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Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers.

ABSTRACT: Disparities in cancer care have been a long-standing challenge. We estimated the genetic ancestry of The Cancer Genome Atlas patients, and performed a pan-cancer analysis on the influence of genetic ancestry on genomic alterations. Compared with European Americans, African Americans (AA) with breast, head and neck, and endometrial cancers exhibit a higher level of chromosomal instability, while a lower level of chromosomal instability was observed in AAs with kidney cancers. The frequencies of TP53 mutations and amplification of CCNE1 were increased in AAs in the cancer types showing higher levels of chromosomal instability. We observed lower frequencies of genomic alterations affecting genes in the PI3K pathway in AA patients across cancers. Our result provides insight into genomic contribution to cancer disparities.

SUBMITTER: Yuan J

PROVIDER: S-EPMC6348897 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers.

Yuan Jiao J Hu Zhongyi Z Mahal Brandon A BA Zhao Sihai D SD Kensler Kevin H KH Pi Jingjiang J Hu Xiaowen X Zhang Youyou Y Wang Yueying Y Jiang Junjie J Li Chunsheng C Zhong Xiaomin X Montone Kathleen T KT Guan Guoqiang G Tanyi Janos L JL Fan Yi Y Xu Xiaowei X Morgan Mark A MA Long Meixiao M Zhang Yuzhen Y Zhang Rugang R Sood Anil K AK Rebbeck Timothy R TR Dang Chi V CV Zhang Lin L

Cancer cell 20181001 4

Disparities in cancer care have been a long-standing challenge. We estimated the genetic ancestry of The Cancer Genome Atlas patients, and performed a pan-cancer analysis on the influence of genetic ancestry on genomic alterations. Compared with European Americans, African Americans (AA) with breast, head and neck, and endometrial cancers exhibit a higher level of chromosomal instability, while a lower level of chromosomal instability was observed in AAs with kidney cancers. The frequencies of T ...[more]

PMID: 30300578

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Project description:BackgroundThe mitochondrial genome is transcribed as continuous polycistrons of RNA containing multiple genes. As a consequence, post-transcriptional events are critical for the regulation of gene expression and therefore all aspects of mitochondrial function. One particularly important process is the m1A/m1G RNA methylation of the ninth position of different mitochondrial tRNAs, which allows efficient processing of mitochondrial mRNAs and protein translation, and de-regulation of genes involved in these processes has been associated with altered mitochondrial function. Although mitochondria play a key role in cancer, the status of mitochondrial RNA processing in tumorigenesis is unknown.MethodsWe measure and assess mitochondrial RNA processing using integrated genomic analysis of RNA sequencing and genotyping data from 1226 samples across 12 different cancer types. We focus on the levels of m1A and m1G RNA methylation in mitochondrial tRNAs in normal and tumor samples and use supervised and unsupervised statistical analysis to compare the levels of these modifications to patient whole genome genotypes, nuclear gene expression, and survival outcomes.ResultsWe find significant changes to m1A and m1G RNA methylation levels in mitochondrial tRNAs in tumor tissues across all cancers. Pathways of RNA processing are strongly associated with methylation levels in normal tissues (P = 3.27 × 10-31), yet these associations are lost in tumors. Furthermore, we report 18 gene-by-disease-state interactions where altered RNA methylation levels occur under cancer status conditional on genotype, implicating genes associated with mitochondrial function or cancer (e.g., CACNA2D2, LMO2, and FLT3) and suggesting that nuclear genetic variation can potentially modulate an individual's ability to maintain unaltered rates of mitochondrial RNA processing under cancer status. Finally, we report a significant association between the magnitude of methylation level changes in tumors and patient survival outcomes.ConclusionsWe report widespread variation of mitochondrial RNA processing between normal and tumor tissues across all cancer types investigated and show that these alterations are likely modulated by patient genotype and may impact patient survival outcomes. These results highlight the potential clinical relevance of altered mitochondrial RNA processing and provide broad new insights into the importance and complexity of these events in cancer.

Project description:BackgroundGenomic alterations in 8 genes are now the targets of FDA-approved therapeutics in non-small cell lung cancer (NSCLC), but their distribution according to genetic ancestry, sex, histology, and smoking is not well established.MethodsUsing multi-institutional genetic testing data from GENIE, we characterize the distribution of targetable genomic alterations in 8 genes among 8675 patients with NSCLC (discovery cohort: DFCI, N = 3115; validation cohort: Duke, Memorial Sloan Kettering Cancer Center, Vanderbilt, N = 5560). For the discovery cohort, we impute genetic ancestry from tumor-only sequencing and identify differences in the frequency of targetable alterations across ancestral groups, smoking pack-years, and histologic subtypes.ResultsWe identified variation in the prevalence of KRASG12C, sensitizing EGFR mutations, MET alterations, ALK, and ROS1 fusions according to the number of smoking pack-years. A novel method for computing continental (African, Asian, European) and Ashkenazi Jewish ancestries from panel sequencing enables quantitative analysis of the correlation between ancestry and mutation rates. This analysis identifies a correlation between Asian ancestry and EGFR mutations and an anti-correlation between Asian ancestry and KRASG12C mutation. It uncovers 2.7-fold enrichment for MET exon 14 skipping mutations and amplifications in patients of Ashkenazi Jewish ancestry. Among never/light smokers, targetable alterations in LUAD are significantly enriched in those with Asian (80%) versus African (49%) and European (55%) ancestry. Finally, we show that 5% of patients with squamous cell carcinoma (LUSC) and 17% of patients with large cell carcinoma (LCLC) harbor targetable alterations.ConclusionsAmong patients with NSCLC, there was significant variability in the prevalence of targetable genomic alterations according to genetic ancestry, histology, and smoking. Patients with LUSC and LCLC have 5% rates of targetable alterations supporting consideration for sequencing in those subtypes.

Dataset Information

Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers.

Publications

Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers.

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