Y disruption, autosomal hypomethylation and poor male lung cancer survival

Abstract

Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA–IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40–10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4–2.0, P = 1.2 × 10–10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.

Transcriptomic Profiling of Intracranial Arteries in Adult Patients With Moyamoya Disease Reveals Novel Insights Into Its Pathogenesis

“…According to the GO analysis, in men with MMD, many sex-specific DEGs take part in the bioprocess of DNA methylation. A previous study has reported that hypomethylation of a specific promoter CpG site of sortilin 1 in endothelial colony-forming cells from MMD was related to endothelial cell function, implying the involvement of hypomethylation of sortilin 1 in MMD pathogenesis (Sung et al, 2018 ) Recently, a study reported that men with lung cancer showed extensive autosomal DNA hypomethylation and a significantly increased risk of death (Willis-Owen et al, 2021 ). This result indicates that the level of aberrant DNA methylation in men and women may lead to a different pathophysiology of MMD.…”

Systemic Profiling of KDM5 Subfamily Signature in Non-Small-Cell Lung Cancer

“…KDM5D, recognized as a sexually dimorphic gene, is 85% identical to KDM5C and more frequently encoded in the Y chromosome of all male tissues. 34,35 Here, we deciphered that KDM5D gene mutations were prominently lower than other KDM5 members in NSCLC. Higher KDM5D expression led to a reduced FP and OS in LUAD and LUSC patients, regardless of the lymphatic metastasis status.…”

Diverse Functions of KDM5 in Cancer: Transcriptional Repressor or Activator?

“…KDM5D, encoded on the Y chromosome, has recently been shown to be a tumor suppressor gene. The incidence of ccRCC and lung cancer is higher in men than in women, and men have poorer outcomes [147,148]. Importantly, the total or partial loss of the Y chromosome, including the KDM5D locus, has been observed not only in prostate cancer but also in ccRCC and lung cancer in males, and lower KDM5D expression is associated with poor prognosis [147][148][149][150].…”