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Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement

Pal Møller, Toni T. Seppälä, Aysel Ahadova, Emma J. Crosbie, Elke Holinski-Feder, Rodney Scott, Saskia Haupt, Gabriela Möslein, Ingrid Winship, Sanne W. Bajwa-ten Broeke, Kelly E. Kohut, Neil Ryan, Peter Bauerfeind, Laura Thomas Orcid Logo, D. Gareth Evans, Stefan Aretz, Rolf H. Sijmons, Elizabeth Half, Karl Heinimann, Karoline Horisberger, Kevin Monahan, Christoph Engel, Giulia Martina Cavestro, Robert Fruscio, Naim Abu-Freha, Levi Zohar, Luigi Laghi, Lucio Bertario, Bernardo Bonanni, Maria Grazia Tibiletti, Leonardo S. Lino-Silva, Carlos Vaccaro, Adriana Della Valle, Benedito Mauro Rossi, Leandro Apolinário da Silva, Ivana Lucia de Oliveira Nascimento, Norma Teresa Rossi, Tadeusz Dębniak, Jukka-Pekka Mecklin, Inge Bernstein, Annika Lindblom, Lone Sunde, Sigve Nakken, Vincent Heuveline, John Burn, Eivind Hovig, Matthias Kloor, Julian R. Sampson, Mev Dominguez-Valentin, (On behalf of the Prospective Lynch Syndrome Database (www.plsd.eu) and The European Hereditary Tumour Group (www.ehtg.org))

Hereditary Cancer in Clinical Practice, Volume: 21, Issue: 1

Swansea University Author: Laura Thomas Orcid Logo

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DOI (Published version): 10.1186/s13053-023-00263-3

Abstract

The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause...

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Published in: Hereditary Cancer in Clinical Practice
ISSN: 1897-4287
Published: Springer Science and Business Media LLC 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa64733
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Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.</abstract><type>Journal Article</type><journal>Hereditary Cancer in Clinical Practice</journal><volume>21</volume><journalNumber>1</journalNumber><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>1897-4287</issnElectronic><keywords>Dominantly inherited micro-satellite instable cancers, MSI cancers, mismatch repair genes, Lynch syndromes</keywords><publishedDay>11</publishedDay><publishedMonth>10</publishedMonth><publishedYear>2023</publishedYear><publishedDate>2023-10-11</publishedDate><doi>10.1186/s13053-023-00263-3</doi><url>http://dx.doi.org/10.1186/s13053-023-00263-3</url><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders/><projectreference/><lastEdited>2023-11-14T12:39:37.1501370</lastEdited><Created>2023-10-12T15:58:19.8303349</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Pal</firstname><surname>Møller</surname><order>1</order></author><author><firstname>Toni T.</firstname><surname>Seppälä</surname><order>2</order></author><author><firstname>Aysel</firstname><surname>Ahadova</surname><order>3</order></author><author><firstname>Emma J.</firstname><surname>Crosbie</surname><order>4</order></author><author><firstname>Elke</firstname><surname>Holinski-Feder</surname><order>5</order></author><author><firstname>Rodney</firstname><surname>Scott</surname><order>6</order></author><author><firstname>Saskia</firstname><surname>Haupt</surname><order>7</order></author><author><firstname>Gabriela</firstname><surname>Möslein</surname><order>8</order></author><author><firstname>Ingrid</firstname><surname>Winship</surname><order>9</order></author><author><firstname>Sanne W. Bajwa-ten</firstname><surname>Broeke</surname><order>10</order></author><author><firstname>Kelly E.</firstname><surname>Kohut</surname><order>11</order></author><author><firstname>Neil</firstname><surname>Ryan</surname><order>12</order></author><author><firstname>Peter</firstname><surname>Bauerfeind</surname><order>13</order></author><author><firstname>Laura</firstname><surname>Thomas</surname><orcid>0000-0002-8621-5285</orcid><order>14</order></author><author><firstname>D. Gareth</firstname><surname>Evans</surname><order>15</order></author><author><firstname>Stefan</firstname><surname>Aretz</surname><order>16</order></author><author><firstname>Rolf H.</firstname><surname>Sijmons</surname><order>17</order></author><author><firstname>Elizabeth</firstname><surname>Half</surname><order>18</order></author><author><firstname>Karl</firstname><surname>Heinimann</surname><order>19</order></author><author><firstname>Karoline</firstname><surname>Horisberger</surname><order>20</order></author><author><firstname>Kevin</firstname><surname>Monahan</surname><order>21</order></author><author><firstname>Christoph</firstname><surname>Engel</surname><order>22</order></author><author><firstname>Giulia Martina</firstname><surname>Cavestro</surname><order>23</order></author><author><firstname>Robert</firstname><surname>Fruscio</surname><order>24</order></author><author><firstname>Naim</firstname><surname>Abu-Freha</surname><order>25</order></author><author><firstname>Levi</firstname><surname>Zohar</surname><order>26</order></author><author><firstname>Luigi</firstname><surname>Laghi</surname><order>27</order></author><author><firstname>Lucio</firstname><surname>Bertario</surname><order>28</order></author><author><firstname>Bernardo</firstname><surname>Bonanni</surname><order>29</order></author><author><firstname>Maria Grazia</firstname><surname>Tibiletti</surname><order>30</order></author><author><firstname>Leonardo S.</firstname><surname>Lino-Silva</surname><order>31</order></author><author><firstname>Carlos</firstname><surname>Vaccaro</surname><order>32</order></author><author><firstname>Adriana Della</firstname><surname>Valle</surname><order>33</order></author><author><firstname>Benedito Mauro</firstname><surname>Rossi</surname><order>34</order></author><author><firstname>Leandro Apolinário da</firstname><surname>Silva</surname><order>35</order></author><author><firstname>Ivana Lucia de Oliveira</firstname><surname>Nascimento</surname><order>36</order></author><author><firstname>Norma Teresa</firstname><surname>Rossi</surname><order>37</order></author><author><firstname>Tadeusz</firstname><surname>Dębniak</surname><order>38</order></author><author><firstname>Jukka-Pekka</firstname><surname>Mecklin</surname><order>39</order></author><author><firstname>Inge</firstname><surname>Bernstein</surname><order>40</order></author><author><firstname>Annika</firstname><surname>Lindblom</surname><order>41</order></author><author><firstname>Lone</firstname><surname>Sunde</surname><order>42</order></author><author><firstname>Sigve</firstname><surname>Nakken</surname><order>43</order></author><author><firstname>Vincent</firstname><surname>Heuveline</surname><order>44</order></author><author><firstname>John</firstname><surname>Burn</surname><order>45</order></author><author><firstname>Eivind</firstname><surname>Hovig</surname><order>46</order></author><author><firstname>Matthias</firstname><surname>Kloor</surname><order>47</order></author><author><firstname>Julian R.</firstname><surname>Sampson</surname><order>48</order></author><author><firstname>Mev</firstname><surname>Dominguez-Valentin</surname><order>49</order></author><author><firstname>(On behalf of the Prospective Lynch Syndrome Database (www.plsd.eu) and The European Hereditary Tumour Group</firstname><surname>(www.ehtg.org))</surname><order>50</order></author></authors><documents><document><filename>64733__28977__ccc2673ad055469b8c077b12daf045e7.pdf</filename><originalFilename>64733.VOR.pdf</originalFilename><uploaded>2023-11-08T16:11:04.7173646</uploaded><type>Output</type><contentLength>1641692</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© The Author(s) 2023. 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spelling v2 64733 2023-10-12 Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement 6f80a1638d852bd88d37afe3aeb2fb62 0000-0002-8621-5285 Laura Thomas Laura Thomas true false 2023-10-12 BMS The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer. Journal Article Hereditary Cancer in Clinical Practice 21 1 Springer Science and Business Media LLC 1897-4287 Dominantly inherited micro-satellite instable cancers, MSI cancers, mismatch repair genes, Lynch syndromes 11 10 2023 2023-10-11 10.1186/s13053-023-00263-3 http://dx.doi.org/10.1186/s13053-023-00263-3 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee 2023-11-14T12:39:37.1501370 2023-10-12T15:58:19.8303349 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Pal Møller 1 Toni T. Seppälä 2 Aysel Ahadova 3 Emma J. Crosbie 4 Elke Holinski-Feder 5 Rodney Scott 6 Saskia Haupt 7 Gabriela Möslein 8 Ingrid Winship 9 Sanne W. Bajwa-ten Broeke 10 Kelly E. Kohut 11 Neil Ryan 12 Peter Bauerfeind 13 Laura Thomas 0000-0002-8621-5285 14 D. Gareth Evans 15 Stefan Aretz 16 Rolf H. Sijmons 17 Elizabeth Half 18 Karl Heinimann 19 Karoline Horisberger 20 Kevin Monahan 21 Christoph Engel 22 Giulia Martina Cavestro 23 Robert Fruscio 24 Naim Abu-Freha 25 Levi Zohar 26 Luigi Laghi 27 Lucio Bertario 28 Bernardo Bonanni 29 Maria Grazia Tibiletti 30 Leonardo S. Lino-Silva 31 Carlos Vaccaro 32 Adriana Della Valle 33 Benedito Mauro Rossi 34 Leandro Apolinário da Silva 35 Ivana Lucia de Oliveira Nascimento 36 Norma Teresa Rossi 37 Tadeusz Dębniak 38 Jukka-Pekka Mecklin 39 Inge Bernstein 40 Annika Lindblom 41 Lone Sunde 42 Sigve Nakken 43 Vincent Heuveline 44 John Burn 45 Eivind Hovig 46 Matthias Kloor 47 Julian R. Sampson 48 Mev Dominguez-Valentin 49 (On behalf of the Prospective Lynch Syndrome Database (www.plsd.eu) and The European Hereditary Tumour Group (www.ehtg.org)) 50 64733__28977__ccc2673ad055469b8c077b12daf045e7.pdf 64733.VOR.pdf 2023-11-08T16:11:04.7173646 Output 1641692 application/pdf Version of Record true © The Author(s) 2023. Distributed under the terms of a Creative Commons Attribution 4.0 International License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
spellingShingle Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
Laura Thomas
title_short Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
title_full Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
title_fullStr Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
title_full_unstemmed Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
title_sort Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
author_id_str_mv 6f80a1638d852bd88d37afe3aeb2fb62
author_id_fullname_str_mv 6f80a1638d852bd88d37afe3aeb2fb62_***_Laura Thomas
author Laura Thomas
author2 Pal Møller
Toni T. Seppälä
Aysel Ahadova
Emma J. Crosbie
Elke Holinski-Feder
Rodney Scott
Saskia Haupt
Gabriela Möslein
Ingrid Winship
Sanne W. Bajwa-ten Broeke
Kelly E. Kohut
Neil Ryan
Peter Bauerfeind
Laura Thomas
D. Gareth Evans
Stefan Aretz
Rolf H. Sijmons
Elizabeth Half
Karl Heinimann
Karoline Horisberger
Kevin Monahan
Christoph Engel
Giulia Martina Cavestro
Robert Fruscio
Naim Abu-Freha
Levi Zohar
Luigi Laghi
Lucio Bertario
Bernardo Bonanni
Maria Grazia Tibiletti
Leonardo S. Lino-Silva
Carlos Vaccaro
Adriana Della Valle
Benedito Mauro Rossi
Leandro Apolinário da Silva
Ivana Lucia de Oliveira Nascimento
Norma Teresa Rossi
Tadeusz Dębniak
Jukka-Pekka Mecklin
Inge Bernstein
Annika Lindblom
Lone Sunde
Sigve Nakken
Vincent Heuveline
John Burn
Eivind Hovig
Matthias Kloor
Julian R. Sampson
Mev Dominguez-Valentin
(On behalf of the Prospective Lynch Syndrome Database (www.plsd.eu) and The European Hereditary Tumour Group (www.ehtg.org))
format Journal article
container_title Hereditary Cancer in Clinical Practice
container_volume 21
container_issue 1
publishDate 2023
institution Swansea University
issn 1897-4287
doi_str_mv 10.1186/s13053-023-00263-3
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
url http://dx.doi.org/10.1186/s13053-023-00263-3
document_store_str 1
active_str 0
description The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
published_date 2023-10-11T12:39:40Z
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score 11.013619

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