Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development
Multiple primary tumors (MPT) have been described in carriers of inherited cancer predisposition genes. However, the genetic etiology of a large proportion of MPT cases remains unclear. We reviewed 267 patients with hereditary cancer predisposition syndromes (HCPS) that underwent genetic counseling...
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| Veröffentlicht in: | Journal of molecular medicine (Berlin, Germany) Germany), 2017-05, Vol.95 (5), p.523-533 |
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| creator | Villacis, Rolando A. R. Basso, Tatiane R. Canto, Luisa M. Pinheiro, Maísa Santiago, Karina M. Giacomazzi, Juliana de Paula, Cláudia A. A. Carraro, Dirce M. Ashton-Prolla, Patrícia Achatz, Maria I. Rogatto, Silvia R. |
| description | Multiple primary tumors (MPT) have been described in carriers of inherited cancer predisposition genes. However, the genetic etiology of a large proportion of MPT cases remains unclear. We reviewed 267 patients with hereditary cancer predisposition syndromes (HCPS) that underwent genetic counseling and selected 22 patients with MPT to perform genomic analysis (CytoScan HD Array, Affymetrix) aiming to identify new alterations related to a high risk of developing MPT. Twenty patients had a positive family history of cancer and 11 met phenotypic criteria for HCPS. Genetic testing for each of the genes associated with these syndromes revealed negative results for pathogenic mutations. Seventeen rare germline copy number variations (CNVs) covering 40 genes were identified in 11 patients, including an
EPCAM
/
MSH2
deletion in one Lynch syndrome patient. An enrichment analysis revealed a significant number of genes (where the CNVs are mapped) associated with carcinogenesis and/or related to functions implicated with tumor development, such as proliferation and cell survival. An interaction network analysis highlighted the importance of
TP53
pathway in cancer emergence. A high number of germline copy-neutral loss of heterozygosity (cnLOH) was identified in nine cases, particularly in two patients. Eighteen genes were covered by both rare CNVs and cnLOH, including 14 related to tumorigenesis and seven genes (
ABCC1
,
KDM4C
,
KIAA0430
,
MYH11, NDE1
,
PIWIL2
, and
ULK2
) specifically associated with cellular growth and proliferation. Overall, we identified 14 cases with rare CNVs and/or cnLOH that may contribute to the risk of MPT development.
Key message
CNVs may explain the risk of hereditary cancer syndromes in MPT patients.
CNVs affecting genes related to cancer are candidates to be involved in MPT risk.
EPCAM
/
MSH2
deletions should be investigated in patients suspected to have LS.
Gene enrichment related to the
TP53
network is associated with MPT development.
cnLOH and CNVs contribute to the risk of MPT development. |
| doi_str_mv | 10.1007/s00109-017-1507-7 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1897374394</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1897374394</sourcerecordid><originalsourceid>FETCH-LOGICAL-c405t-69697ca6dcfd9bf4ad27136d04577e7e98d276df7d93e3c5b00e1d58fd2baf53</originalsourceid><addsrcrecordid>eNp1kU2PFCEQhonRuOPu_gAvhsSLFxQaGpqj2fiVbGKy2TthoNplpaEFWuO_X8YZjTGxLpUUT71F1YvQc0ZfM0rVm0opo5pQpggbqSLqEdoxwQfChKCP0Y5qIcmgmDxDz2q977QatXiKzoaJai6Z3KH1xhbAX6AsMSTANjYotoWcKg4JO5scFFIg2ga-YwkqtrVmF34VfoR2h9sd4BLqV5xnvGyxhTUCXktYbPmJ27bkgj18h5jXBVK7QE9mGytcnvI5un3_7vbqI7n-_OHT1dtr4gQdG5FaauWs9G72ej8L6_seXHoqRqVAgZ56QfpZec2Bu3FPKTA_TrMf9nYe-Tl6dZRdS_62QW1mCdVBjDZB3qphk1ZcCa5FR1_-g97nraT-uQPFeI9h6hQ7Uq7kWgvM5rSiYdQc3DBHN0w_sjm4YVTveXFS3vYL-D8dv8_fgeEI1P6Uugt_jf6v6gMhWJbG</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1891333328</pqid></control><display><type>article</type><title>Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>Villacis, Rolando A. R. ; Basso, Tatiane R. ; Canto, Luisa M. ; Pinheiro, Maísa ; Santiago, Karina M. ; Giacomazzi, Juliana ; de Paula, Cláudia A. A. ; Carraro, Dirce M. ; Ashton-Prolla, Patrícia ; Achatz, Maria I. ; Rogatto, Silvia R.</creator><creatorcontrib>Villacis, Rolando A. R. ; Basso, Tatiane R. ; Canto, Luisa M. ; Pinheiro, Maísa ; Santiago, Karina M. ; Giacomazzi, Juliana ; de Paula, Cláudia A. A. ; Carraro, Dirce M. ; Ashton-Prolla, Patrícia ; Achatz, Maria I. ; Rogatto, Silvia R.</creatorcontrib><description>Multiple primary tumors (MPT) have been described in carriers of inherited cancer predisposition genes. However, the genetic etiology of a large proportion of MPT cases remains unclear. We reviewed 267 patients with hereditary cancer predisposition syndromes (HCPS) that underwent genetic counseling and selected 22 patients with MPT to perform genomic analysis (CytoScan HD Array, Affymetrix) aiming to identify new alterations related to a high risk of developing MPT. Twenty patients had a positive family history of cancer and 11 met phenotypic criteria for HCPS. Genetic testing for each of the genes associated with these syndromes revealed negative results for pathogenic mutations. Seventeen rare germline copy number variations (CNVs) covering 40 genes were identified in 11 patients, including an
EPCAM
/
MSH2
deletion in one Lynch syndrome patient. An enrichment analysis revealed a significant number of genes (where the CNVs are mapped) associated with carcinogenesis and/or related to functions implicated with tumor development, such as proliferation and cell survival. An interaction network analysis highlighted the importance of
TP53
pathway in cancer emergence. A high number of germline copy-neutral loss of heterozygosity (cnLOH) was identified in nine cases, particularly in two patients. Eighteen genes were covered by both rare CNVs and cnLOH, including 14 related to tumorigenesis and seven genes (
ABCC1
,
KDM4C
,
KIAA0430
,
MYH11, NDE1
,
PIWIL2
, and
ULK2
) specifically associated with cellular growth and proliferation. Overall, we identified 14 cases with rare CNVs and/or cnLOH that may contribute to the risk of MPT development.
Key message
CNVs may explain the risk of hereditary cancer syndromes in MPT patients.
CNVs affecting genes related to cancer are candidates to be involved in MPT risk.
EPCAM
/
MSH2
deletions should be investigated in patients suspected to have LS.
Gene enrichment related to the
TP53
network is associated with MPT development.
cnLOH and CNVs contribute to the risk of MPT development.</description><identifier>ISSN: 0946-2716</identifier><identifier>EISSN: 1432-1440</identifier><identifier>DOI: 10.1007/s00109-017-1507-7</identifier><identifier>PMID: 28093616</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adult ; Biomedical and Life Sciences ; Biomedicine ; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics ; DNA Copy Number Variations - genetics ; Epithelial Cell Adhesion Molecule - genetics ; Female ; Genetic Predisposition to Disease - genetics ; Germ-Line Mutation ; Human Genetics ; Humans ; Internal Medicine ; Loss of Heterozygosity - genetics ; Male ; Molecular Medicine ; MutS Homolog 2 Protein - genetics ; Neoplasms - genetics ; Original Article</subject><ispartof>Journal of molecular medicine (Berlin, Germany), 2017-05, Vol.95 (5), p.523-533</ispartof><rights>Springer-Verlag Berlin Heidelberg 2017</rights><rights>Journal of Molecular Medicine is a copyright of Springer, 2017.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-69697ca6dcfd9bf4ad27136d04577e7e98d276df7d93e3c5b00e1d58fd2baf53</citedby><cites>FETCH-LOGICAL-c405t-69697ca6dcfd9bf4ad27136d04577e7e98d276df7d93e3c5b00e1d58fd2baf53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00109-017-1507-7$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00109-017-1507-7$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28093616$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Villacis, Rolando A. R.</creatorcontrib><creatorcontrib>Basso, Tatiane R.</creatorcontrib><creatorcontrib>Canto, Luisa M.</creatorcontrib><creatorcontrib>Pinheiro, Maísa</creatorcontrib><creatorcontrib>Santiago, Karina M.</creatorcontrib><creatorcontrib>Giacomazzi, Juliana</creatorcontrib><creatorcontrib>de Paula, Cláudia A. A.</creatorcontrib><creatorcontrib>Carraro, Dirce M.</creatorcontrib><creatorcontrib>Ashton-Prolla, Patrícia</creatorcontrib><creatorcontrib>Achatz, Maria I.</creatorcontrib><creatorcontrib>Rogatto, Silvia R.</creatorcontrib><title>Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development</title><title>Journal of molecular medicine (Berlin, Germany)</title><addtitle>J Mol Med</addtitle><addtitle>J Mol Med (Berl)</addtitle><description>Multiple primary tumors (MPT) have been described in carriers of inherited cancer predisposition genes. However, the genetic etiology of a large proportion of MPT cases remains unclear. We reviewed 267 patients with hereditary cancer predisposition syndromes (HCPS) that underwent genetic counseling and selected 22 patients with MPT to perform genomic analysis (CytoScan HD Array, Affymetrix) aiming to identify new alterations related to a high risk of developing MPT. Twenty patients had a positive family history of cancer and 11 met phenotypic criteria for HCPS. Genetic testing for each of the genes associated with these syndromes revealed negative results for pathogenic mutations. Seventeen rare germline copy number variations (CNVs) covering 40 genes were identified in 11 patients, including an
EPCAM
/
MSH2
deletion in one Lynch syndrome patient. An enrichment analysis revealed a significant number of genes (where the CNVs are mapped) associated with carcinogenesis and/or related to functions implicated with tumor development, such as proliferation and cell survival. An interaction network analysis highlighted the importance of
TP53
pathway in cancer emergence. A high number of germline copy-neutral loss of heterozygosity (cnLOH) was identified in nine cases, particularly in two patients. Eighteen genes were covered by both rare CNVs and cnLOH, including 14 related to tumorigenesis and seven genes (
ABCC1
,
KDM4C
,
KIAA0430
,
MYH11, NDE1
,
PIWIL2
, and
ULK2
) specifically associated with cellular growth and proliferation. Overall, we identified 14 cases with rare CNVs and/or cnLOH that may contribute to the risk of MPT development.
Key message
CNVs may explain the risk of hereditary cancer syndromes in MPT patients.
CNVs affecting genes related to cancer are candidates to be involved in MPT risk.
EPCAM
/
MSH2
deletions should be investigated in patients suspected to have LS.
Gene enrichment related to the
TP53
network is associated with MPT development.
cnLOH and CNVs contribute to the risk of MPT development.</description><subject>Adult</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Colorectal Neoplasms, Hereditary Nonpolyposis - genetics</subject><subject>DNA Copy Number Variations - genetics</subject><subject>Epithelial Cell Adhesion Molecule - genetics</subject><subject>Female</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Germ-Line Mutation</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Loss of Heterozygosity - genetics</subject><subject>Male</subject><subject>Molecular Medicine</subject><subject>MutS Homolog 2 Protein - genetics</subject><subject>Neoplasms - genetics</subject><subject>Original Article</subject><issn>0946-2716</issn><issn>1432-1440</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kU2PFCEQhonRuOPu_gAvhsSLFxQaGpqj2fiVbGKy2TthoNplpaEFWuO_X8YZjTGxLpUUT71F1YvQc0ZfM0rVm0opo5pQpggbqSLqEdoxwQfChKCP0Y5qIcmgmDxDz2q977QatXiKzoaJai6Z3KH1xhbAX6AsMSTANjYotoWcKg4JO5scFFIg2ga-YwkqtrVmF34VfoR2h9sd4BLqV5xnvGyxhTUCXktYbPmJ27bkgj18h5jXBVK7QE9mGytcnvI5un3_7vbqI7n-_OHT1dtr4gQdG5FaauWs9G72ej8L6_seXHoqRqVAgZ56QfpZec2Bu3FPKTA_TrMf9nYe-Tl6dZRdS_62QW1mCdVBjDZB3qphk1ZcCa5FR1_-g97nraT-uQPFeI9h6hQ7Uq7kWgvM5rSiYdQc3DBHN0w_sjm4YVTveXFS3vYL-D8dv8_fgeEI1P6Uugt_jf6v6gMhWJbG</recordid><startdate>20170501</startdate><enddate>20170501</enddate><creator>Villacis, Rolando A. R.</creator><creator>Basso, Tatiane R.</creator><creator>Canto, Luisa M.</creator><creator>Pinheiro, Maísa</creator><creator>Santiago, Karina M.</creator><creator>Giacomazzi, Juliana</creator><creator>de Paula, Cláudia A. A.</creator><creator>Carraro, Dirce M.</creator><creator>Ashton-Prolla, Patrícia</creator><creator>Achatz, Maria I.</creator><creator>Rogatto, Silvia R.</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</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>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20170501</creationdate><title>Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development</title><author>Villacis, Rolando A. R. ; Basso, Tatiane R. ; Canto, Luisa M. ; Pinheiro, Maísa ; Santiago, Karina M. ; Giacomazzi, Juliana ; de Paula, Cláudia A. A. ; Carraro, Dirce M. ; Ashton-Prolla, Patrícia ; Achatz, Maria I. ; Rogatto, Silvia R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-69697ca6dcfd9bf4ad27136d04577e7e98d276df7d93e3c5b00e1d58fd2baf53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adult</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Colorectal Neoplasms, Hereditary Nonpolyposis - genetics</topic><topic>DNA Copy Number Variations - genetics</topic><topic>Epithelial Cell Adhesion Molecule - genetics</topic><topic>Female</topic><topic>Genetic Predisposition to Disease - genetics</topic><topic>Germ-Line Mutation</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Loss of Heterozygosity - genetics</topic><topic>Male</topic><topic>Molecular Medicine</topic><topic>MutS Homolog 2 Protein - genetics</topic><topic>Neoplasms - genetics</topic><topic>Original Article</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Villacis, Rolando A. R.</creatorcontrib><creatorcontrib>Basso, Tatiane R.</creatorcontrib><creatorcontrib>Canto, Luisa M.</creatorcontrib><creatorcontrib>Pinheiro, Maísa</creatorcontrib><creatorcontrib>Santiago, Karina M.</creatorcontrib><creatorcontrib>Giacomazzi, Juliana</creatorcontrib><creatorcontrib>de Paula, Cláudia A. A.</creatorcontrib><creatorcontrib>Carraro, Dirce M.</creatorcontrib><creatorcontrib>Ashton-Prolla, Patrícia</creatorcontrib><creatorcontrib>Achatz, Maria I.</creatorcontrib><creatorcontrib>Rogatto, Silvia R.</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>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Journal of molecular medicine (Berlin, Germany)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Villacis, Rolando A. R.</au><au>Basso, Tatiane R.</au><au>Canto, Luisa M.</au><au>Pinheiro, Maísa</au><au>Santiago, Karina M.</au><au>Giacomazzi, Juliana</au><au>de Paula, Cláudia A. A.</au><au>Carraro, Dirce M.</au><au>Ashton-Prolla, Patrícia</au><au>Achatz, Maria I.</au><au>Rogatto, Silvia R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development</atitle><jtitle>Journal of molecular medicine (Berlin, Germany)</jtitle><stitle>J Mol Med</stitle><addtitle>J Mol Med (Berl)</addtitle><date>2017-05-01</date><risdate>2017</risdate><volume>95</volume><issue>5</issue><spage>523</spage><epage>533</epage><pages>523-533</pages><issn>0946-2716</issn><eissn>1432-1440</eissn><abstract>Multiple primary tumors (MPT) have been described in carriers of inherited cancer predisposition genes. However, the genetic etiology of a large proportion of MPT cases remains unclear. We reviewed 267 patients with hereditary cancer predisposition syndromes (HCPS) that underwent genetic counseling and selected 22 patients with MPT to perform genomic analysis (CytoScan HD Array, Affymetrix) aiming to identify new alterations related to a high risk of developing MPT. Twenty patients had a positive family history of cancer and 11 met phenotypic criteria for HCPS. Genetic testing for each of the genes associated with these syndromes revealed negative results for pathogenic mutations. Seventeen rare germline copy number variations (CNVs) covering 40 genes were identified in 11 patients, including an
EPCAM
/
MSH2
deletion in one Lynch syndrome patient. An enrichment analysis revealed a significant number of genes (where the CNVs are mapped) associated with carcinogenesis and/or related to functions implicated with tumor development, such as proliferation and cell survival. An interaction network analysis highlighted the importance of
TP53
pathway in cancer emergence. A high number of germline copy-neutral loss of heterozygosity (cnLOH) was identified in nine cases, particularly in two patients. Eighteen genes were covered by both rare CNVs and cnLOH, including 14 related to tumorigenesis and seven genes (
ABCC1
,
KDM4C
,
KIAA0430
,
MYH11, NDE1
,
PIWIL2
, and
ULK2
) specifically associated with cellular growth and proliferation. Overall, we identified 14 cases with rare CNVs and/or cnLOH that may contribute to the risk of MPT development.
Key message
CNVs may explain the risk of hereditary cancer syndromes in MPT patients.
CNVs affecting genes related to cancer are candidates to be involved in MPT risk.
EPCAM
/
MSH2
deletions should be investigated in patients suspected to have LS.
Gene enrichment related to the
TP53
network is associated with MPT development.
cnLOH and CNVs contribute to the risk of MPT development.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>28093616</pmid><doi>10.1007/s00109-017-1507-7</doi><tpages>11</tpages></addata></record> |
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| ispartof | Journal of molecular medicine (Berlin, Germany), 2017-05, Vol.95 (5), p.523-533 |
| issn | 0946-2716 1432-1440 |
| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Adult Biomedical and Life Sciences Biomedicine Colorectal Neoplasms, Hereditary Nonpolyposis - genetics DNA Copy Number Variations - genetics Epithelial Cell Adhesion Molecule - genetics Female Genetic Predisposition to Disease - genetics Germ-Line Mutation Human Genetics Humans Internal Medicine Loss of Heterozygosity - genetics Male Molecular Medicine MutS Homolog 2 Protein - genetics Neoplasms - genetics Original Article |
| title | Rare germline alterations in cancer-related genes associated with the risk of multiple primary tumor development |
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