Why male predominance across many human cancer types?

A special study, from IRB Barcelona, have identified a signature of proteins that are differentially expressed between male and female tumor samples. The researchers conducted a study to determine whether Drosophila experimental models of malignant growth may serve to investigate the cell biological axes that control sex-linked tumor dimorphism. The results have been found that the conserved chromatin reader PHD finger protein 7 (Phf7) depletion reduces sex-dependent differences in gene expression and suppresses the enhanced malignant traits of male tumors. If these findings are confirmed by further studies, which strongly suggest a role for Phf7 as regulators of sex-linked tumor dimorphism. The next step will be to study these genes as targets to suppress sex-linked malignant traits. According to the researchers.

The study have been published in the journal Science Advances. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Background

The notable male predominance across many human cancer types remains unexplained. Cancer susceptibility and mortality rate are significantly higher in the male population, even after occupational and behavioral risk factors are taken into account. Male predominance is also observed in childhood malignancies that present themselves in very young infants before puberty. Studies covering a wide panel of cancer types show that the expression of many clinically relevant genes is strongly sex biased in malignant tumors. hence suggesting molecular sexual dimorphism at the cellular level as a key determinant of sex-linked disparities in cancer. Understanding the molecular basis of sex-linked differences in cancer incidence and survival may pave the way for gender-specific, more efficient therapeutic strategies. However, the molecular cell biology for sex disparities in cancer remains very poorly understood.

Drosophila can be used to experimentally induce a wide range of tumors that affect a variety of organs in both adult flies and developing larvae. These tumor types range from hyperplasias to frankly malignant neoplasias that exhibit classic hallmarks of mammalian cancer. In addition, natural hyperplasias can develop in the adult fly testis and gut and are age dependent. Some Drosophila tumors are being used as experimental models for leukemia, neuroblastoma, glioblastoma, ovarian cancer, and others.

RESULTS

1. l(3)mbt tumors, but not brat tumors, show gender-dependent malignant traits

As a first step to investigate whether malignant growth is affected by the sex of the tumor bearer, we studied the anatomy of l(3)mbt and brat, male and female larval brain lobes stained with 4′,6-diamidino-2-phenylindole (DAPI) to label DNA and immunostained with antiMiranda (Mira) and anti–DE-cadherin antibodies. After staining with DAPI and anti–DE-cadherin antibody, male mbt brain lobes present a long and convoluted NE that reaches medially and is embedded in strongly DAPI-positive tissue (likely a tumorous version of the medulla) that invades most of the brain lobe including the central brain (CB). In female mbt brain lobes, however, the NE and the tissue that stains strongly with DAPI are restricted to the lateral half of the lobe, and the CB remains distinct. Differences in the fraction of the brain lobe area occupied by the NE and the CB are highly significant between mbt males and their female siblings (P < 10−4) and insignificant between mbt females and wild-type brains of either sex.

Why male predominance across many human cancer types 1

2.The mbt proteome is sex dependent

This mbt proteome sex-linked dimorphic signature (pSDS) includes 66 proteins that are more expressed in males (M-pSDS) and 61 that are overexpressed in females (F-pSDS). M-pSDS and F-pSDS proteins appear as two distinct clouds that are well apart in plots showing the expression level of proteins in male versus female mbt tumor samples, but are mixed in plots showing sex-dependent expression levels in wild-type samples.

Why male predominance across many human cancer types 2

3.Phf7

Visualization of our RNA-sequencing (RNA-seq) data in Integrated Genome Browser shows that Phf7-RC, estimated by the number of reads that map to the Phf7-RC–specific exon, is absent in wild-type samples, but is expressed in mbt tumor samples, at a higher level in males than in females. This conclusion is further substantiated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) data.

Why male predominance across many human cancer types 3

Phf7 depletion suppresses sex-linked dimorphism by inhibiting male-specific phenotypic traits. The researchers found that depletion of Phf7 has no effect on wild-type brain lobe development, which is consistent with its reported strictly male germline function in flies. Depletion of Phf7 has little effect on the anatomy of female mbt tumors but significantly suppresses the two main anatomy traits that make male mbt tumors distinct: It brings about a significant reduction of the NE (P = 6 × 10−5) that no longer spreads over the brain lobe and the recovery of a well-defined CB region (P = 10−8) . In allograft assays, depletion of Phf7 results in a significant drop in host lethality, from 93% down to 38%. Depletion of Phf7 suppresses both the anatomy traits and the greater growth potential that make mbt tumors more aggressive in males than in their female siblings.

Conclusion

These results strongly suggest that Phf7 contributes to bringing about sex-linked molecular disparities in mbt tumors by acting in male tissue both up-regulating M-tSDS genes and down-regulating F-tSDS genes while having little, if any, effect in the expression of either of these signatures in female samples.

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[1] Molnar C, Heinen J P, Reina J, et al. The histone code reader PHD finger protein 7 controls sex-linked disparities in gene expression and malignancy in Drosophila[J]. Science Advances, 2019, 5(8): eaaw7965.