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Article ; Online: Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer

Veronica Rendo / Snehangshu Kundu / Natallia Rameika / Viktor Ljungström / Richard Svensson / Kimmo Palin / Lauri Aaltonen / Ivaylo Stoimenov / Tobias Sjöblom

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 13

Abstract: Abstract Therapies targeting somatic bystander genetic events represent a new avenue for cancer treatment. We recently identified a subset of colorectal cancer (CRC) patients who are heterozygous for a wild-type and a low activity allele (NAT2*6) but ... ...

Abstract	Abstract Therapies targeting somatic bystander genetic events represent a new avenue for cancer treatment. We recently identified a subset of colorectal cancer (CRC) patients who are heterozygous for a wild-type and a low activity allele (NAT26) but lack the wild-type allele in their tumors due to loss of heterozygosity (LOH) at 8p22. These tumors were sensitive to treatment with a cytotoxic substrate of NAT2 (6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine, APA), and pointed to NAT2 loss being a therapeutically exploitable vulnerability of CRC tumors. To better estimate the total number of treatable CRC patients, we here determined whether tumor cells retaining also other NAT2 low activity variants after LOH respond to APA treatment. The prevalent low activity alleles NAT25 and NAT214, but not NAT27, were found to be low metabolizers with high sensitivity to APA. By analysis of two different CRC patient cohorts, we detected heterozygosity for NAT2 alleles targetable by APA, along with allelic imbalances pointing to LOH, in ~ 24% of tumors. Finally, to haplotype the NAT2 locus in tumor and patient-matched normal samples in a clinical setting, we develop and demonstrate a long-read sequencing based assay. In total, > 79.000 CRC patients per year fulfil genetic criteria for high sensitivity to a NAT2 LOH therapy and their eligibility can be assessed by clinical sequencing.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: MTG16 regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors

JCI Insight, Vol 7, Iss

2022 Volume 10

Abstract: Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional ... ...

Abstract	Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium–induced (DSS-induced) colitis. Transcriptomic analyses implicated increased Ephrussi box–binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a mouse model with a point mutation that attenuates MTG16:E protein interactions (Mtg16P209T), we showed that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein–mediated transcription. Mimicking murine colitis, MTG16 expression was increased in biopsies from patients with active IBD compared with unaffected controls. Finally, uncoupling MTG16:E protein interactions partially phenocopied the enhanced tumorigenicity of Mtg16–/– colon in the azoxymethane/DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colon homeostasis, colitis, and cancer.
Keywords	Cell biology ; Gastroenterology ; Medicine ; R
Subject code	570
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Parity associates with chromosomal damage in uterine leiomyomas

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 10

Abstract: Many factors have been associated with chromosomal damage, including mechanical forces in a constrained cellular environment. Here the authors reveal an association between parity and chromosomal damage by analysing karyotypes of 1946 uterine leiomyomas. ...

Abstract	Many factors have been associated with chromosomal damage, including mechanical forces in a constrained cellular environment. Here the authors reveal an association between parity and chromosomal damage by analysing karyotypes of 1946 uterine leiomyomas.
Keywords	Science ; Q
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Multiple clinical characteristics separate MED12-mutation-positive and -negative uterine leiomyomas

Hanna-Riikka Heinonen / Annukka Pasanen / Oskari Heikinheimo / Tomas Tanskanen / Kimmo Palin / Jaana Tolvanen / Pia Vahteristo / Jari Sjöberg / Esa Pitkänen / Ralf Bützow / Netta Mäkinen / Lauri A. Aaltonen

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

2017 Volume 7

Abstract: Abstract Up to 86% of uterine leiomyomas harbour somatic mutations in mediator complex subunit 12 (MED12). These mutations have been associated with conventional histology, smaller tumour size, and larger number of tumours within the uterus. Prior ... ...

Abstract	Abstract Up to 86% of uterine leiomyomas harbour somatic mutations in mediator complex subunit 12 (MED12). These mutations have been associated with conventional histology, smaller tumour size, and larger number of tumours within the uterus. Prior studies, with limited sample sizes, have failed to detect associations between other clinical features and MED12 mutations. Here, we prospectively collected 763 uterine leiomyomas and the corresponding normal myometrial tissue from 244 hysterectomy patients, recorded tumour characteristics, collected clinical data from medical records, and screened the tissue samples for MED12 mutations to assess potential associations between clinical variables and mutation status. Out of 763 leiomyomas, 599 (79%) harboured a MED12 mutation. In the analysis of tumour characteristics, positive MED12-mutation status was significantly associated with smaller tumour size, conventional histology, and subserous location, relative to intramural. In the analysis of clinical variables, the number of MED12-mutation-positive tumours showed an inverse association with parity, and the number of mutation-negative tumours showed a positive association with a history of pelvic inflammatory disease. This study confirmed the previously reported differences and discovered novel differentiating features for MED12-mutation-positive and -negative leiomyomas. These findings emphasise the relevance of specific driver mutations in genesis and presentation of uterine leiomyomas.
Keywords	Medicine ; R ; Science ; Q
Subject code	616 ; 610
Language	English
Publishing date	2017-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Detection of subclonal L1 transductions in colorectal cancer by long-distance inverse-PCR and Nanopore sequencing

Barun Pradhan / Tatiana Cajuso / Riku Katainen / Päivi Sulo / Tomas Tanskanen / Outi Kilpivaara / Esa Pitkänen / Lauri A. Aaltonen / Liisa Kauppi / Kimmo Palin

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

2017 Volume 12

Abstract: Abstract Long interspersed nuclear elements-1 (L1s) are a large family of retrotransposons. Retrotransposons are repetitive sequences that are capable of autonomous mobility via a copy-and-paste mechanism. In most copy events, only the L1 sequence is ... ...

Abstract	Abstract Long interspersed nuclear elements-1 (L1s) are a large family of retrotransposons. Retrotransposons are repetitive sequences that are capable of autonomous mobility via a copy-and-paste mechanism. In most copy events, only the L1 sequence is inserted, however, they can also mobilize the flanking non-repetitive region by a process known as 3′ transduction. L1 insertions can contribute to genome plasticity and cause potentially tumorigenic genomic instability. However, detecting the activity of a particular source L1 and identifying new insertions stemming from it is a challenging task with current methodological approaches. We developed a long-distance inverse PCR (LDI-PCR) based approach to monitor the mobility of active L1 elements based on their 3′ transduction activity. LDI-PCR requires no prior knowledge of the insertion target region. By applying LDI-PCR in conjunction with Nanopore sequencing (Oxford Nanopore Technologies) on one L1 reported to be particularly active in human cancer genomes, we detected 14 out of 15 3′ transductions previously identified by whole genome sequencing in two different colorectal tumour samples. In addition we discovered 25 novel highly subclonal insertions. Furthermore, the long sequencing reads produced by LDI-PCR/Nanopore sequencing enabled the identification of both the 5′ and 3′ junctions and revealed detailed insertion sequence information.
Keywords	Nanopore Sequencing ; Oxford Nanopore Technologies ; Long Interspersed Nuclear Elements (LINE) ; Candidate Insertion ; Target-primed Reverse Transcription (TPRT) ; Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2017-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability

Niko Välimäki / Heli Kuisma / Annukka Pasanen / Oskari Heikinheimo / Jari Sjöberg / Ralf Bützow / Nanna Sarvilinna / Hanna-Riikka Heinonen / Jaana Tolvanen / Simona Bramante / Tomas Tanskanen / Juha Auvinen / Outi Uimari / Amjad Alkodsi / Rainer Lehtonen / Eevi Kaasinen / Kimmo Palin / Lauri A Aaltonen

eLife, Vol

2018 Volume 7

Abstract: Uterine leiomyomas (ULs) are benign tumors that are a major burden to women’s health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk ... ...

Abstract	Uterine leiomyomas (ULs) are benign tumors that are a major burden to women’s health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.
Keywords	uterine leiomyoma ; genome-wide association study ; leiomyomagenesis ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival

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

2019 Volume 9

Abstract: Retrotransposons are usually dormant in healthy tissue, but become activated during malignancy. Here, in colorectal cancer, Cajuso et al. show that retrotransposon activity associates with clinical features of the disease. ...

Abstract	Retrotransposons are usually dormant in healthy tissue, but become activated during malignancy. Here, in colorectal cancer, Cajuso et al. show that retrotransposon activity associates with clinical features of the disease.
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: Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival

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

2019 Volume 9

Abstract	Retrotransposons are usually dormant in healthy tissue, but become activated during malignancy. Here, in colorectal cancer, Cajuso et al. show that retrotransposon activity associates with clinical features of the disease.
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: Integrating sequence, evolution and functional genomics in regulatory genomics

Vingron, Martin / Alvis Brazma / Esko Ukkonen / Jacques van Helden / Kimmo Palin / Olivier Sand / Richard Coulson / Thomas Manke

Genome biology. 2009 Jan., v. 10, no. 1

2009

Abstract: With genome analysis expanding from the study of genes to the study of gene regulation, 'regulatory genomics' utilizes sequence information, evolution and functional genomics measurements to unravel how regulatory information is encoded in the genome. ...

Abstract	With genome analysis expanding from the study of genes to the study of gene regulation, 'regulatory genomics' utilizes sequence information, evolution and functional genomics measurements to unravel how regulatory information is encoded in the genome.
Keywords	evolution ; genes ; genomics ; sequence analysis
Language	English
Dates of publication	2009-01
Size	p. 2084.
Publishing place	Springer-Verlag
Document type	Article
ZDB-ID	2040529-7
ISSN	1474-760X ; 1465-6914 ; 1465-6906
ISSN (online)	1474-760X ; 1465-6914
ISSN	1465-6906
DOI	10.1186/gb-2009-10-1-202
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer

Johanna Kondelin / Kari Salokas / Lilli Saarinen / Kristian Ovaska / Heli Rauanheimo / Roosa‐Maria Plaketti / Jiri Hamberg / Xiaonan Liu / Leena Yadav / Alexandra E Gylfe / Tatiana Cajuso / Ulrika A Hänninen / Kimmo Palin / Heikki Ristolainen / Riku Katainen / Eevi Kaasinen / Tomas Tanskanen / Mervi Aavikko / Minna Taipale /

Jussi Taipale / Laura Renkonen‐Sinisalo / Anna Lepistö / Selja Koskensalo / Jan Böhm / Jukka‐Pekka Mecklin / Halit Ongen / Emmanouil T Dermitzakis / Outi Kilpivaara / Pia Vahteristo / Mikko Turunen / Sampsa Hautaniemi / Sari Tuupanen / Auli Karhu / Niko Välimäki / Markku Varjosalo / Esa Pitkänen / Lauri A Aaltonen

EMBO Molecular Medicine, Vol 10, Iss 9, Pp n/a-n/a (2018)

2018

Abstract: Abstract Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite‐stable ...

Abstract	Abstract Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite‐stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit‐targeted area from 24 exome‐sequenced sporadic MSI CRCs and respective normals, and 12 whole‐genome‐sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well‐established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular.
Keywords	cancer genetics ; colorectal cancer ; microsatellite instability ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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