Detection of PMS2 Mutations by Screening Hereditary Nonpolyposis Colon Cancer Families from Denmark and Sweden

Henrik Okkels; Kristina Lagerstedt-Robinsson; Friedrik P. Wikman; Thomas V.O. Hansen; Ihab Lolas; Lars Joachim Lindberg; Henrik B. Krarup

doi:10.1089/gtmb.2018.0316

Detection of PMS2 Mutations by Screening Hereditary Nonpolyposis Colon Cancer Families from Denmark and Sweden

Henrik Okkels^*, Kristina Lagerstedt-Robinsson, Friedrik P. Wikman, Thomas V.O. Hansen, Ihab Lolas, Lars Joachim Lindberg, Henrik B. Krarup

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin - Molekylær Medicinsk afdeling (MOMA)

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

3 Citationer (Scopus)

Abstract

Background and Aims: Hereditary nonpolyposis colon cancer (HNPCC) and Lynch syndrome (LS) are characterized by defects in the mismatch repair (MMR) system, which protects the integrity of the genome. Pathogenic variants in four MMR genes (MLH1, MSH2, MSH6, and PMS2) are responsible for LS, an autosomal, dominant hereditary disease that occurs with a frequency of 2-5% among all colorectal cancer cases. It has been estimated that ∼2-5% of all pathogenic variants found in the four MMR genes in LS cases are detected in the PMS2 gene. An overview of detected variants is presented here. Materials and Methods: Long-range (LR) PMS2 polymerase chain reaction (PCR) and PMS2 multiplex ligation probe amplification (MLPA) assays were used to detect PMS2 variants in ∼1500 probands. In a subset of the probands, pathogenic PMS2 variants were detected by next-generation sequencing, and all detected variants were confirmed by LR-PCR combined with an MLPA assay. Results: A summary of PMS2 mutation analyses performed on colon cancer patients from molecular diagnostic laboratories in Denmark and Sweden is presented. By screening ∼1500 HNPCC probands, a total of 40 different PMS2 variants were detected in 71 probands (5%); 20 variants were classified as pathogenic (C5), 2 variants as likely pathogenic (C4), 15 variants as variants of unknown significance (VUSs) (C3), 1 variant as likely benign (C2), and 2 variants as benign (C1). In total, 22/71 (31%) of the probands carried a pathogenic sequence variant. Among the probands with isolated loss of pPMS2 expression, the fraction of pathogenic variants was 20/35 (55%). Conclusions: Approximately 5% of the probands found in the Danish and Swedish populations presented here carried a PMS2 variant. In this study, six novel pathogenic variants and seven VUSs are reported.

Originalsprog	Engelsk
Tidsskrift	Genetic Testing and Molecular Biomarkers
Vol/bind	23
Nummer	9
Sider (fra-til)	688-695
Antal sider	8
ISSN	1945-0265
DOI	https://doi.org/10.1089/gtmb.2018.0316
Status	Udgivet - 2019

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@article{663267d99af14a61a984d8c40fd6d4ee,

title = "Detection of PMS2 Mutations by Screening Hereditary Nonpolyposis Colon Cancer Families from Denmark and Sweden",

abstract = "Background and Aims: Hereditary nonpolyposis colon cancer (HNPCC) and Lynch syndrome (LS) are characterized by defects in the mismatch repair (MMR) system, which protects the integrity of the genome. Pathogenic variants in four MMR genes (MLH1, MSH2, MSH6, and PMS2) are responsible for LS, an autosomal, dominant hereditary disease that occurs with a frequency of 2-5% among all colorectal cancer cases. It has been estimated that ∼2-5% of all pathogenic variants found in the four MMR genes in LS cases are detected in the PMS2 gene. An overview of detected variants is presented here. Materials and Methods: Long-range (LR) PMS2 polymerase chain reaction (PCR) and PMS2 multiplex ligation probe amplification (MLPA) assays were used to detect PMS2 variants in ∼1500 probands. In a subset of the probands, pathogenic PMS2 variants were detected by next-generation sequencing, and all detected variants were confirmed by LR-PCR combined with an MLPA assay. Results: A summary of PMS2 mutation analyses performed on colon cancer patients from molecular diagnostic laboratories in Denmark and Sweden is presented. By screening ∼1500 HNPCC probands, a total of 40 different PMS2 variants were detected in 71 probands (5%); 20 variants were classified as pathogenic (C5), 2 variants as likely pathogenic (C4), 15 variants as variants of unknown significance (VUSs) (C3), 1 variant as likely benign (C2), and 2 variants as benign (C1). In total, 22/71 (31%) of the probands carried a pathogenic sequence variant. Among the probands with isolated loss of pPMS2 expression, the fraction of pathogenic variants was 20/35 (55%). Conclusions: Approximately 5% of the probands found in the Danish and Swedish populations presented here carried a PMS2 variant. In this study, six novel pathogenic variants and seven VUSs are reported.",

keywords = "HNPCC, long-range PCR, Lynch syndrome, pathogenic variants, PMS2",

author = "Henrik Okkels and Kristina Lagerstedt-Robinsson and Wikman, {Friedrik P.} and Hansen, {Thomas V.O.} and Ihab Lolas and Lindberg, {Lars Joachim} and Krarup, {Henrik B.}",

year = "2019",

doi = "10.1089/gtmb.2018.0316",

language = "English",

volume = "23",

pages = "688--695",

journal = "Genetic Testing and Molecular Biomarkers",

issn = "1945-0265",

publisher = "Mary Ann Liebert Inc.",

number = "9",

}

Detection of PMS2 Mutations by Screening Hereditary Nonpolyposis Colon Cancer Families from Denmark and Sweden. / Okkels, Henrik; Lagerstedt-Robinsson, Kristina; Wikman, Friedrik P. et al.
I: Genetic Testing and Molecular Biomarkers, Bind 23, Nr. 9, 2019, s. 688-695.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Detection of PMS2 Mutations by Screening Hereditary Nonpolyposis Colon Cancer Families from Denmark and Sweden

AU - Okkels, Henrik

AU - Lagerstedt-Robinsson, Kristina

AU - Wikman, Friedrik P.

AU - Hansen, Thomas V.O.

AU - Lolas, Ihab

AU - Lindberg, Lars Joachim

AU - Krarup, Henrik B.

PY - 2019

Y1 - 2019

N2 - Background and Aims: Hereditary nonpolyposis colon cancer (HNPCC) and Lynch syndrome (LS) are characterized by defects in the mismatch repair (MMR) system, which protects the integrity of the genome. Pathogenic variants in four MMR genes (MLH1, MSH2, MSH6, and PMS2) are responsible for LS, an autosomal, dominant hereditary disease that occurs with a frequency of 2-5% among all colorectal cancer cases. It has been estimated that ∼2-5% of all pathogenic variants found in the four MMR genes in LS cases are detected in the PMS2 gene. An overview of detected variants is presented here. Materials and Methods: Long-range (LR) PMS2 polymerase chain reaction (PCR) and PMS2 multiplex ligation probe amplification (MLPA) assays were used to detect PMS2 variants in ∼1500 probands. In a subset of the probands, pathogenic PMS2 variants were detected by next-generation sequencing, and all detected variants were confirmed by LR-PCR combined with an MLPA assay. Results: A summary of PMS2 mutation analyses performed on colon cancer patients from molecular diagnostic laboratories in Denmark and Sweden is presented. By screening ∼1500 HNPCC probands, a total of 40 different PMS2 variants were detected in 71 probands (5%); 20 variants were classified as pathogenic (C5), 2 variants as likely pathogenic (C4), 15 variants as variants of unknown significance (VUSs) (C3), 1 variant as likely benign (C2), and 2 variants as benign (C1). In total, 22/71 (31%) of the probands carried a pathogenic sequence variant. Among the probands with isolated loss of pPMS2 expression, the fraction of pathogenic variants was 20/35 (55%). Conclusions: Approximately 5% of the probands found in the Danish and Swedish populations presented here carried a PMS2 variant. In this study, six novel pathogenic variants and seven VUSs are reported.

AB - Background and Aims: Hereditary nonpolyposis colon cancer (HNPCC) and Lynch syndrome (LS) are characterized by defects in the mismatch repair (MMR) system, which protects the integrity of the genome. Pathogenic variants in four MMR genes (MLH1, MSH2, MSH6, and PMS2) are responsible for LS, an autosomal, dominant hereditary disease that occurs with a frequency of 2-5% among all colorectal cancer cases. It has been estimated that ∼2-5% of all pathogenic variants found in the four MMR genes in LS cases are detected in the PMS2 gene. An overview of detected variants is presented here. Materials and Methods: Long-range (LR) PMS2 polymerase chain reaction (PCR) and PMS2 multiplex ligation probe amplification (MLPA) assays were used to detect PMS2 variants in ∼1500 probands. In a subset of the probands, pathogenic PMS2 variants were detected by next-generation sequencing, and all detected variants were confirmed by LR-PCR combined with an MLPA assay. Results: A summary of PMS2 mutation analyses performed on colon cancer patients from molecular diagnostic laboratories in Denmark and Sweden is presented. By screening ∼1500 HNPCC probands, a total of 40 different PMS2 variants were detected in 71 probands (5%); 20 variants were classified as pathogenic (C5), 2 variants as likely pathogenic (C4), 15 variants as variants of unknown significance (VUSs) (C3), 1 variant as likely benign (C2), and 2 variants as benign (C1). In total, 22/71 (31%) of the probands carried a pathogenic sequence variant. Among the probands with isolated loss of pPMS2 expression, the fraction of pathogenic variants was 20/35 (55%). Conclusions: Approximately 5% of the probands found in the Danish and Swedish populations presented here carried a PMS2 variant. In this study, six novel pathogenic variants and seven VUSs are reported.

KW - HNPCC

KW - long-range PCR

KW - Lynch syndrome

KW - pathogenic variants

KW - PMS2

UR - http://www.scopus.com/inward/record.url?scp=85072234290&partnerID=8YFLogxK

U2 - 10.1089/gtmb.2018.0316

DO - 10.1089/gtmb.2018.0316

M3 - Journal article

C2 - 31433215

AN - SCOPUS:85072234290

SN - 1945-0265

VL - 23

SP - 688

EP - 695

JO - Genetic Testing and Molecular Biomarkers

JF - Genetic Testing and Molecular Biomarkers

IS - 9

ER -

Detection of PMS2 Mutations by Screening Hereditary Nonpolyposis Colon Cancer Families from Denmark and Sweden

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