Genome-wide germline correlates of the epigenetic landscape of prostate cancer

Houlahan, Kathleen E.; Shiah, Yu Jia; Gusev, Alexander; Yuan, Jiapei; Ahmed, Musaddeque; Shetty, Anamay; Ramanand, Susmita G.; Yao, Cindy Q.; Bell, Connor; O’Connor, Edward; Huang, Vincent; Fraser, Michael; Heisler, Lawrence E.; Livingstone, Julie; Yamaguchi, Takafumi N.; Rouette, Alexandre; Foucal, Adrien; Espiritu, Shadrielle M. G.; Sinha, Ankit; Sam, Michelle; Timms, Lee; Johns, Jeremy; Wong, Ada; Murison, Alex; Orain, Michèle; Picard, Valérie; Hovington, Hélène; Bergeron, Alain; Lacombe, Louis; Lupien, Mathieu; Fradet, Yves; Têtu, Bernard; Mcpherson, John Douglas; Paşaniuc, Bogdan; Kislinger, Thomas; Chua, Melvin L.K.; Pomerantz, Mark; Kwast, Theodorus van der; Freedman, Matthew L.; Mani, Ram S.; He, Housheng Hansen; Bristow, Robert G.; Boutros, Paul C.

doi:10.1038/s41591-019-0579-z

Cited by 55 publications

(47 citation statements)

References 83 publications

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“…This includes a region on chromosome 7 spanning 26 genes that is amplified in 88% (9/11) of tumors of East Asian ancestry in our cohort. These data provide us with evidence that genes are mutated at different frequencies in individuals of different ancestry, providing further strong support to the idea that germline variation is essential for understanding the emergence of somatic phenotypes [22].…”

Section: Resultssupporting

confidence: 58%

“…Increasingly evidence now shows that germline genetic variation strongly shapes the somatic profiles and evolutionary history of prostate cancer. Both rare deleterious variants in DNA damage response (DDR) genes and common polymorphisms have been shown to do so in Caucasian populations [2,22]. Recent sequencing studies have shown that tumors arising in men of Asian, African or African-American ancestry show distinct somatic mutational features [23][24][25][26].…”

Section: Discussionmentioning

confidence: 99%

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Molecular Profiles of Prostate Cancer in Men of Middle Eastern Ancestry Identifies Key Differences with Western Populations: A Multiethnic SNP Array Study

Albawardi¹,

Livingstone²,

Marzooqi³

et al. 2021

Preprint

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Background: Our knowledge of prostate cancer (PCa) genomics mainly reflects European (EUR) and Asian (ASN) populations. Our understanding of the influence of Middle Eastern (ME) and African (AFR) ancestry on the mutational profiles of prostate cancer is limited. Design, setting and participants: To characterize genomic differences between ME, EUR, ASN and AFR ancestry, fluorescent in situ hybridization (FISH) studies for NKX3-1 deletions and MYC amplification was carried out on 42 tumors arising in individuals of ME ancestry. These were supplemented by analysis of copy number profiles of 401 tumors of all ancestries. Outcome measurement and statistical analysis: FISH results of NKX3-1 and MYC were assessed in the ME cohort and compared to other ancestries. Gene level copy number aberrations (CNAs) for each sample were statistically compared between ancestry groups. Results and Limitation: NKX3-1 deletions by FISH were observed in 17/42 (17.5%) prostate tumors arising in men of ME ancestry, while MYC amplifications were only observed in 1/42 (0.23%). Using CNAs called from arrays, the incidence of NKX3-1 deletions was significantly lower in ME vs. other ancestries (20% vs. 52%; p = 2.3 x 10-3). No differences in MYC amplifications was noted between the two cohorts using array-based CNAs. Across the genome, tumors arising in men of ME ancestry had fewer CNAs than those of other ancestries (p = 0.014). Additionally, the somatic amplification of 21 specific genes was more frequent in tumors arising in men of ME vs. EUR ancestry (Proportions test; Q < 0.05). Those included amplifications in the glutathione S-transferase family on chromosome 1 (GSTM1, GSTM2, GSTM5) and the IQ Motif Containing family on chromosome 3 (IQCF1, IQCF2, IQCF13, IQCF4, IQCF5, IQCF6). Conclusion: Significant differences in genetic background exists between different ancestries. The lower number of somatic CNAs observed in prostate cancer arising in men of ME ancestry may explain the relatively good prognosis in this population. Larger studies are warranted.

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Section: Resultssupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Molecular Profiles of Prostate Cancer in Men of Middle Eastern Ancestry Identifies Key Differences with Western Populations: A Multiethnic SNP Array Study

Albawardi¹,

Livingstone²,

Marzooqi³

et al. 2021

Preprint

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“…The risk-associated allele at rs339331 increases HOXB13 binding in a transcriptional enhancer, resulting in the allele-specific upregulation of RFX6, which enhances prostate cancer cell proliferation, migration, and invasion [151]. Because rs339331 is associated with CpG methylation [152], DNA methylation might mediate the regulatory chain between HOXB13 and RFX6. The prostate cancer risk polymorphism rs684232 has been reported to function as an eQTL.…”

Section: Prostate Cancermentioning

confidence: 99%

Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases

Tseng

Wong

Liao

et al. 2021

IJMS

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Variants of transcription factor binding sites (TFBSs) constitute an important part of the human genome. Current evidence demonstrates close links between nucleotides within TFBSs and gene expression. There are multiple pathways through which genomic sequences located in TFBSs regulate gene expression, and recent genome-wide association studies have shown the biological significance of TFBS variation in human phenotypes. However, numerous challenges remain in the study of TFBS polymorphisms. This article aims to cover the current state of understanding as regards the genomic features of TFBSs and TFBS variants; the mechanisms through which TFBS variants regulate gene expression; the approaches to studying the effects of nucleotide changes that create or disrupt TFBSs; the challenges faced in studies of TFBS sequence variations; the effects of natural selection on collections of TFBSs; in addition to the insights gained from the study of TFBS alleles related to gout, its associated comorbidities (increased body mass index, chronic kidney disease, diabetes, dyslipidemia, coronary artery disease, ischemic heart disease, hypertension, hyperuricemia, osteoporosis, and prostate cancer), and the treatment responses of patients.

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“…Genetic factors are among the many elements that influence an individual's PSA level, and indeed many aspects of prostate cancer biology. [14] There are multiple reports of various singlenucleotide polymorphisms (SNPs) correlating with serum PSA levels. [15][16][17][18][19][20] One SNP that repeatedly shows this connection is rs17632542 on chromosome 19 in the kallikrein-3 gene leading to lower serum PSA levels than expected.…”

Section: Introductionmentioning

confidence: 99%

Targeted Mass Spectrometry of a Clinically Relevant PSA Variant from Post‐DRE Urines for Quantitation and Genotype Determination

Otto

Correll

Engstroem

et al. 2020

Proteomics Clinical Apps

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Purpose: The rs17632542 single nucleotide polymorphism (SNP) results in lower serum prostate specific antigen (PSA) levels which may further mitigate against its clinical utility as a prostate cancer biomarker. Post-digital rectal exam (post-DRE) urine is a minimally invasive fluid that is currently utilized in prostate cancer diagnosis. To detect and quantitate the variant protein in urine. Experimental design: Fifty-three post-DRE urines from rs17632542 genotyped individuals processed and analyzed by liquid chromatography/mass spectrometry (LC-MS) in a double-blinded randomized study. The ability to distinguish between homozygous wild-type, heterozygous, or homozygous variant is examined before unblinding. Results: Stable-isotope labeled peptides are used in the detection and quantitation of three peptides of interest in each sample using parallel reaction monitoring (PRM). Using these data, groupings are predicted using hierarchical clustering in R. Accuracy of the predictions show 100% concordance across the 53 samples, including individuals homozygous and heterozygous for the SNP. Conclusions and clinical relevance: The study demonstrates that MS based peptide variant quantitation in urine could be useful in determining patient genotype expression. This assay provides a tool to evaluate the utility of PSA variant (rs17632542) in parallel with current and forthcoming urine biomarker panels.

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Genome-wide germline correlates of the epigenetic landscape of prostate cancer

Cited by 55 publications

References 83 publications

Molecular Profiles of Prostate Cancer in Men of Middle Eastern Ancestry Identifies Key Differences with Western Populations: A Multiethnic SNP Array Study

Molecular Profiles of Prostate Cancer in Men of Middle Eastern Ancestry Identifies Key Differences with Western Populations: A Multiethnic SNP Array Study

Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases

Targeted Mass Spectrometry of a Clinically Relevant PSA Variant from Post‐DRE Urines for Quantitation and Genotype Determination

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