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 singularLoYof one chromosome arm in 1.0% (q-arm) and 2.8% (p-arm), completeLoYin 52.5%.LoYwas strongly associated with shortened overall-survival (OS). Patients with preserved Y chromosome had a median OS of 58.8 months, patients withLoYan OS of 19.4 months (p< 0.001). Multivariate analysis showedLoYas an independent prognostic marker with a hazard ratio of 1.835 (95% CI 1.233-2.725).LoYcorrelated withTP53mutations (p= 0.003),KRASamplification (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. TheLoYis heterogeneously distributed within the tumor, but corresponding lymph node metastases frequently show homogeneousLoY,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. TheLoYin EAC may be biologically and functionally relevant and additional genomic or functional analyses are needed.