Project description:BackgroundA better understanding of lung cancer etiology and the development of screening biomarkers have important implications for lung cancer prevention.MethodsWe included 623 matched case-control pairs from the Cancer Prevention Study (CPS) cohorts. Pre-diagnosis blood samples were collected between 1998 and 2001 in the CPS-II Nutrition cohort and 2006 and 2013 in the CPS-3 cohort and were sent for metabolomics profiling simultaneously. Cancer-free controls at the time of case diagnosis were 1:1 matched to cases on date of birth, blood draw date, sex, and race/ethnicity. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression, controlling for confounders. The Benjamini-Hochberg method was used to correct for multiple comparisons.ResultsSphingomyelin (d18:0/22:0) (OR: 1.32; 95% CI: 1.15, 1.53, FDR = 0.15) and taurodeoxycholic acid 3-sulfate (OR: 1.33; 95% CI: 1.14, 1.55, FDR = 0.15) were positively associated with lung cancer risk. Participants diagnosed within 3 years of blood draw had a 55% and 48% higher risk of lung cancer per standard deviation increase in natural log-transformed sphingomyelin (d18:0/22:0) and taurodeoxycholic acid 3-sulfate level, while 26% and 28% higher risk for those diagnosed beyond 3 years, compared to matched controls. Lipid and amino acid metabolism accounted for 47% to 80% of lung cancer-associated metabolites at P < 0.05 across all participants and subgroups. Notably, ever-smokers exhibited a higher proportion of lung cancer-associated metabolites (P < 0.05) in xenobiotic- and lipid-associated pathways, whereas never-smokers showed a more pronounced involvement of amino acid- and lipid-associated metabolic pathways.ConclusionsThis is the largest prospective study examining untargeted metabolic profiles regarding lung cancer risk. Sphingomyelin (d18:0/22:0), a sphingolipid, and taurodeoxycholic acid 3-sulfate, a bile salt, may be risk factors and potential screening biomarkers for lung cancer. Lipid and amino acid metabolism may contribute significantly to lung cancer etiology which varied by smoking status.

Project description:Cancer-associated fibroblasts (CAFs) have been recognized as important contributors to cancer development and progression. However, opposing evidence has been published whether CAFs, in addition to epigenetic, also undergo somatic genetic alterations and whether these changes contribute to carcinogenesis and tumour progression. We combined multiparameter DNA flow cytometry, flow-sorting and 6K SNP-arrays to study DNA aneuploidy, % S-phase, loss of heterozygosity (LOH) and copy number alterations (CNAs) to study somatic genetic alterations in cervical cancer-associated stromal cell fractions (n = 58) from formalin-fixed, paraffin-embedded (FFPE) samples. Tissue sections were examined for the presence of CAFs. Microsatellite analysis was used to study LOH. By flow cytometry we found no proof for DNA aneuploidy in the vimentin-positive stromal cell fractions of any samples (CV G0G1 population 3.7% +/- 1.2; S-phase 1.4% +/- 1.8). The genotype concordance between the stromal cells and the paired normal endometrium samples was > 99.9%. No evidence for CNAs or LOH was found in the stromal cell fractions. In contrast, high frequencies of DNA content abnormalities (43/57), a significant higher S-phase (14.6% +/- 8.5)(p = 0.0001) and substantial numbers of CNAs and LOH were identified in the keratin-positive epithelial cell fractions (CV G0G1 population 4.1% +/- 1.0). Smooth muscle actin and vimentin immunohistochemistry verified the presence of CAFs in all cases tested. LOH hot-spots on chromosomes 3p, 4p and 6p were confirmed by microsatellite analysis but the stromal cell fractions showed retention of heterozygosity only. From our study we conclude that stromal cell fractions from cervical carcinomas are DNA diploid, have a genotype undistinguishable from patient-matched normal tissue and are genetically stable. Stromal genetic changes do not seem to play a role during cervical carcinogenesis and progression. In addition, the stromal cell fraction of cervical carcinomas can be used as reference allowing large retrospective studies of archival FFPE tissues for which no normal reference tissue is available. Paired experiment, Endometrial (non-tumor) cells vs stromal cells from cervical tumors. Biological replicates: 58 patients. From 5 tumors also the tumor fraction was profiled.

Project description:Recurrent non-medullary thyroid carcinoma (NMTC) is a rare disease. We initially characterized 27 recurrent NMTC: 13 papillary thyroid cancers (PTC), 10 oncocytic follicular carcinomas (FTC-OV), and 4 non-oncocytic follicular carcinomas (FTC). A validation cohort composed of benign and malignant (both recurrent and non-recurrent) thyroid tumours was subsequently analysed (n = 20). Methods Data from genome-wide SNP arrays and flow cytometry were combined to determine the chromosomal dosage (allelic state) in these tumours, including mutation analysis of components of PIK3CA/AKT and MAPK pathways. Results All FTC-OVs showed a very distinct pattern of genomic alterations. Ten out of 10 FTC-OV cases showed near-haploidisation with or without subsequent genome endoreduplication. Near-haploidisation was seen in 5/10 as extensive chromosome-wide monosomy (allelic state [A]) with near-haploid DNA indices and retention of especially chromosome 7 (seen as a heterozygous allelic state [AB]). In the remaining 5/10 chromosomal allelic states AA with near diploid DNA indices were seen with allelic state AABB of chromosome 7, suggesting endoreduplication after preceding haploidisation. The latter was supported by the presence of both near-haploid and endoreduplicated tumour fractions in some of the cases. Results were confirmed using FISH analysis. Relatively to FTC-OV limited numbers of genomic alterations were identified in other types of recurrent NMTC studied, except for chromosome 22q which showed alterations in 6 of 13 PTCs. Only two HRAS, but no mutations of EGFR or BRAF were found in FTC-OV. The validation cohort showed two additional tumours with the distinct pattern of genomic alterations (both with oncocytic features and recurrent). Conclusions We demonstrate that recurrent FTC-OV is frequently characterised by genome-wide DNA haploidisation, heterozygous retention of chromosome 7, and endoreduplication of a near-haploid genome. Whether normal gene dosage on especially chromosome 7 (containing EGFR, BRAF, cMET) is crucial for FTC-OV tumour survival is an important topic for future research. 28 thyroid tumors from 27 patients were profiled by SNP array. Comparisons between different types were made.

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Lung cancer metabolomics analysis

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