Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review
Abstract Background Constitutional mismatch repair deficiency (CMMRD) results from a biallelic germline pathogenic variant in a mismatch repair (MMR) gene. The most common CMMRD-associated malignancies are brain tumors; an accurate diagnosis is challenging when a malignant brain tumor is the only tu...
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | BMC Medical Genomics |
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| Online Access: | https://doi.org/10.1186/s12920-022-01403-9 |
| _version_ | 1828056657953816576 |
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| author | Shumpei Onishi Fumiyuki Yamasaki Kazuya Kuraoka Akira Taguchi Takeshi Takayasu Kiwamu Akagi Takao Hinoi |
| author_facet | Shumpei Onishi Fumiyuki Yamasaki Kazuya Kuraoka Akira Taguchi Takeshi Takayasu Kiwamu Akagi Takao Hinoi |
| author_sort | Shumpei Onishi |
| collection | DOAJ |
| description | Abstract Background Constitutional mismatch repair deficiency (CMMRD) results from a biallelic germline pathogenic variant in a mismatch repair (MMR) gene. The most common CMMRD-associated malignancies are brain tumors; an accurate diagnosis is challenging when a malignant brain tumor is the only tumor at presentation. We describe two cases of glioblastoma as the initial CMMRD malignancy and discuss current diagnostic and therapeutic challenges. Case presentation Two children with brain tumors without remarkable family history had biallelic pathogenic germline variants in PMS2. Patient 1: A 6-year-old girl presented biallelic PMS2 germline pathogenic variants. Glioblastomas at the left frontal lobe and right temporal lobe were resistant to immune-checkpoint inhibitor, temozolomide, and bevacizumab. Patient 2: A 10-year-old boy presented biallelic PMS2 germline variants. His glioblastoma with primitive neuroectodermal tumor-like features responded to chemoradiotherapy, but he developed advanced colon cancer and acute lymphocytic leukemia. In both patients, only a monoallelic PMS2 germline variant was detected by conventional gene tests. PMS2 immunohistochemistry showed lack of staining at both the tumors and normal tissue as vascular endothelial cells. Further gene tests revealed large genomic deletion including the entire PMS2 gene, confirming biallelic PMS2 germline variants. Conclusion Conventional multi-gene panel tests are insufficient for detecting large deletions of MMR genes, resulting in misdiagnoses of CMMRD as Lynch syndrome. PMS2 variants have low cancer penetrance; family histories may thus be absent. Long-range gene analyses or immunohistochemical staining of MMR proteins in normal tissue should be considered for pediatric brain tumors with a single allele MMR variant when CMMRD is suspected. |
| first_indexed | 2024-04-10T20:59:04Z |
| format | Article |
| id | doaj.art-a0d42c79fdac484cafcc1e53782ffc57 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-04-10T20:59:04Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-a0d42c79fdac484cafcc1e53782ffc572023-01-22T12:27:52ZengBMCBMC Medical Genomics1755-87942023-01-011611910.1186/s12920-022-01403-9Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature reviewShumpei Onishi0Fumiyuki Yamasaki1Kazuya Kuraoka2Akira Taguchi3Takeshi Takayasu4Kiwamu Akagi5Takao Hinoi6Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Diagnostic Pathology, National Hospital Organization Kure Medical Center and Chugoku Cancer CenterDepartment of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Molecular Diagnosis and Cancer Prevention, Saitama Cancer CenterDepartment of Clinical and Molecular Genetics, Hiroshima University HospitalAbstract Background Constitutional mismatch repair deficiency (CMMRD) results from a biallelic germline pathogenic variant in a mismatch repair (MMR) gene. The most common CMMRD-associated malignancies are brain tumors; an accurate diagnosis is challenging when a malignant brain tumor is the only tumor at presentation. We describe two cases of glioblastoma as the initial CMMRD malignancy and discuss current diagnostic and therapeutic challenges. Case presentation Two children with brain tumors without remarkable family history had biallelic pathogenic germline variants in PMS2. Patient 1: A 6-year-old girl presented biallelic PMS2 germline pathogenic variants. Glioblastomas at the left frontal lobe and right temporal lobe were resistant to immune-checkpoint inhibitor, temozolomide, and bevacizumab. Patient 2: A 10-year-old boy presented biallelic PMS2 germline variants. His glioblastoma with primitive neuroectodermal tumor-like features responded to chemoradiotherapy, but he developed advanced colon cancer and acute lymphocytic leukemia. In both patients, only a monoallelic PMS2 germline variant was detected by conventional gene tests. PMS2 immunohistochemistry showed lack of staining at both the tumors and normal tissue as vascular endothelial cells. Further gene tests revealed large genomic deletion including the entire PMS2 gene, confirming biallelic PMS2 germline variants. Conclusion Conventional multi-gene panel tests are insufficient for detecting large deletions of MMR genes, resulting in misdiagnoses of CMMRD as Lynch syndrome. PMS2 variants have low cancer penetrance; family histories may thus be absent. Long-range gene analyses or immunohistochemical staining of MMR proteins in normal tissue should be considered for pediatric brain tumors with a single allele MMR variant when CMMRD is suspected.https://doi.org/10.1186/s12920-022-01403-9Constitutional mismatch repair deficiencyCMMRDLynch syndromeGlioblastomaColon cancerAcute lymphocytic leukemia |
| spellingShingle | Shumpei Onishi Fumiyuki Yamasaki Kazuya Kuraoka Akira Taguchi Takeshi Takayasu Kiwamu Akagi Takao Hinoi Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review BMC Medical Genomics Constitutional mismatch repair deficiency CMMRD Lynch syndrome Glioblastoma Colon cancer Acute lymphocytic leukemia |
| title | Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review |
| title_full | Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review |
| title_fullStr | Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review |
| title_full_unstemmed | Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review |
| title_short | Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review |
| title_sort | diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency cmmrd two case reports and a literature review |
| topic | Constitutional mismatch repair deficiency CMMRD Lynch syndrome Glioblastoma Colon cancer Acute lymphocytic leukemia |
| url | https://doi.org/10.1186/s12920-022-01403-9 |
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