Somatic mutations precede acute myeloid leukemia years before diagnosis
The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women’s Health Initiative who were...
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| Veröffentlicht in: | Nature medicine 2018-07, Vol.24 (7), p.1015-1023 |
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| creator | Desai, Pinkal Mencia-Trinchant, Nuria Savenkov, Oleksandr Simon, Michael S. Cheang, Gloria Lee, Sangmin Samuel, Michael Ritchie, Ellen K. Guzman, Monica L. Ballman, Karla V. Roboz, Gail J. Hassane, Duane C. |
| description | The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women’s Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in
IDH1
,
IDH2
,
TP53
,
DNMT3A
,
TET2
and spliceosome genes significantly increased the odds of developing AML. All subjects with
TP53
mutations (
n
= 21 out of 21 patients) and
IDH1
and
IDH2
(
n
= 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered.
Somatic mutations detected years before diagnosis increase the odds of development of acute myeloid leukemia in women. |
| doi_str_mv | 10.1038/s41591-018-0081-z |
| format | Article |
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IDH1
,
IDH2
,
TP53
,
DNMT3A
,
TET2
and spliceosome genes significantly increased the odds of developing AML. All subjects with
TP53
mutations (
n
= 21 out of 21 patients) and
IDH1
and
IDH2
(
n
= 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered.
Somatic mutations detected years before diagnosis increase the odds of development of acute myeloid leukemia in women.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/s41591-018-0081-z</identifier><identifier>PMID: 29988143</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/67/1990/283/1897 ; 631/67/69 ; 692/699/67/2324 ; Acute myelocytic leukemia ; Acute myeloid leukemia ; Alleles ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Case-Control Studies ; Clonal Evolution ; Deoxyribonucleic acid ; Diagnosis ; Disease Progression ; DNA ; DNA sequencing ; Female ; Gene mutation ; Genes ; Genetic aspects ; Health ; Health promotion ; Humans ; Infectious Diseases ; Latency ; Leukemia ; Leukemia, Myeloid, Acute - blood ; Leukemia, Myeloid, Acute - diagnosis ; Leukemia, Myeloid, Acute - genetics ; Metabolic Diseases ; Methyltransferases ; Molecular Medicine ; Multivariate Analysis ; Mutation ; Mutation - genetics ; Mutation Rate ; Myeloid leukemia ; Neurosciences ; Odds Ratio ; p53 Protein ; Patients ; Peripheral blood ; Risk Factors ; Tumor proteins ; Women ; Women's health</subject><ispartof>Nature medicine, 2018-07, Vol.24 (7), p.1015-1023</ispartof><rights>The Author(s) 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c589z-dbc8bea1b73a0157e18e54b1d12d50f0eb4351cc96185394b1e1f3959156ba713</citedby><cites>FETCH-LOGICAL-c589z-dbc8bea1b73a0157e18e54b1d12d50f0eb4351cc96185394b1e1f3959156ba713</cites><orcidid>0000-0002-9262-8246</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41591-018-0081-z$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41591-018-0081-z$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29988143$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Desai, Pinkal</creatorcontrib><creatorcontrib>Mencia-Trinchant, Nuria</creatorcontrib><creatorcontrib>Savenkov, Oleksandr</creatorcontrib><creatorcontrib>Simon, Michael S.</creatorcontrib><creatorcontrib>Cheang, Gloria</creatorcontrib><creatorcontrib>Lee, Sangmin</creatorcontrib><creatorcontrib>Samuel, Michael</creatorcontrib><creatorcontrib>Ritchie, Ellen K.</creatorcontrib><creatorcontrib>Guzman, Monica L.</creatorcontrib><creatorcontrib>Ballman, Karla V.</creatorcontrib><creatorcontrib>Roboz, Gail J.</creatorcontrib><creatorcontrib>Hassane, Duane C.</creatorcontrib><title>Somatic mutations precede acute myeloid leukemia years before diagnosis</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women’s Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in
IDH1
,
IDH2
,
TP53
,
DNMT3A
,
TET2
and spliceosome genes significantly increased the odds of developing AML. All subjects with
TP53
mutations (
n
= 21 out of 21 patients) and
IDH1
and
IDH2
(
n
= 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered.
Somatic mutations detected years before diagnosis increase the odds of development of acute myeloid leukemia in women.</description><subject>631/67/1990/283/1897</subject><subject>631/67/69</subject><subject>692/699/67/2324</subject><subject>Acute myelocytic leukemia</subject><subject>Acute myeloid leukemia</subject><subject>Alleles</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Case-Control Studies</subject><subject>Clonal Evolution</subject><subject>Deoxyribonucleic acid</subject><subject>Diagnosis</subject><subject>Disease Progression</subject><subject>DNA</subject><subject>DNA sequencing</subject><subject>Female</subject><subject>Gene mutation</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Health</subject><subject>Health promotion</subject><subject>Humans</subject><subject>Infectious Diseases</subject><subject>Latency</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - blood</subject><subject>Leukemia, Myeloid, Acute - diagnosis</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Metabolic Diseases</subject><subject>Methyltransferases</subject><subject>Molecular Medicine</subject><subject>Multivariate Analysis</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Mutation Rate</subject><subject>Myeloid leukemia</subject><subject>Neurosciences</subject><subject>Odds Ratio</subject><subject>p53 Protein</subject><subject>Patients</subject><subject>Peripheral blood</subject><subject>Risk Factors</subject><subject>Tumor proteins</subject><subject>Women</subject><subject>Women's health</subject><issn>1078-8956</issn><issn>1546-170X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkt9r1TAUx4so7of-Ab5IQZD50Jlz07TJizCGzsFg4FR8C2l62pvZJtekFe_9601357bKFSQPJ-R8zjc5Od8keQHkGAjlb0MOTEBGgGeEcMg2j5J9YHmRQUm-PY57UvKMC1bsJQchXBNCKGHiabK3EIJzyOl-cnblejUYnfbjEKOzIV151FhjqvQ4YNqvsXOmTjscv2NvVLpG5UNaYeM8prVRrXXBhGfJk0Z1AZ_fxsPky4f3n08_ZheXZ-enJxeZZlxssrrSvEIFVUkVAVYicGR5BTUsakYaglVOGWgtCuCMiphBaKiIXbKiUiXQw-TdVnc1Vj3WGu3gVSdX3vTKr6VTRs4z1ixl637KgueCchoFjm4FvPsxYhhkb4LGrlMW3RjkghRl_JuCTeirv9BrN3ob27uhgHBOynuqVR1KYxsX79WTqDxh5aLggtJJK9tBtWgxPtJZbEw8nvHHO_i46jgEvbPgzawgMgP-Glo1hiDPrz79P3v5dc6-fsAuUXXDMrhuvPHKHIQtqL0LwWNzNxQgcrKr3NpVRrvKya5yE2tePpzmXcUff0ZgsQVCTNkW_f0I_q36Gz8a8jA</recordid><startdate>20180701</startdate><enddate>20180701</enddate><creator>Desai, Pinkal</creator><creator>Mencia-Trinchant, Nuria</creator><creator>Savenkov, Oleksandr</creator><creator>Simon, Michael S.</creator><creator>Cheang, Gloria</creator><creator>Lee, Sangmin</creator><creator>Samuel, Michael</creator><creator>Ritchie, Ellen K.</creator><creator>Guzman, Monica L.</creator><creator>Ballman, Karla V.</creator><creator>Roboz, Gail J.</creator><creator>Hassane, Duane C.</creator><general>Nature Publishing Group US</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9262-8246</orcidid></search><sort><creationdate>20180701</creationdate><title>Somatic mutations precede acute myeloid leukemia years before diagnosis</title><author>Desai, Pinkal ; Mencia-Trinchant, Nuria ; Savenkov, Oleksandr ; Simon, Michael S. ; Cheang, Gloria ; Lee, Sangmin ; Samuel, Michael ; Ritchie, Ellen K. ; Guzman, Monica L. ; Ballman, Karla V. ; Roboz, Gail J. ; Hassane, Duane C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c589z-dbc8bea1b73a0157e18e54b1d12d50f0eb4351cc96185394b1e1f3959156ba713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>631/67/1990/283/1897</topic><topic>631/67/69</topic><topic>692/699/67/2324</topic><topic>Acute myelocytic leukemia</topic><topic>Acute myeloid leukemia</topic><topic>Alleles</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Case-Control Studies</topic><topic>Clonal Evolution</topic><topic>Deoxyribonucleic acid</topic><topic>Diagnosis</topic><topic>Disease Progression</topic><topic>DNA</topic><topic>DNA sequencing</topic><topic>Female</topic><topic>Gene mutation</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Health</topic><topic>Health promotion</topic><topic>Humans</topic><topic>Infectious Diseases</topic><topic>Latency</topic><topic>Leukemia</topic><topic>Leukemia, Myeloid, Acute - blood</topic><topic>Leukemia, Myeloid, Acute - diagnosis</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Metabolic Diseases</topic><topic>Methyltransferases</topic><topic>Molecular Medicine</topic><topic>Multivariate Analysis</topic><topic>Mutation</topic><topic>Mutation - genetics</topic><topic>Mutation Rate</topic><topic>Myeloid leukemia</topic><topic>Neurosciences</topic><topic>Odds Ratio</topic><topic>p53 Protein</topic><topic>Patients</topic><topic>Peripheral blood</topic><topic>Risk Factors</topic><topic>Tumor proteins</topic><topic>Women</topic><topic>Women's health</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Desai, Pinkal</creatorcontrib><creatorcontrib>Mencia-Trinchant, Nuria</creatorcontrib><creatorcontrib>Savenkov, Oleksandr</creatorcontrib><creatorcontrib>Simon, Michael S.</creatorcontrib><creatorcontrib>Cheang, Gloria</creatorcontrib><creatorcontrib>Lee, Sangmin</creatorcontrib><creatorcontrib>Samuel, Michael</creatorcontrib><creatorcontrib>Ritchie, Ellen K.</creatorcontrib><creatorcontrib>Guzman, Monica L.</creatorcontrib><creatorcontrib>Ballman, Karla V.</creatorcontrib><creatorcontrib>Roboz, Gail J.</creatorcontrib><creatorcontrib>Hassane, Duane C.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</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 Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Desai, Pinkal</au><au>Mencia-Trinchant, Nuria</au><au>Savenkov, Oleksandr</au><au>Simon, Michael S.</au><au>Cheang, Gloria</au><au>Lee, Sangmin</au><au>Samuel, Michael</au><au>Ritchie, Ellen K.</au><au>Guzman, Monica L.</au><au>Ballman, Karla V.</au><au>Roboz, Gail J.</au><au>Hassane, Duane C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Somatic mutations precede acute myeloid leukemia years before diagnosis</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2018-07-01</date><risdate>2018</risdate><volume>24</volume><issue>7</issue><spage>1015</spage><epage>1023</epage><pages>1015-1023</pages><issn>1078-8956</issn><eissn>1546-170X</eissn><abstract>The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women’s Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in
IDH1
,
IDH2
,
TP53
,
DNMT3A
,
TET2
and spliceosome genes significantly increased the odds of developing AML. All subjects with
TP53
mutations (
n
= 21 out of 21 patients) and
IDH1
and
IDH2
(
n
= 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered.
Somatic mutations detected years before diagnosis increase the odds of development of acute myeloid leukemia in women.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>29988143</pmid><doi>10.1038/s41591-018-0081-z</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-9262-8246</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 631/67/1990/283/1897 631/67/69 692/699/67/2324 Acute myelocytic leukemia Acute myeloid leukemia Alleles Biomedical and Life Sciences Biomedicine Cancer Research Case-Control Studies Clonal Evolution Deoxyribonucleic acid Diagnosis Disease Progression DNA DNA sequencing Female Gene mutation Genes Genetic aspects Health Health promotion Humans Infectious Diseases Latency Leukemia Leukemia, Myeloid, Acute - blood Leukemia, Myeloid, Acute - diagnosis Leukemia, Myeloid, Acute - genetics Metabolic Diseases Methyltransferases Molecular Medicine Multivariate Analysis Mutation Mutation - genetics Mutation Rate Myeloid leukemia Neurosciences Odds Ratio p53 Protein Patients Peripheral blood Risk Factors Tumor proteins Women Women's health |
| title | Somatic mutations precede acute myeloid leukemia years before diagnosis |
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