Brain Tumors and the Lynch Syndrome

Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors

Laboratory Investigation ◽

10.1038/s41374-021-00694-3 ◽

2021 ◽

Author(s):

Hyunhee Kim ◽

Ka Young Lim ◽

Jin Woo Park ◽

Jeongwan Kang ◽

Jae Kyung Won ◽

...

Keyword(s):

Brain Tumor ◽

Brain Tumors ◽

Lynch Syndrome ◽

Mismatch Repair ◽

Statistical Significance ◽

Biological Behavior ◽

Molecular Characteristics ◽

Genetic Profile ◽

Who Grade ◽

Primary Brain Tumors

AbstractMismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n = 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n = 2), diffuse midline glioma (DMG) H3 K27M-mutant (n = 1), and pleomorphic xanthoastrocytoma (PXA) (n = 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (10/13) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options.

Download Full-text

OMIC-08. COMPOUND HETEROZYGOSITY OF POLE AND PMS2 LEADS TO CMMRD-LIKE PHENOTYPE- “POLYNCH” SYNDROME

Neuro-Oncology ◽

10.1093/neuonc/noab090.155 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i38-i39

Author(s):

Orli Michaeli ◽

Hagay Ladany ◽

Yosef E Maruvka ◽

Ayelet Erez ◽

Shay Ben Shachar ◽

...

Keyword(s):

Brain Tumors ◽

Lynch Syndrome ◽

Mismatch Repair ◽

De Novo ◽

Clinical Manifestations ◽

Dna Polymerase Epsilon ◽

Pathogenic Variants ◽

Repair Deficiency ◽

Mutation Burden ◽

Desmoplastic Medulloblastoma

Abstract Mono-allelic germline pathogenic variants (PV) in one of the mismatch repair (MMR) system genes cause Lynch syndrome, associated mainly with colon and endometrial cancer in adults. Germline PVs in DNA polymerase epsilon (POLE) are associated with a dominantly inherited syndrome which confers risk for polyposis and colon cancer. Brain tumors have been described as part of Lynch syndrome and POLE associated syndrome, mostly in adults. Constitutional mismatch repair deficiency (CMMRd) is caused by bi-allelic mutations in the MMR genes, associated with multiple café au lait macules (CAMs) and high incidence of pediatric cancer, including brain tumors. Both MMRD and POLE associated tumors have high tumor mutation burden (TMB), however, microsatellite status is usually unstable in MMR tumors, and stable in POLE. Germline POLE and CMMRd tumors have different mutational signatures, as is signature of MMR tumors with secondary somatic POLE. We describe a 4.5 y/o male who presented with a grossly metastatic SHH-activated, TP53-wildtype desmoplastic medulloblastoma. Physical examination was noted for CAMs. Family history was positive for a heterozygous POLE variant with variable clinical manifestations. Immunohistochemistry of the tumor showed loss of nuclear expression of the MMR gene PMS2, specifically in tumor cells. Analysis showed exceptionally high TMB (up to 276 Mut/Mb) and both the MMR and the POLE signatures. Germline analysis detected the familial POLE variant as well as a de novo heterozygous PMS2 PV. The phenotype of the patient together with the tumor’s features, led us to classify this case as a CMMRd-like. The patient had a partial response to intensive chemotherapy and is currently on immunotherapy without radiation. Collectively, our data suggest that heterozygous simultaneous germline mutations in MMR and polymerase genes can lead to novel “POLYNCH syndrome” that manifests with an ultra-hypermutant aggressive tumor and requires appropriate treatment and surveillance.

Download Full-text