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Article ; Online: Single-cell characterization of step-wise acquisition of carboplatin resistance in ovarian cancer

Alexander T. Wenzel / Devora Champa / Hrishi Venkatesh / Si Sun / Cheng-Yu Tsai / Jill P. Mesirov / Jack D. Bui / Stephen B. Howell / Olivier Harismendy

npj Systems Biology and Applications, Vol 8, Iss 1, Pp 1-

2022 Volume 9

Abstract: Abstract The molecular underpinnings of acquired resistance to carboplatin are poorly understood and often inconsistent between in vitro modeling studies. After sequential treatment cycles, multiple isogenic clones reached similar levels of resistance, ... ...

Abstract	Abstract The molecular underpinnings of acquired resistance to carboplatin are poorly understood and often inconsistent between in vitro modeling studies. After sequential treatment cycles, multiple isogenic clones reached similar levels of resistance, but significant transcriptional heterogeneity. Gene-expression based virtual synchronization of 26,772 single cells from 2 treatment steps and 4 resistant clones was used to evaluate the activity of Hallmark gene sets in proliferative (P) and quiescent (Q) phases. Two behaviors were associated with resistance: (1) broad repression in the P phase observed in all clones in early resistant steps and (2) prevalent induction in Q phase observed in the late treatment step of one clone. Furthermore, the induction of IFNα response in P phase or Wnt-signaling in Q phase were observed in distinct resistant clones. These observations suggest a model of resistance hysteresis, where functional alterations of the P and Q phase states affect the dynamics of the successive transitions between drug exposure and recovery, and prompts for a precise monitoring of single-cell states to develop more effective schedules for, or combination of, chemotherapy treatments.
Keywords	Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Exome-wide analysis of bi-allelic alterations identifies a Lynch phenotype in The Cancer Genome Atlas

Alexandra R. Buckley / Trey Ideker / Hannah Carter / Olivier Harismendy / Nicholas J. Schork

Genome Medicine, Vol 10, Iss 1, Pp 1-

2018 Volume 15

Abstract: Abstract Background Cancer susceptibility germline variants generally require somatic alteration of the remaining allele to drive oncogenesis and, in some cases, tumor mutational profiles. Whether combined germline and somatic bi-allelic alterations are ... ...

Abstract	Abstract Background Cancer susceptibility germline variants generally require somatic alteration of the remaining allele to drive oncogenesis and, in some cases, tumor mutational profiles. Whether combined germline and somatic bi-allelic alterations are universally required for germline variation to influence tumor mutational profile is unclear. Here, we performed an exome-wide analysis of the frequency and functional effect of bi-allelic alterations in The Cancer Genome Atlas (TCGA). Methods We integrated germline variant, somatic mutation, somatic methylation, and somatic copy number loss data from 7790 individuals from TCGA to identify germline and somatic bi-allelic alterations in all coding genes. We used linear models to test for association between mono- and bi-allelic alterations and somatic microsatellite instability (MSI) and somatic mutational signatures. Results We discovered significant enrichment of bi-allelic alterations in mismatch repair (MMR) genes and identified six bi-allelic carriers with elevated MSI, consistent with Lynch syndrome. In contrast, we find little evidence of an effect of mono-allelic germline variation on MSI. Using MSI burden and bi-allelic alteration status, we reclassify two variants of unknown significance in MSH6 as potentially pathogenic for Lynch syndrome. Extending our analysis of MSI to a set of 127 DNA damage repair (DDR) genes, we identified a novel association between methylation of SHPRH and MSI burden. Conclusions We find that bi-allelic alterations are infrequent in TCGA but most frequently occur in BRCA1/2 and MMR genes. Our results support the idea that bi-allelic alteration is required for germline variation to influence tumor mutational profile. Overall, we demonstrate that integrating germline, somatic, and epigenetic alterations provides new understanding of somatic mutational profiles.
Keywords	Cancer genomics ; Cancer germline ; Cancer predisposition ; TCGA ; Microsatellite instability ; Lynch syndrome ; Medicine ; R ; Genetics ; QH426-470
Subject code	572
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: HNRNPK maintains epidermal progenitor function through transcription of proliferation genes and degrading differentiation promoting mRNAs

Jingting Li / Yifang Chen / Xiaojun Xu / Jackson Jones / Manisha Tiwari / Ji Ling / Ying Wang / Olivier Harismendy / George L. Sen

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 14

Abstract: Maintenance of high turnover in tissues such as epidermis requires balance between proliferation and differentiation. Here the authors show that HNRNPK promotes RNA Polymerase II binding to proliferation and self-renewal genes as well as degradation of ... ...

Abstract	Maintenance of high turnover in tissues such as epidermis requires balance between proliferation and differentiation. Here the authors show that HNRNPK promotes RNA Polymerase II binding to proliferation and self-renewal genes as well as degradation of differentiation promoting mRNAs together with DDX6 in epidermis.
Keywords	Science ; Q
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Method for improving sequence coverage uniformity of targeted genomic intervals amplified by LR-PCR using Illumina GA sequencing-by-synthesis technology

Olivier Harismendy / Kelly A. Frazer

BioTechniques, Vol 46, Iss 3, Pp 229-

2009 Volume 231

Abstract: One approach for high-throughput population-based sequencing of targeted intervals in the human genome is to amplify the regions using long-range PCR (LR-PCR) followed by sequencing with next-generation sequencing (NGS) technologies. Utilizing this ... ...

Abstract	One approach for high-throughput population-based sequencing of targeted intervals in the human genome is to amplify the regions using long-range PCR (LR-PCR) followed by sequencing with next-generation sequencing (NGS) technologies. Utilizing this method, we have observed that the 50 bp located at the amplicon ends account for more than 50% of the sequenced bases and that the sequence coverage depth of base pairs within an amplicon is highly variable. Here we propose an explanation for the overrepresentation of the amplicon ends and show that the use of 5′-blocked primers for the LR-PCR reaction reduces their overrepresentation. Furthermore, we demonstrate that using a 600-bp library insert size rather than the standard 200-bp insert size results in more uniform sequence coverage depth. The capability to increase sequence coverage uniformity greatly improves the effective throughput of NGS platforms.
Keywords	next-generation sequencing ; coverage ; long-range PCR ; Biology (General) ; QH301-705.5
Subject code	630
Language	English
Publishing date	2009-03-01T00:00:00Z
Publisher	Future Science Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: HNRNPK maintains epidermal progenitor function through transcription of proliferation genes and degrading differentiation promoting mRNAs

Jingting Li / Yifang Chen / Xiaojun Xu / Jackson Jones / Manisha Tiwari / Ji Ling / Ying Wang / Olivier Harismendy / George L. Sen

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 14

Abstract	Maintenance of high turnover in tissues such as epidermis requires balance between proliferation and differentiation. Here the authors show that HNRNPK promotes RNA Polymerase II binding to proliferation and self-renewal genes as well as degradation of differentiation promoting mRNAs together with DDX6 in epidermis.
Keywords	Science ; Q
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mutational profiling of micro-dissected pre-malignant lesions from archived specimens

Daniela Nachmanson / Joseph Steward / Huazhen Yao / Adam Officer / Eliza Jeong / Thomas J. O’Keefe / Farnaz Hasteh / Kristen Jepsen / Gillian L. Hirst / Laura J. Esserman / Alexander D. Borowsky / Olivier Harismendy

BMC Medical Genomics, Vol 13, Iss 1, Pp 1-

2020 Volume 15

Abstract: Abstract Background Systematic cancer screening has led to the increased detection of pre-malignant lesions (PMLs). The absence of reliable prognostic markers has led mostly to over treatment resulting in potentially unnecessary stress, or insufficient ... ...

Abstract	Abstract Background Systematic cancer screening has led to the increased detection of pre-malignant lesions (PMLs). The absence of reliable prognostic markers has led mostly to over treatment resulting in potentially unnecessary stress, or insufficient treatment and avoidable progression. Importantly, most mutational profiling studies have relied on PML synchronous to invasive cancer, or performed in patients without outcome information, hence limiting their utility for biomarker discovery. The limitations in comprehensive mutational profiling of PMLs are in large part due to the significant technical and methodological challenges: most PML specimens are small, fixed in formalin and paraffin embedded (FFPE) and lack matching normal DNA. Methods Using test DNA from a highly degraded FFPE specimen, multiple targeted sequencing approaches were evaluated, varying DNA input amount (3–200 ng), library preparation strategy (BE: Blunt-End, SS: Single-Strand, AT: A-Tailing) and target size (whole exome vs. cancer gene panel). Variants in high-input DNA from FFPE and mirrored frozen specimens were used for PML-specific variant calling training and testing, respectively. The resulting approach was applied to profile and compare multiple regions micro-dissected (mean area 5 mm2) from 3 breast ductal carcinoma in situ (DCIS). Results Using low-input FFPE DNA, BE and SS libraries resulted in 4.9 and 3.7 increase over AT libraries in the fraction of whole exome covered at 20x (BE:87%, SS:63%, AT:17%). Compared to high-confidence somatic mutations from frozen specimens, PML-specific variant filtering increased recall (BE:85%, SS:80%, AT:75%) and precision (BE:93%, SS:91%, AT:84%) to levels expected from sampling variation. Copy number alterations were consistent across all tested approaches and only impacted by the design of the capture probe-set. Applied to DNA extracted from 9 micro-dissected regions (8 PML, 1 normal epithelium), the approach achieved comparable performance, illustrated the data adequacy to identify candidate driver events (GATA3 mutations, ERBB2 or FGFR1 gains, TP53 loss) and measure intra-lesion genetic heterogeneity. Conclusion Alternate experimental and analytical strategies increased the accuracy of DNA sequencing from archived micro-dissected PML regions, supporting the deeper molecular characterization of early cancer lesions and achieving a critical milestone in the development of biology-informed prognostic markers and precision chemo-prevention strategies.
Keywords	Targeted sequencing ; Cancer progression ; Pre-malignant lesion ; Variant calling ; FFPE ; Micro-dissection ; Internal medicine ; RC31-1245 ; Genetics ; QH426-470
Subject code	616
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prevalence of cancer susceptibility variants in patients with multiple Lynch syndrome related cancers

Yoon Young Choi / Su-Jin Shin / Jae Eun Lee / Lisa Madlensky / Seung-Tae Lee / Ji Soo Park / Jeong-Hyeon Jo / Hyunki Kim / Daniela Nachmanson / Xiaojun Xu / Sung Hoon Noh / Jae-Ho Cheong / Olivier Harismendy

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 9

Abstract: Abstract Along with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often ... ...

Abstract	Abstract Along with early-onset cancers, multiple primary cancers (MPCs) are likely resulting from increased genetic susceptibility; however, the associated predisposition genes or prevalence of the pathogenic variants genes in MPC patients are often unknown. We screened 71 patients with MPC of the stomach, colorectal, and endometrium, sequencing 65 cancer predisposition genes. A subset of 19 patients with early-onset MPC of stomach and colorectum were further evaluated for variants in cancer related genes using both normal and tumor whole exome sequencing. Among 71 patients with MPCs, variants classified to be pathogenic were observed in 15 (21.1%) patients and affected Lynch Syndrome (LS) genes: MLH1 (n = 10), MSH6 (n = 2), PMS2 (n = 2), and MSH2 (n = 1). All carriers had tumors with high microsatellite instability and 13 of them (86.7%) were early-onset, consistent with LS. In 19 patients with early-onset MPCs, loss of function (LoF) variants in RECQL5 were more prevalent in non-LS MPC than in matched sporadic cancer patients (OR = 31.6, 2.73–1700.6, p = 0.001). Additionally, there were high-confidence LoF variants at FANCG and CASP8 in two patients accompanied by somatic loss of heterozygosity in tumor, respectively. The results suggest that genetic screening should be considered for synchronous cancers and metachronous MPCs of the LS tumor spectrum, particularly in early-onset. Susceptibility variants in non-LS genes for MPC patients may exist, but evidence for their role is more elusive than for LS patients.
Keywords	Medicine ; R ; Science ; Q
Subject code	616 ; 610
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: PinAPL-Py

Philipp N. Spahn / Tyler Bath / Ryan J. Weiss / Jihoon Kim / Jeffrey D. Esko / Nathan E. Lewis / Olivier Harismendy

Scientific Reports, Vol 7, Iss 1, Pp 1-

A comprehensive web-application for the analysis of CRISPR/Cas9 screens

2017 Volume 8

Abstract: Abstract Large-scale genetic screens using CRISPR/Cas9 technology have emerged as a major tool for functional genomics. With its increased popularity, experimental biologists frequently acquire large sequencing datasets for which they often do not have ... ...

Abstract	Abstract Large-scale genetic screens using CRISPR/Cas9 technology have emerged as a major tool for functional genomics. With its increased popularity, experimental biologists frequently acquire large sequencing datasets for which they often do not have an easy analysis option. While a few bioinformatic tools have been developed for this purpose, their utility is still hindered either due to limited functionality or the requirement of bioinformatic expertise. To make sequencing data analysis of CRISPR/Cas9 screens more accessible to a wide range of scientists, we developed a Platform-independent Analysis of Pooled Screens using Python (PinAPL-Py), which is operated as an intuitive web-service. PinAPL-Py implements state-of-the-art tools and statistical models, assembled in a comprehensive workflow covering sequence quality control, automated sgRNA sequence extraction, alignment, sgRNA enrichment/depletion analysis and gene ranking. The workflow is set up to use a variety of popular sgRNA libraries as well as custom libraries that can be easily uploaded. Various analysis options are offered, suitable to analyze a large variety of CRISPR/Cas9 screening experiments. Analysis output includes ranked lists of sgRNAs and genes, and publication-ready plots. PinAPL-Py helps to advance genome-wide screening efforts by combining comprehensive functionality with user-friendly implementation. PinAPL-Py is freely accessible at http://pinapl-py.ucsd.edu with instructions and test datasets.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-11-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response

Meghana Pagadala / Timothy J. Sears / Victoria H. Wu / Eva Pérez-Guijarro / Hyo Kim / Andrea Castro / James V. Talwar / Cristian Gonzalez-Colin / Steven Cao / Benjamin J. Schmiedel / Shervin Goudarzi / Divya Kirani / Jessica Au / Tongwu Zhang / Teresa Landi / Rany M. Salem / Gerald P. Morris / Olivier Harismendy / Sandip Pravin Patel /

Ludmil B. Alexandrov / Jill P. Mesirov / Maurizio Zanetti / Chi-Ping Day / Chun Chieh Fan / Wesley K. Thompson / Glenn Merlino / J. Silvio Gutkind / Pandurangan Vijayanand / Hannah Carter

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 22

Abstract: Abstract With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 ... ...

Abstract	Abstract With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.
Keywords	Science ; Q
Subject code	610
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: ADAR1-mediated RNA-editing of 3′UTRs in breast cancer

Eduardo A. Sagredo / Alejandro Blanco / Alfredo I. Sagredo / Paola Pérez / Gonzalo Sepúlveda-Hermosilla / Fernanda Morales / Bettina Müller / Ricardo Verdugo / Katherine Marcelain / Olivier Harismendy / Ricardo Armisén

Biological Research, Vol 51, Iss 1, Pp 1-

2018 Volume 10

Abstract: Abstract Background Whole transcriptome RNA variant analyses have shown that adenosine deaminases acting on RNA (ADAR) enzymes modify a large proportion of cellular RNAs, contributing to transcriptome diversity and cancer evolution. Despite the advances ... ...

Abstract	Abstract Background Whole transcriptome RNA variant analyses have shown that adenosine deaminases acting on RNA (ADAR) enzymes modify a large proportion of cellular RNAs, contributing to transcriptome diversity and cancer evolution. Despite the advances in the understanding of ADAR function in breast cancer, ADAR RNA editing functional consequences are not fully addressed. Results We characterized A to G(I) mRNA editing in 81 breast cell lines, showing increased editing at 3′UTR and exonic regions in breast cancer cells compared to immortalized non-malignant cell lines. In addition, tumors from the BRCA TCGA cohort show a 24% increase in editing over normal breast samples when looking at 571 well-characterized UTRs targeted by ADAR1. Basal-like subtype breast cancer patients with high level of ADAR1 mRNA expression shows a worse clinical outcome and increased editing in their 3′UTRs. Interestingly, editing was particularly increased in the 3′UTRs of ATM, GINS4 and POLH transcripts in tumors, which correlated with their mRNA expression. We confirmed the role of ADAR1 in this regulation using a shRNA in a breast cancer cell line (ZR-75-1). Conclusions Altogether, these results revealed a significant association between the mRNA editing in genes related to cancer-relevant pathways and clinical outcomes, suggesting an important role of ADAR1 expression and function in breast cancer.
Keywords	Breast cancer ; ADAR1 ; 3′UTR ; Editing ; Biology (General) ; QH301-705.5
Subject code	616 ; 610
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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