Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer

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 lack the wild-type allele in their tumors due to...

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Autores principales:	Veronica Rendo, Snehangshu Kundu, Natallia Rameika, Viktor Ljungström, Richard Svensson, Kimmo Palin, Lauri Aaltonen, Ivaylo Stoimenov, Tobias Sjöblom
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0075eeada5c6431e9aaae378bc12e7b8
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spelling	oai:doaj.org-article:0075eeada5c6431e9aaae378bc12e7b82021-12-02T13:46:37ZDefining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer10.1038/s41598-020-80288-z2045-2322https://doaj.org/article/0075eeada5c6431e9aaae378bc12e7b82020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80288-zhttps://doaj.org/toc/2045-2322Abstract 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.Veronica RendoSnehangshu KunduNatallia RameikaViktor LjungströmRichard SvenssonKimmo PalinLauri AaltonenIvaylo StoimenovTobias SjöblomNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Veronica Rendo Snehangshu Kundu Natallia Rameika Viktor Ljungström Richard Svensson Kimmo Palin Lauri Aaltonen Ivaylo Stoimenov Tobias Sjöblom Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
description	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.
format	article
author	Veronica Rendo Snehangshu Kundu Natallia Rameika Viktor Ljungström Richard Svensson Kimmo Palin Lauri Aaltonen Ivaylo Stoimenov Tobias Sjöblom
author_facet	Veronica Rendo Snehangshu Kundu Natallia Rameika Viktor Ljungström Richard Svensson Kimmo Palin Lauri Aaltonen Ivaylo Stoimenov Tobias Sjöblom
author_sort	Veronica Rendo
title	Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
title_short	Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
title_full	Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
title_fullStr	Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
title_full_unstemmed	Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer
title_sort	defining eligible patients for allele-selective chemotherapies targeting nat2 in colorectal cancer
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/0075eeada5c6431e9aaae378bc12e7b8
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Defining eligible patients for allele-selective chemotherapies targeting NAT2 in colorectal cancer

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