Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction
Purpose Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases POLE and POLD1 . Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not y...
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| Veröffentlicht in: | Genetics in medicine 2020-09, Vol.22 (9), p.1533-1541 |
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| creator | Hamzaoui, Nadim Alarcon, Flora Leulliot, Nicolas Guimbaud, Rosine Buecher, Bruno Colas, Chrystelle Corsini, Carole Nuel, Gregory Terris, Benoît Laurent-Puig, Pierre Chaussade, Stanislas Dhooge, Marion Madru, Clément Clauser, Eric |
| description | Purpose
Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases
POLE
and
POLD1
. Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified.
Methods
We sequenced
POLE
and
POLD1
exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of
POLE
variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes.
Results
Pathogenic
POLE
exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2–17.5), 48.5% (33.2–60.3), and 74% (51.6–86.1). Cumulative risk of glioblastoma was 18.7% (3.2–25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site.
Conclusion
The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to
POLE
variant carriers. |
| doi_str_mv | 10.1038/s41436-020-0828-z |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_hal_p</sourceid><recordid>TN_cdi_hal_primary_oai_HAL_hal_03263541v1</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2474986585</sourcerecordid><originalsourceid>FETCH-LOGICAL-c477t-837efc0ad0b55245af828d16debc876fedea040a5c996ab73c6cb5284fb602be3</originalsourceid><addsrcrecordid>eNp9kc9PFTEQxxsjEUT_AC-miScTVvq73SMhCCQvgQOem9luC8V922e7i-H5z9vHIp701OnMZ76TmS9CHyj5Qgk3x0VQwVVDGGmIYabZvkIHVPL640q9rjFpTcMVIfvobSn3hFDNGXmD9jkTTFCtDtCvcz_6KbojXKY8u2nOMBxhGHsc5tFNMY0wYHcHGdzkc9zCLoVTwNdXqzO8ScPj2mcoHm9ySiF76ON4ix8gRxingmEY0s-CHYzOZ5xj-V5B38cn5XdoL8BQ_Pvn9xB9-3p2c3rRrK7OL09PVo0TWk-N4doHR6AnnZRMSAh1156q3nfOaBV874EIAtK1rYJOc6dcJ5kRoVOEdZ4fos-L7h0MdpPjGvKjTRDtxcnK7nKEM8WloA-0sp8Wtu7zY_ZlsvdpzvUIxTKhRWuUNPL_FG-pkVK3laIL5XIqJfvwMpwSuzPQLgbaaqDdGWi3tefjs_LcrX3_0vHHsQqwBSi1NN76_Hf0v1V_A77lp84</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2439185579</pqid></control><display><type>article</type><title>Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>ProQuest Central UK/Ireland</source><source>Alma/SFX Local Collection</source><creator>Hamzaoui, Nadim ; Alarcon, Flora ; Leulliot, Nicolas ; Guimbaud, Rosine ; Buecher, Bruno ; Colas, Chrystelle ; Corsini, Carole ; Nuel, Gregory ; Terris, Benoît ; Laurent-Puig, Pierre ; Chaussade, Stanislas ; Dhooge, Marion ; Madru, Clément ; Clauser, Eric</creator><creatorcontrib>Hamzaoui, Nadim ; Alarcon, Flora ; Leulliot, Nicolas ; Guimbaud, Rosine ; Buecher, Bruno ; Colas, Chrystelle ; Corsini, Carole ; Nuel, Gregory ; Terris, Benoît ; Laurent-Puig, Pierre ; Chaussade, Stanislas ; Dhooge, Marion ; Madru, Clément ; Clauser, Eric</creatorcontrib><description>Purpose
Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases
POLE
and
POLD1
. Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified.
Methods
We sequenced
POLE
and
POLD1
exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of
POLE
variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes.
Results
Pathogenic
POLE
exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2–17.5), 48.5% (33.2–60.3), and 74% (51.6–86.1). Cumulative risk of glioblastoma was 18.7% (3.2–25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site.
Conclusion
The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to
POLE
variant carriers.</description><identifier>ISSN: 1098-3600</identifier><identifier>EISSN: 1530-0366</identifier><identifier>DOI: 10.1038/s41436-020-0828-z</identifier><identifier>PMID: 32424176</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Adenomatous Polyposis Coli ; Adult ; Aged ; Biomedical and Life Sciences ; Biomedicine ; Brain cancer ; Colorectal cancer ; Colorectal Neoplasms - epidemiology ; Colorectal Neoplasms - genetics ; DNA Polymerase II - genetics ; Genetic counseling ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Human Genetics ; Humans ; Laboratory Medicine ; Life Sciences ; Middle Aged ; Poly-ADP-Ribose Binding Proteins - genetics ; Santé publique et épidémiologie ; Survival analysis</subject><ispartof>Genetics in medicine, 2020-09, Vol.22 (9), p.1533-1541</ispartof><rights>American College of Medical Genetics and Genomics 2020</rights><rights>American College of Medical Genetics and Genomics 2020.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-837efc0ad0b55245af828d16debc876fedea040a5c996ab73c6cb5284fb602be3</citedby><cites>FETCH-LOGICAL-c477t-837efc0ad0b55245af828d16debc876fedea040a5c996ab73c6cb5284fb602be3</cites><orcidid>0000-0003-4630-9401 ; 0000-0001-8475-5459 ; 0000-0001-9910-2354</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2439185579?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,64385,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32424176$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03263541$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Hamzaoui, Nadim</creatorcontrib><creatorcontrib>Alarcon, Flora</creatorcontrib><creatorcontrib>Leulliot, Nicolas</creatorcontrib><creatorcontrib>Guimbaud, Rosine</creatorcontrib><creatorcontrib>Buecher, Bruno</creatorcontrib><creatorcontrib>Colas, Chrystelle</creatorcontrib><creatorcontrib>Corsini, Carole</creatorcontrib><creatorcontrib>Nuel, Gregory</creatorcontrib><creatorcontrib>Terris, Benoît</creatorcontrib><creatorcontrib>Laurent-Puig, Pierre</creatorcontrib><creatorcontrib>Chaussade, Stanislas</creatorcontrib><creatorcontrib>Dhooge, Marion</creatorcontrib><creatorcontrib>Madru, Clément</creatorcontrib><creatorcontrib>Clauser, Eric</creatorcontrib><title>Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction</title><title>Genetics in medicine</title><addtitle>Genet Med</addtitle><addtitle>Genet Med</addtitle><description>Purpose
Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases
POLE
and
POLD1
. Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified.
Methods
We sequenced
POLE
and
POLD1
exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of
POLE
variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes.
Results
Pathogenic
POLE
exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2–17.5), 48.5% (33.2–60.3), and 74% (51.6–86.1). Cumulative risk of glioblastoma was 18.7% (3.2–25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site.
Conclusion
The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to
POLE
variant carriers.</description><subject>Adenomatous Polyposis Coli</subject><subject>Adult</subject><subject>Aged</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain cancer</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - epidemiology</subject><subject>Colorectal Neoplasms - genetics</subject><subject>DNA Polymerase II - genetics</subject><subject>Genetic counseling</subject><subject>Genetic Predisposition to Disease</subject><subject>Germ-Line Mutation</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Laboratory Medicine</subject><subject>Life Sciences</subject><subject>Middle Aged</subject><subject>Poly-ADP-Ribose Binding Proteins - genetics</subject><subject>Santé publique et épidémiologie</subject><subject>Survival analysis</subject><issn>1098-3600</issn><issn>1530-0366</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9kc9PFTEQxxsjEUT_AC-miScTVvq73SMhCCQvgQOem9luC8V922e7i-H5z9vHIp701OnMZ76TmS9CHyj5Qgk3x0VQwVVDGGmIYabZvkIHVPL640q9rjFpTcMVIfvobSn3hFDNGXmD9jkTTFCtDtCvcz_6KbojXKY8u2nOMBxhGHsc5tFNMY0wYHcHGdzkc9zCLoVTwNdXqzO8ScPj2mcoHm9ySiF76ON4ix8gRxingmEY0s-CHYzOZ5xj-V5B38cn5XdoL8BQ_Pvn9xB9-3p2c3rRrK7OL09PVo0TWk-N4doHR6AnnZRMSAh1156q3nfOaBV874EIAtK1rYJOc6dcJ5kRoVOEdZ4fos-L7h0MdpPjGvKjTRDtxcnK7nKEM8WloA-0sp8Wtu7zY_ZlsvdpzvUIxTKhRWuUNPL_FG-pkVK3laIL5XIqJfvwMpwSuzPQLgbaaqDdGWi3tefjs_LcrX3_0vHHsQqwBSi1NN76_Hf0v1V_A77lp84</recordid><startdate>20200901</startdate><enddate>20200901</enddate><creator>Hamzaoui, Nadim</creator><creator>Alarcon, Flora</creator><creator>Leulliot, Nicolas</creator><creator>Guimbaud, Rosine</creator><creator>Buecher, Bruno</creator><creator>Colas, Chrystelle</creator><creator>Corsini, Carole</creator><creator>Nuel, Gregory</creator><creator>Terris, Benoît</creator><creator>Laurent-Puig, Pierre</creator><creator>Chaussade, Stanislas</creator><creator>Dhooge, Marion</creator><creator>Madru, Clément</creator><creator>Clauser, Eric</creator><general>Nature Publishing Group US</general><general>Elsevier Limited</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0003-4630-9401</orcidid><orcidid>https://orcid.org/0000-0001-8475-5459</orcidid><orcidid>https://orcid.org/0000-0001-9910-2354</orcidid></search><sort><creationdate>20200901</creationdate><title>Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction</title><author>Hamzaoui, Nadim ; Alarcon, Flora ; Leulliot, Nicolas ; Guimbaud, Rosine ; Buecher, Bruno ; Colas, Chrystelle ; Corsini, Carole ; Nuel, Gregory ; Terris, Benoît ; Laurent-Puig, Pierre ; Chaussade, Stanislas ; Dhooge, Marion ; Madru, Clément ; Clauser, Eric</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-837efc0ad0b55245af828d16debc876fedea040a5c996ab73c6cb5284fb602be3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adenomatous Polyposis Coli</topic><topic>Adult</topic><topic>Aged</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain cancer</topic><topic>Colorectal cancer</topic><topic>Colorectal Neoplasms - epidemiology</topic><topic>Colorectal Neoplasms - genetics</topic><topic>DNA Polymerase II - genetics</topic><topic>Genetic counseling</topic><topic>Genetic Predisposition to Disease</topic><topic>Germ-Line Mutation</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Laboratory Medicine</topic><topic>Life Sciences</topic><topic>Middle Aged</topic><topic>Poly-ADP-Ribose Binding Proteins - genetics</topic><topic>Santé publique et épidémiologie</topic><topic>Survival analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hamzaoui, Nadim</creatorcontrib><creatorcontrib>Alarcon, Flora</creatorcontrib><creatorcontrib>Leulliot, Nicolas</creatorcontrib><creatorcontrib>Guimbaud, Rosine</creatorcontrib><creatorcontrib>Buecher, Bruno</creatorcontrib><creatorcontrib>Colas, Chrystelle</creatorcontrib><creatorcontrib>Corsini, Carole</creatorcontrib><creatorcontrib>Nuel, Gregory</creatorcontrib><creatorcontrib>Terris, Benoît</creatorcontrib><creatorcontrib>Laurent-Puig, Pierre</creatorcontrib><creatorcontrib>Chaussade, Stanislas</creatorcontrib><creatorcontrib>Dhooge, Marion</creatorcontrib><creatorcontrib>Madru, Clément</creatorcontrib><creatorcontrib>Clauser, Eric</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Genetics in medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hamzaoui, Nadim</au><au>Alarcon, Flora</au><au>Leulliot, Nicolas</au><au>Guimbaud, Rosine</au><au>Buecher, Bruno</au><au>Colas, Chrystelle</au><au>Corsini, Carole</au><au>Nuel, Gregory</au><au>Terris, Benoît</au><au>Laurent-Puig, Pierre</au><au>Chaussade, Stanislas</au><au>Dhooge, Marion</au><au>Madru, Clément</au><au>Clauser, Eric</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction</atitle><jtitle>Genetics in medicine</jtitle><stitle>Genet Med</stitle><addtitle>Genet Med</addtitle><date>2020-09-01</date><risdate>2020</risdate><volume>22</volume><issue>9</issue><spage>1533</spage><epage>1541</epage><pages>1533-1541</pages><issn>1098-3600</issn><eissn>1530-0366</eissn><abstract>Purpose
Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases
POLE
and
POLD1
. Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified.
Methods
We sequenced
POLE
and
POLD1
exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of
POLE
variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes.
Results
Pathogenic
POLE
exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2–17.5), 48.5% (33.2–60.3), and 74% (51.6–86.1). Cumulative risk of glioblastoma was 18.7% (3.2–25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site.
Conclusion
The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to
POLE
variant carriers.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>32424176</pmid><doi>10.1038/s41436-020-0828-z</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-4630-9401</orcidid><orcidid>https://orcid.org/0000-0001-8475-5459</orcidid><orcidid>https://orcid.org/0000-0001-9910-2354</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Genetics in medicine, 2020-09, Vol.22 (9), p.1533-1541 |
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| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; ProQuest Central UK/Ireland; Alma/SFX Local Collection |
| subjects | Adenomatous Polyposis Coli Adult Aged Biomedical and Life Sciences Biomedicine Brain cancer Colorectal cancer Colorectal Neoplasms - epidemiology Colorectal Neoplasms - genetics DNA Polymerase II - genetics Genetic counseling Genetic Predisposition to Disease Germ-Line Mutation Human Genetics Humans Laboratory Medicine Life Sciences Middle Aged Poly-ADP-Ribose Binding Proteins - genetics Santé publique et épidémiologie Survival analysis |
| title | Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction |
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