Genetic ancestry contributes to somatic mutations in lung cancers from admixed Latin American populations
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ABSTRACT:
PROVIDER: EGAS00001004752 | EGA |
REPOSITORIES: EGA
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Project description:INTRODUCTION: CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. METHODS: We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non-small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. RESULTS: p16 inactivation was the major mechanism of RB pathway perturbation in non-small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. CONCLUSION: Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status. 40 NSCLC cell lines were profiled on Illumina WG6-V3 expression arrays. They consist of 4 groups of 10 cell lines each: non-smokers with EGFR mutation, non-smokers with EGFR wild-type, smokers with KRAS mutation, smokers with KRAS wild-type. Note that smoking status is not always clear.
2015-06-22 | E-GEOD-63882 | biostudies-arrayexpress
Project description:While mutations in the KRAS oncogene are amongst the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS, EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.
2015-10-21 | GSE72094 | GEO
Project description:The genetic structure of some native Bolivians has been substantially influenced by admixture from Europeans, which we estimate to have occurred approximately 360 – 384 years ago. Consistent with historical accounts of male admixture, Y-chromosome haplogroups typical of Europeans were found in 39% of our Bolivian samples. No evidence of African admixture was found in native Bolivians. The Mesoamerican Totonacs have little evidence of European or African admixture. Our analysis indicates that some admixed Bolivians have Native American mtDNA and Y-chromosomes but harbor up to 30% European autosomal ancestry, demonstrating the need for autosomal markers to assess ancestry in admixed populations. From a dense genome-wide panel of 815,377 markers, we developed a set of 324 AIMs, specific for Native American ancestry. As few a 40-50 of these markers successfully predict New World ancestry in the ascertainment panel of Bolivians and Totonacs. The markers easily distinguish New World from Old World ancestry, even for populations more closely related to the Americas such as central and eastern Asians, and were effective for New World vs. Old World comparisons in five other geographically and culturally distinct populations of the Americas. SNPs demonstrating very high divergence between the two Native American populations and major Old World populations are found on haplotypes that are shared and occur at similar frequencies in other indigenous low-admixture American populations examined here (i.e. Pima, Maya, Colombian, Karitiana, and Surui). After excluding the possibility of recent relatedness, our results indicate that native Bolivians and Totonacs share ancestry with other American populations through a substantial contribution from a common founding population, population bottlenecks, and possible natural selection on functional variation.
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Project description:INTRODUCTION: CDKN2A (p16) inactivation is common in lung cancer and occurs via homozygous deletions, methylation of promoter region, or point mutations. Although p16 promoter methylation has been linked to KRAS mutation and smoking, the associations between p16 inactivation mechanisms and other common genetic mutations and smoking status are still controversial or unknown. METHODS: We determined all three p16 inactivation mechanisms with the use of multiple methodologies for genomic status, methylation, RNA, and protein expression, and correlated them with EGFR, KRAS, STK11 mutations and smoking status in 40 cell lines and 45 tumor samples of primary non-small-cell lung carcinoma. We also performed meta-analyses to investigate the impact of smoke exposure on p16 inactivation. RESULTS: p16 inactivation was the major mechanism of RB pathway perturbation in non-small-cell lung carcinoma, with homozygous deletion being the most frequent method, followed by methylation and the rarer point mutations. Inactivating mechanisms were tightly correlated with loss of mRNA and protein expression. p16 inactivation occurred at comparable frequencies regardless of mutational status of EGFR, KRAS, and STK11, however, the major inactivation mechanism of p16 varied. p16 methylation was linked to KRAS mutation but was mutually exclusive with EGFR mutation. Cell lines and tumor samples demonstrated similar results. Our meta-analyses confirmed a modest positive association between p16 promoter methylation and smoking. CONCLUSION: Our results confirm that all the inactivation mechanisms are truly associated with loss of gene product and identify specific associations between p16 inactivation mechanisms and other genetic changes and smoking status.
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Project description:HCC515 lung cells with dox-inducible KEAP1 knockdown and/or STK11 re-addition, under two different metabolic stress conditions, baseline vs. suspension, were transcriptionally profiled to investigate whether KEAP1 knockdown can rescue metabolic defects in STK11-null cancer cells and how the regulation of the transcriptome by KEAP1 knockdown is affected by STK11 status and different metabolic stress conditions. In lung adenocarcinoma (LUAD), stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in roughly a quarter of patients, often in the context of STK11 tumor suppressor loss. In this study, we demonstrate that NRF2 activation in the context of concurrent KRAS mutation and STK11 loss promotes aggressive LUAD tumor behavior in both human and mouse preclinical models. This phenotype is associated with metabolic rewiring and rescue by NRF2 of redox stress, high in STK11 null tumors. Applying a novel, pan-lung cancer, diagnostic NRF2 activation gene expression signature that is independent of frequently co-occurring mutations, we dissect the independent contributions of the three most frequent genetic events in human LUAD (NRF2 activation, STK11 loss and KRAS mutations) on patient prognosis and clinical responses in a dataset of second-line LUAD patients treated with immunotherapy or chemotherapy (OAK trial). Our findings underscore that both individual effects and epistatic relationships among oncogenic and tumor suppressor pathways influence tumor biology, immune contexture and patient clinical outcomes. Our work also highlights the value of lung cancer disease sub-classification based on genetic and expression profiling as part of patient clinical management.
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2011-11-01 | E-GEOD-31210 | biostudies-arrayexpress