Y chromosome loss is a frequent event in Barrett’s adenocarcinoma and associated with poor outcome

Background: The loss of the Y chromosome in various malignant diseases has been described previously. There are no reliable information on the actual frequency, significance and homogeneity of Y chromosome loss (LoY) in esophageal adenocarcinoma (EAC). Methods: 400 male EAC including lymph-node metastases were analyzed with commercially available Y chromosome specific fluorescence in-situ probes. The results were correlated with molecular and immunohistochemical markers and clinicopathological aspects. Results: The entire cohort (n = 400) showed a singular LoY of one chromosome arm in 1.0% (q-arm) and 2.8% (p-arm), complete LoY in 52.5%. LoY was strongly associated with shortened overall-survival (OS). Patients with preserved Y chromosome had a median OS of 58.8 months, patients with LoY an OS of 19.4 months (p < 0.001). Multivariate analysis showed LoY as an independent prognostic marker with a hazard ratio of 1.835 (95% CI 1.233–2.725). LoY correlated with TP53 mutations (p = 0.003), KRAS amplification (p = 0.004), loss of ARID1a (p = 0.045) and presence of LAG3 (p = 0.018). Conclusions: Loss of the Y chromosome is a very common phenomenon in EAC. The LoY is heterogeneously distributed within the tumor, but corresponding lymph node metastases frequently show homogeneous LoY, indicating a selection and metastasizing advantage with poor prognosis. To date, the male predominance of EAC (7–9:1) is unclear, so genetic explanatory models are favored. The LoY in EAC may be biologically and functionally relevant and additional genomic or functional analyses are needed.

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Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

10.1101/2021.05.21.445116 ◽

2021 ◽

Author(s):

Anna Köferle ◽

Andreas Schlattl ◽

Alexandra Hörmann ◽

Fiona Spreitzer ◽

Alexandra M. Popa ◽

...

Keyword(s):

Y Chromosome ◽

Therapeutic Strategy ◽

Sex Chromosome ◽

De Novo ◽

Chromosome Loss ◽

Potential Candidate ◽

Loss Of Function ◽

Male Patients ◽

Tumour Cell Lines ◽

Paralog Gene

Genetic networks are characterized by extensive buffering. During tumour evolution, disruption of these functional redundancies can create de novo vulnerabilities that are specific to cancer cells. In this regard, paralog genes are of particular interest, as the loss of one paralog gene can render tumour cells dependent on a remaining paralog. To systematically identify cancer-relevant paralog dependencies, we searched for candidate dependencies using CRISPR screens and publicly available loss-of-function datasets. Our analysis revealed >2,000 potential candidate dependencies, several of which were subsequently experimentally validated. We provide evidence that DNAJC15-DNAJC19, FAM50A-FAM50B and RPP25-RPP25L are novel cancer relevant paralog dependencies. Importantly, our analysis also revealed unexpected redundancies between sex chromosome genes. We show that chrX- and chrY- encoded paralogs, as exemplified by ZFX-ZFY, DDX3X-DDX3Y and EIF1AX-EIF1AY, are functionally linked so that tumour cell lines from male patients with Y-chromosome loss become exquisitely dependent on the chrX-encoded gene. We therefore propose genetic redundancies between chrX- and chrY- encoded paralogs as a general therapeutic strategy for human tumours that have lost the Y-chromosome.

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