, the mutation-based diagnostic model yielded limited sensitivity, and combined detection of methylation markers and mutation in fecal DNA did not improve the assay performance. Meanwhile, a diagnostic model based on the relative abundance of bacterial species showed inferior performance than the methylation-based model. Finally, integrated diagnostic model combining both methylation and microbial markers showed an enhanced performance (AUC= 0.95) compared to methylation markers alone. Conclusions: The multi-gene fecal DNA methylation test provided remarkable diagnostic performance for CRCs and APLs. Furthermore, multi-target assay integrating both methylation and microbial markers may further improve the diagnostic performance. Our findings may aid in the development of novel diagnostic tools for CRC.

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“…The captured mtDNA libraries were sequenced on Illumina HiSeqXTen (Illumina) platform using paired-end (PE) of 150 bp. For cohort 2, the detailed protocol for library construction and whole exome sequencing (WES) with the WESplus gene panel, which is an upgraded version of the standard WES and can capture mitochondrial DNA (HaploX Biotechnology, Shenzhen, China), has been previously described 27 . The sequencing in cohort 2 was performed on NovaSeq 6000 platform (Illumina) using PE 150.…”

Section: Methodsmentioning

confidence: 99%

Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer

Guo¹,

Liu²,

Ji³

et al. 2023

Theranostics

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Rationale: Mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutations and subsequent metabolic defects are closely involved in tumorigenesis and progression in a cancer-type specific manner. To date, the mutational pattern of mtDNA somatic mutations in colorectal cancer (CRC) tissues and its clinical implication are still not completely clear. Methods: In the present study, we generated a large mtDNA somatic mutation dataset from three CRC cohorts (432, 1,015, and 845 patients, respectively) and then most comprehensively characterized the CRC-specific evolutionary pattern and its clinical implication. Results: Our results showed that the mtDNA control region (mtCTR) with a high mutation density exhibited a distinct mutation spectrum characterizing a high enrichment of L-strand C > T mutations, which was contrary to the H-strand C > T mutational bias observed in the mtDNA coding region (mtCDR) (P < 0.001). Further analysis clearly confirmed the relaxed evolutionary selection of mtCTR mutations, which was mainly characterized by the similar distribution of hypervariable region (HVS) and non-HVS mutation density. Moreover, significant negative selection was identified in mutations of mtDNA complex V (ATP6/ATP8) and tRNA loop regions. Although our data showed that oxidative metabolism was commonly increased in CRC cells, mtDNA somatic mutations in CRC tissues were not closely associated with mitochondrial biogenesis, oxidative metabolism, and clinical progression, suggesting a cancer-type specific relationship between mtDNA mutations and mitochondrial metabolic functions in CRC cells. Conclusion:Our study identified the CRC-specific evolutionary mode of mtDNA mutations, which is possibly matched to specific mitochondrial metabolic remodeling and confers new mechanic insight into CRC tumorigenesis.

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Comprehensive profiling of 1015 patients’ exomes reveals genomic-clinical associations in colorectal cancer

Cited by 29 publications

References 72 publications

Tumor genomic profiling and personalized tracking of circulating tumor DNA in Vietnamese colorectal cancer patients

Tumor genomic profiling and personalized tracking of circulating tumor DNA in Vietnamese colorectal cancer patients

Identification of multi-omic biomarkers from Fecal DNA for improved Detection of Colorectal Cancer and precancerous lesions

Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer

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