Primary Reference: Jalali, A et al. Cancer Research. March 29, 2021.
Genes: POT1
Germline POT1 mutations are linked to increased risk in a spectrum of cancers. This group recently identified a series of novel germline POT1 mutations that predispose carrier families to the development of glioma. While these associations are strong, how glioma-associated POT1 mutations contribute to the development of this cancer is still unclear.
This study showed that POT1-G95C increases proliferation in glioma-initiating cells in vitro and in progenitor populations in the developing brain. In a mouse model, loss of Pot1a/b led to decreased survival in females compared to males. These findings were corroborated in human glioma, in which low POT1 expression correlated with decreased survival among females.
Further, transcriptomic and immunohistochemistry profiling of Pot1a/b-deficient glioma found that tumors in females had decreased expression of immune markers and increased expression of cell cycle signatures. Similar sex-dependent trends were observed in human gliomas that had low expression of POT1.
The researchers note that: “Together, our studies demonstrate context-dependent functions for POT1 mutation or loss in driving progenitor proliferation in the developing brain and sexual dimorphism in glioma.”
Additional resource:
Sex difference of mutation clonality in diffuse glioma evolution. Zhang, H. et al. Neuro Oncol. Feb. 14, 2019.
This study used an “integrated framework to infer the timing and clonal status of mutations” in ~600 diffuse gliomas from The Cancer Genome Atlas (TCGA) including glioblastomas (GBMs) and low-grade gliomas (LGGs), and investigated the sex difference of mutation clonality. They found higher overall and subclonal mutation burden in female patients with different grades of gliomas, which could be largely explained by the mutations of the X chromosome. Some well-established drivers were identified showing sex-biased clonality, such as CDH18 and ATRX. They also found that mutations in genes of the mitogen-activated protein kinase (MAPK) signaling pathway were more likely to be clonal in female patients with GBM, whereas mutations in genes involved in the receptor tyrosine kinase signaling pathway were more likely to be clonal in male patients with LGG.
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