Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis
Colorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant <i>MLH1</i> and <i>MSH2</i> alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/12/10/1350 |
| _version_ | 1827651294706270208 |
|---|---|
| author | Esther Schamschula Miriam Kinzel Annekatrin Wernstedt Klaus Oberhuber Hendrik Gottschling Simon Schnaiter Nicolaus Friedrichs Sabine Merkelbach-Bruse Johannes Zschocke Richard Gallon Katharina Wimmer |
| author_facet | Esther Schamschula Miriam Kinzel Annekatrin Wernstedt Klaus Oberhuber Hendrik Gottschling Simon Schnaiter Nicolaus Friedrichs Sabine Merkelbach-Bruse Johannes Zschocke Richard Gallon Katharina Wimmer |
| author_sort | Esther Schamschula |
| collection | DOAJ |
| description | Colorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant <i>MLH1</i> and <i>MSH2</i> alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency (CMMRD), and polymerase proofreading-associated polyposis (PPAP). Yet, 60% of AYA-CRC cases remain unexplained. In two teenage siblings with multiple adenomas and CRC, we identified a maternally inherited heterozygous <i>PMS2</i> exon 12 deletion, NM_000535.7:c.2007-786_2174+493del1447, and a paternally inherited <i>POLD1</i> variant, NP_002682.2:p.Asp316Asn. Comprehensive molecular tumor analysis revealed ultra-mutation (>100 Mut/Mb) and a large contribution of COSMIC signature SBS20 in both siblings’ CRCs, confirming their predisposition to AYA-CRC results from a high propensity for somatic MMR deficiency (MMRd) compounded by a constitutional Pol δ proofreading defect. COSMIC signature SBS20 as well as SBS26 in the index patient’s CRC were associated with an early mutation burst, suggesting MMRd was an early event in tumorigenesis. The somatic second hits in <i>PMS2</i> were through loss of heterozygosity (LOH) in both tumors, suggesting PPd-independent acquisition of MMRd. Taken together, these patients represent the first cases of cancer predisposition due to heterozygous variants in <i>PMS2</i> and <i>POLD1.</i> Analysis of their CRCs supports that <i>POLD1</i>-mutated tumors acquire hypermutation only with concurrent MMRd. |
| first_indexed | 2024-03-09T20:37:41Z |
| format | Article |
| id | doaj.art-337cc4e8d5b0408a9c929a8731c0e320 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T20:37:41Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-337cc4e8d5b0408a9c929a8731c0e3202023-11-23T23:07:15ZengMDPI AGBiomolecules2218-273X2022-09-011210135010.3390/biom12101350Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in TumorigenesisEsther Schamschula0Miriam Kinzel1Annekatrin Wernstedt2Klaus Oberhuber3Hendrik Gottschling4Simon Schnaiter5Nicolaus Friedrichs6Sabine Merkelbach-Bruse7Johannes Zschocke8Richard Gallon9Katharina Wimmer10Institute of Human Genetics, Medizinische Universität Innsbruck, 6020 Innsbruck, AustriaMedicover Humangenetik—Berlin-Lichtenberg, 10315 Berlin, GermanyInstitute of Human Genetics, Medizinische Universität Innsbruck, 6020 Innsbruck, AustriaInstitute of Human Genetics, Medizinische Universität Innsbruck, 6020 Innsbruck, AustriaInstitute of Human Genetics, Medizinische Universität Innsbruck, 6020 Innsbruck, AustriaInstitute of Human Genetics, Medizinische Universität Innsbruck, 6020 Innsbruck, AustriaInstitute of Pathology, University of Cologne, 50924 Cologne, GermanyInstitute of Pathology, University of Cologne, 50924 Cologne, GermanyInstitute of Human Genetics, Medizinische Universität Innsbruck, 6020 Innsbruck, AustriaTranslational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UKInstitute of Human Genetics, Medizinische Universität Innsbruck, 6020 Innsbruck, AustriaColorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant <i>MLH1</i> and <i>MSH2</i> alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency (CMMRD), and polymerase proofreading-associated polyposis (PPAP). Yet, 60% of AYA-CRC cases remain unexplained. In two teenage siblings with multiple adenomas and CRC, we identified a maternally inherited heterozygous <i>PMS2</i> exon 12 deletion, NM_000535.7:c.2007-786_2174+493del1447, and a paternally inherited <i>POLD1</i> variant, NP_002682.2:p.Asp316Asn. Comprehensive molecular tumor analysis revealed ultra-mutation (>100 Mut/Mb) and a large contribution of COSMIC signature SBS20 in both siblings’ CRCs, confirming their predisposition to AYA-CRC results from a high propensity for somatic MMR deficiency (MMRd) compounded by a constitutional Pol δ proofreading defect. COSMIC signature SBS20 as well as SBS26 in the index patient’s CRC were associated with an early mutation burst, suggesting MMRd was an early event in tumorigenesis. The somatic second hits in <i>PMS2</i> were through loss of heterozygosity (LOH) in both tumors, suggesting PPd-independent acquisition of MMRd. Taken together, these patients represent the first cases of cancer predisposition due to heterozygous variants in <i>PMS2</i> and <i>POLD1.</i> Analysis of their CRCs supports that <i>POLD1</i>-mutated tumors acquire hypermutation only with concurrent MMRd.https://www.mdpi.com/2218-273X/12/10/1350digeniccolorectal cancer (CRC) in adolescents and young adults (AYA)POL-LYNCHLynch syndrome (LS)polymerase proofreading (PP)Pol δ |
| spellingShingle | Esther Schamschula Miriam Kinzel Annekatrin Wernstedt Klaus Oberhuber Hendrik Gottschling Simon Schnaiter Nicolaus Friedrichs Sabine Merkelbach-Bruse Johannes Zschocke Richard Gallon Katharina Wimmer Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis Biomolecules digenic colorectal cancer (CRC) in adolescents and young adults (AYA) POL-LYNCH Lynch syndrome (LS) polymerase proofreading (PP) Pol δ |
| title | Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis |
| title_full | Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis |
| title_fullStr | Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis |
| title_full_unstemmed | Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis |
| title_short | Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis |
| title_sort | teenage onset colorectal cancers in a digenic cancer predisposition syndrome provide clues for the interaction between mismatch repair and polymerase δ proofreading deficiency in tumorigenesis |
| topic | digenic colorectal cancer (CRC) in adolescents and young adults (AYA) POL-LYNCH Lynch syndrome (LS) polymerase proofreading (PP) Pol δ |
| url | https://www.mdpi.com/2218-273X/12/10/1350 |
| work_keys_str_mv | AT estherschamschula teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis AT miriamkinzel teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis AT annekatrinwernstedt teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis AT klausoberhuber teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis AT hendrikgottschling teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis AT simonschnaiter teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis AT nicolausfriedrichs teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis AT sabinemerkelbachbruse teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis AT johanneszschocke teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis AT richardgallon teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis AT katharinawimmer teenageonsetcolorectalcancersinadigeniccancerpredispositionsyndromeprovidecluesfortheinteractionbetweenmismatchrepairandpolymerasedproofreadingdeficiencyintumorigenesis |