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Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis

Multiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencin...

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Autores principales: Wallander, Karin, Thonberg, Håkan, Nilsson, Daniel, Tham, Emma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555269/
https://www.ncbi.nlm.nih.gov/pubmed/34711244
http://dx.doi.org/10.1186/s13053-021-00203-z
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author Wallander, Karin
Thonberg, Håkan
Nilsson, Daniel
Tham, Emma
author_facet Wallander, Karin
Thonberg, Håkan
Nilsson, Daniel
Tham, Emma
author_sort Wallander, Karin
collection PubMed
description Multiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencing (WGS/WES) in ten individuals with three or more primary tumours, with no previous findings on standard clinical genetic investigations. In one individual with a clinical diagnosis of MEN1, a likely pathogenic cryptic splice site variant was detected in the MEN1 gene. The variant (c.654C > A) is synonymous but we showed in a cDNA analysis that it affects splicing and leads to a frameshift, with the theoretical new amino acid sequence p.(Gly219Glufs*13). In one individual with metachronous colorectal cancers, ovarian cancer, endometrial cancer and chronic lymphocytic leukaemia, we found a likely pathogenic variant in the MLH1 gene (c.27G > A), and two risk factor variants in the genes CHEK2 and HOXB13. The MLH1 variant is synonymous but has previously been shown to be associated to constitutional low-grade hypermethylation of the MLH1 promoter, and segregates with disease in families with colorectal and endometrial cancer. No pathogenic single nucleotide or structural variants were detected in the remaining eight individuals in the study. The pathogenic variants found by WGS/WES were in genes already sequenced by Sanger sequencing and WES in the clinic, without any findings. We conclude that, in individuals with an unequivocal clinical diagnosis of a specific hereditary cancer syndrome, where standard clinical testing failed to detect a causative variant, re-analysis may lead to a diagnosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13053-021-00203-z.
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spelling pubmed-85552692021-10-29 Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis Wallander, Karin Thonberg, Håkan Nilsson, Daniel Tham, Emma Hered Cancer Clin Pract Research Multiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencing (WGS/WES) in ten individuals with three or more primary tumours, with no previous findings on standard clinical genetic investigations. In one individual with a clinical diagnosis of MEN1, a likely pathogenic cryptic splice site variant was detected in the MEN1 gene. The variant (c.654C > A) is synonymous but we showed in a cDNA analysis that it affects splicing and leads to a frameshift, with the theoretical new amino acid sequence p.(Gly219Glufs*13). In one individual with metachronous colorectal cancers, ovarian cancer, endometrial cancer and chronic lymphocytic leukaemia, we found a likely pathogenic variant in the MLH1 gene (c.27G > A), and two risk factor variants in the genes CHEK2 and HOXB13. The MLH1 variant is synonymous but has previously been shown to be associated to constitutional low-grade hypermethylation of the MLH1 promoter, and segregates with disease in families with colorectal and endometrial cancer. No pathogenic single nucleotide or structural variants were detected in the remaining eight individuals in the study. The pathogenic variants found by WGS/WES were in genes already sequenced by Sanger sequencing and WES in the clinic, without any findings. We conclude that, in individuals with an unequivocal clinical diagnosis of a specific hereditary cancer syndrome, where standard clinical testing failed to detect a causative variant, re-analysis may lead to a diagnosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13053-021-00203-z. BioMed Central 2021-10-28 /pmc/articles/PMC8555269/ /pubmed/34711244 http://dx.doi.org/10.1186/s13053-021-00203-z Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wallander, Karin
Thonberg, Håkan
Nilsson, Daniel
Tham, Emma
Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis
title Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis
title_full Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis
title_fullStr Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis
title_full_unstemmed Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis
title_short Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis
title_sort massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555269/
https://www.ncbi.nlm.nih.gov/pubmed/34711244
http://dx.doi.org/10.1186/s13053-021-00203-z
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