Early Presentation of Homozygous Mismatch Repair Deficient Glioblastoma in Teen With Lynch Syndrome: Implications for Treatment and Surveillance

Thomsen, William; Maese, Luke; Vagher, Jennie; Moore, Kevin R.; Cheshier, Samuel; Hofmann, J; Bruggers, Carol S.

doi:10.1200/po.20.00323

Cited by 3 publications

(5 citation statements)

References 33 publications

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“…These findings are partially in line with the established tumor spectrum in adults with LS, which includes high‐grade brain tumors, although solid malignancies in the GI‐tract, female reproductive system, hepatobiliairy system and renal system are more prevalent 1 . Several case reports confirm that high‐grade brain cancers and CRC are also diagnosed occasionally in children with LS, suggesting a possible association 8–10 …”

Section: Introductionsupporting

confidence: 79%

“…1 Several case reports confirm that high-grade brain cancers and CRC are also diagnosed occasionally in children with LS, suggesting a possible association. [8][9][10] MMR deficiency in the tumor can indicate causality of the underlying LS in cancer development. MMR deficiency can be confirmed by demonstrating the presence of a second hit, including loss of heterozygosity (LOH), in the MMR gene, a high tumor mutational load (TML) and contributions of mutational signatures reminiscent of MMR defects.…”

Section: Introductionmentioning

confidence: 99%

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Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations

Weijers,

Hirsch,

Bakhuizen

et al. 2024

Intl Journal of Cancer

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Lynch syndrome (LS) predisposes to cancer in adulthood and is caused by heterozygous germline variants in a mismatch repair (MMR) gene. Recent studies show an increased prevalence of LS among children with cancer, suggesting a causal relationship. For LS‐spectrum (LSS) cancers, including high‐grade gliomas and colorectal cancer, causality has been supported by typical MMR‐related tumor characteristics, but for non‐LSS cancers, causality is unclear. We characterized 20 malignant tumors of 18 children with LS, including 16 non‐LSS tumors. We investigated second hits, tumor mutational load, mutational signatures and MMR protein expression. In all LSS tumors and three non‐LSS tumors, we detected MMR deficiency caused by second hit somatic alterations. Furthermore, these MMR‐deficient tumors carried driver variants that likely originated as a consequence of MMR deficiency. However, in 13 non‐LSS tumors (81%), a second hit and MMR deficiency were absent, thus a causal link between LS and cancer development in these children is lacking. These findings demonstrate that causality of LS in children with cancer, which can be determined by molecular tumor characterization, seems to be restricted to specific tumor types. Large molecular and epidemiological studies are needed to further refine the tumor spectrum in children with LS.

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Section: Introductionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations

Weijers,

Hirsch,

Bakhuizen

et al. 2024

Intl Journal of Cancer

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“…61,62 It is unclear if patients with LS and IDH-mutant glioma can benefit from this treatment strategy given these tumors' lower levels of PD-1 expression. 63,64 TSC Description TSC is best known for its association with hamartomas in various organs. The genes affected are TSC1, which encodes hamartin, and TSC2, which affects tuberin, both of which have a downstream rapamycin (mTOR) pathway effect that influences cell growth regulation and proliferation.…”

Section: Novel Treatmentsmentioning

confidence: 99%

“…61,62 It is unclear if patients with LS and IDH- mutant glioma can benefit from this treatment strategy given these tumors' lower levels of PD-1 expression. 63,64…”

Section: Ls Constitutional Mismatch Repair Deficiency and Turcot Synd...mentioning

confidence: 99%

Therapeutic Strategies for Gliomas Associated With Cancer Predisposition Syndromes

Lam,

Kamiya-Matsuoka,

Slopis

et al. 2024

JCO Precis Oncol

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PURPOSE The purpose of this article was to provide an overview of syndromic gliomas. DESIGN The authors conducted a nonsystematic literature review. RESULTS Cancer predisposition syndromes (CPSs) are genetic conditions that increase one's risk for certain types of cancer compared with the general population. Syndromes that can predispose one to developing gliomas include neurofibromatosis, Li-Fraumeni syndrome, Lynch syndrome, and tuberous sclerosis complex. The standard treatment for sporadic glioma may involve resection, radiation therapy, and/or alkylating chemotherapy. However, DNA-damaging approaches, such as radiation and alkylating agents, may increase the risk of secondary malignancies and other complications in patients with CPSs. In some cases, depending on genetic aberrations, targeted therapies or immunotherapeutic approaches may be considered. Data on clinical characteristics, therapeutic strategies, and prognosis of syndromic gliomas remain limited. CONCLUSION In this review, we provide an overview of syndromic gliomas with a focus on management for patients with CPSs and the role of novel treatments that can be considered.

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“…1,2 While ICIs against the programmeddeath-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis have not shown efficacy either alone or in combination with bevacizumab or temozolomide in sporadic newly diagnosed or recurrent glioblastoma (GB) (Table 1), a few reported cases of GB associated with germline replication-repair defects (gRRDs) have shown tumor responses to anti-PD-1 agents. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Brilliant responses to these agents have been reported in biallelic mismatchrepair deficiency syndrome (BMMRDS) characterized by the appearance of CNS tumors and hematological cancers at early ages. Benefit from ICIs has also been reported in LS-associated GB (Table 2).…”

Section: Introductionmentioning

confidence: 99%

Durable benefit and change in TCR clonality with nivolumab in a Lynch syndrome–associated glioma

et al. 2022

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Germline replication-repair deficient (gRRD) gliomas are exceptional events, and only a few of them have been treated with immune checkpoint inhibitors (ICIs). Contrary to sporadic gliomas, where ICIs have failed to show any objective benefit, the very few patients with gRRD gliomas treated with ICIs to date seem to benefit from programmed-death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, either in terms of durable responses or in terms of survival. T-cell immunohistochemistry (IHC) and T-cell receptor (TCR) repertoire using high-throughput next-generation sequencing (NGS) with the Oncomine TCR-Beta-SR assay (Thermo Fisher Scientific) were analyzed in pre- and post-nivolumab tumor biopsies obtained from a patient with a Lynch syndrome-associated glioma due to a germline pathogenic hMLH1 mutation. The aim was to describe changes in the T-cell quantity and clonality after treatment with nivolumab to better understand the role of acquired immunity in gRRD gliomas. The patient showed a slow disease progression and overall survival of 10 months since the start of anti-PD-1 therapy with excellent tolerance. A very scant T-cell infiltrate was observed both at initial diagnosis and after four cycles of nivolumab. The drastic change observed in TCR clonality in the post-nivolumab biopsy may be explained by the highly spatial and temporal heterogeneity of glioblastomas. Despite the durable benefit from nivolumab, the scant T-cell infiltrate possibly explains the lack of objective response to anti-PD-1 therapy. The major change in TCR clonality observed after nivolumab possibly reflects the evolving molecular heterogeneity in a highly pre-treated disease. An in-deep review of the available literature regarding the role of ICIs in both sporadic and gRRD gliomas was conducted.

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Early Presentation of Homozygous Mismatch Repair Deficient Glioblastoma in Teen With Lynch Syndrome: Implications for Treatment and Surveillance

Cited by 3 publications

References 33 publications

Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations

Molecular analysis of cancer genomes in children with Lynch syndrome: Exploring causal associations

Therapeutic Strategies for Gliomas Associated With Cancer Predisposition Syndromes

Durable benefit and change in TCR clonality with nivolumab in a Lynch syndrome–associated glioma

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