Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer

Wang, Bi-Dar; Ceniccola, Kristin; Hwang, Sujin; Andrawis, Ramez; Horvath, Anélia; Freedman, Jennifer A.; Olender, Jacqueline; Knapp, S.; Ching, Travers; Garmire, Lana X.; Patel, Vyomesh; García-Blanco, Mariano A.; Patierno, Steven R.; Lee, Norman H.

doi:10.1038/ncomms15921

Cited by 76 publications

(82 citation statements)

References 66 publications

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“…Because 22Rv1 was derived from a xenograft of CWR22R cells which was serially propagated in mice, it would be appropriate to also assign this mixed ancestral racial classification to the CWR22R cell line. The implications of 22Rv1 and CWR22R carrying AFR genetic ancestry are far reaching as genetic factors associated with AFR ancestry have been recently linked to prostate tumor aggressive properties . Further studies are needed to determine if these cell lines carry any of these factors.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have provided compelling evidence in support of the notion that PCa health disparities result from the interplay of multiple factors, including biological/genetic factors . For instance, several recent studies have reported genomic differences between AA men with PCa and Caucasian or European American (EA) with PCa, suggesting a potential role for biological mediators in driving PCa mortality disparities . Understanding how these mediators contribute to increased PCa mortality in AA men requires mechanistic functional studies in pre‐clinical cellular and animal models of PCa.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14] For instance, several recent studies have reported genomic differences between AA men with PCa and Caucasian or European American (EA) with PCa, suggesting a potential role for biological mediators in driving PCa mortality disparities. [14][15][16][17][18][19][20][21][22][23][24][25][26][27] Understanding how these mediators contribute to increased PCa mortality in AA men requires mechanistic functional studies in preclinical cellular and animal models of PCa.…”

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confidence: 99%

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The 22Rv1 prostate cancer cell line carries mixed genetic ancestry: Implications for prostate cancer health disparities research using pre‐clinical models

et al. 2017

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BACKGROUND Understanding how biological factors contribute to prostate cancer (PCa) health disparities requires mechanistic functional analysis of specific genes or pathways in pre-clinical cellular and animal models of this malignancy. The 22Rv1 human prostatic carcinoma cell line was originally derived from the parental CWR22R cell line. Although 22Rv1 has been well characterized and used in numerous mechanistic studies, no racial identifier has ever been disclosed for this cell line. In accordance with the need for racial diversity in cancer biospecimens and recent guidelines by the NIH on authentication of key biological resources, we sought to determine the ancestry of 22RV1 and authenticate previously reported racial identifications for four other PCa cell lines. METHODS We used 29 established Ancestry Informative Marker (AIM) single nucleotide polymorphisms (SNPs) to conduct DNA ancestry analysis and assign ancestral proportions to a panel of five PCa cell lines that included 22Rv1, PC3, DU145, MDA-PCa-2b, and RC-77T/E. RESULTS We found that 22Rv1 carries mixed genetic ancestry. The main ancestry proportions for this cell line were 0.41 West African (AFR) and 0.42 European (EUR). In addition, we verified the previously reported racial identifications for PC3 (0.73 EUR), DU145 (0.63 EUR), MDA-PCa-2b (0.73 AFR), and RC-77T/E (0.74 AFR) cell lines. CONCLUSIONS Considering the mortality disparities associated with PCa, which disproportionately affect African American men, there remains a burden on the scientific community to diversify the availability of biospecimens, including cell lines, for mechanistic studies on potential biological mediators of these disparities. This study is beneficial by identifying another PCa cell line that carries substantial AFR ancestry. This finding may also open the door to new perspectives on previously published studies using this cell line.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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The 22Rv1 prostate cancer cell line carries mixed genetic ancestry: Implications for prostate cancer health disparities research using pre‐clinical models

et al. 2017

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“…This shared genetic background may confer similarities in cancer incidence and outcomes in populations. Recent large-scale genomic profile studies in individual cancer types, such as prostate (Huang et al, 2017; Petrovics et al, 2015; Powell et al, 2013; Wang et al, 2017), breast (Ademuyiwa et al, 2017; Huo et al, 2017; Keenan et al, 2015; Loo et al, 2011), colon (Guda et al, 2015), lung (Araujo et al, 2015; Campbell et al, 2017; Kytola et al, 2017), gastric (Schumacher et al, 2017), esophageal (Deng et al, 2017), and kidney (Krishnan et al, 2016) cancers have robustly demonstrated that genomic differences in cancers exist among distinct racial and ethnic populations. Consistently, it has been reported that the genetic background of patients may influence specific somatic alterations in cancer genomes during tumorigenesis (Carter et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers

et al. 2018

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SUMMARY 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.

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“…Furthermore, melanoma tumors often develop drug resistance to BRAF(V600E) inhibitors by expressing a shorter isoform of mutated BRAF that lacks the RAS binding domain and allows BRAF(V600E) proteins to dimerize and signal in a RAS independent manner (Poulikakos et al, 2011;Samatar and Poulikakos, 2014). Other splice variants are used as prognostic biomarkers in the clinic, such as the Variant 7 of the Androgen Receptor (AR)-V7, which when overexpressed in hormonerefractory prostate cancer patients, correlates with poor patient survival and higher recurrence rates (B.-D. Wang et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Pathogenic impact of transcript isoform switching in 1209 cancer samples covering 27 cancer types using an isoform-specific interaction network

Kahraman

Mering

2019

Preprint

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Under normal conditions, cells of almost all tissue types express the same predominant canonical transcript isoform at each gene locus. In cancer, however, splicing regulation is often disturbed, leading to cancer-specific switches in the most dominant transcripts (MDT). But what is the pathogenic impact of these switches and how are they driving oncogenesis? To address these questions, we have analyzed isoform-specific protein-protein interaction disruptions in 1209 cancer samples covering 27 different cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project of the International Cancer Genomics Consortium (ICGC). Our study revealed large variations in the number of cancer-specific MDT (cMDT) between cancer types. While carcinomas of the head and neck, or brain, had none or only a few cMDT, cancers of the female reproduction organs showed the highest number of cMDT. Interestingly, in contrast to the mutational load, the number of cMDT was tissue-specific, i.e. cancers arising from the same primary tissue had a similar number of cMDT. Some cMDT were found in 100% of all samples in a cancer type, making them candidates for diagnostic biomarkers.cMDT showed a tendency to fall at densely populated network regions where they disrupted protein interactions in the proximity of pathogenic cancer genes. A gene ontology enrichment analysis showed that these disruptions occurred mostly in enzyme signaling, protein translation, and RNA splicing pathways. Interestingly, no significant correlation between the number of cMDT and the number of coding or non-coding mutations could be identified. However, some transcript expressions correlated with mutations in non-coding splice-site and promoter regions of their genes. This work demonstrates for the first time the large extent of cancer-specific alterations in alternative splicing for 27 different cancer types. It highlights distinct and common patterns of cMDT and suggests novel pathogenic transcripts and markers that induce large network disruptions in cancers.

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Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer

Cited by 76 publications

References 66 publications

The 22Rv1 prostate cancer cell line carries mixed genetic ancestry: Implications for prostate cancer health disparities research using pre‐clinical models

The 22Rv1 prostate cancer cell line carries mixed genetic ancestry: Implications for prostate cancer health disparities research using pre‐clinical models

Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers

Pathogenic impact of transcript isoform switching in 1209 cancer samples covering 27 cancer types using an isoform-specific interaction network

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