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Incidence of LKB1 inactivation in Esophageal Adenocarcinoma
Timothy G. Whitsett1, Sumeet K. Mittal1, Jennifer M. Eschbacher2, *Michael A. Smith1, *Ross M. Bremner1, Landon J Inge1
1Norton Thoracic Insitute., St. Joseph's Hospital and Medical Center, Phoenix, AZ;2St. Joseph's Hospital and Medical Center, Phoenix, AZ

Objective: The incidence of esophageal adenocarcinoma (EA) has increased by over 400% over a span of 30 years. Apart from mutations in TP53 gene, there is little data on genetic drivers of EAC. First identified as the causal gene for the familial cancer disorder, Peutz-Jegher's Syndrome (PJS), Liver Kinase B1 (LKB1/STK11) has emerged as a multi-functional tumor suppressor regulating cell growth, differentiation and metabolism. Notably, PJS patients are at increased risk of gastro-esophageal cancers. Somatic inactivation of LKB1 has been described in several tumor types; however whether LKB1 inactivation has a role in EA is unknown. In the present study, we have analyzed publicly available genomic data of EA patients and patient samples from our own institution to assess the incidence of LKB1 inactivation in EA. Methods: Chromosomal deletion and mRNA expression of LKB1 in EA was investigated using publically available data (The Cancer Genome Atlas (TCGA) and www.oncomine.org). Protein expression was assessed by immunohistochemical (IHC) staining for LKB1 in a tissue microarray (TMA) containing EA (n=29), dysplastic Barrett's Esophagus (BE) (n=16) and non-dysplastic BE (n=3) from patients treated at a single institution. Results: Analysis of EA data in the TCGA dataset revealed deletion of chromosome 19p13.3, containing the LKB1 gene locus, was significant (q=8.603x10-6). Single copy loss (shallow deletion) of LKB1 was present in 57% of EA samples (50 out of 87), while mRNA expression of LKB1 in EA samples with single copy loss was significantly lower compared to EA samples diploid for LKB1 (p=0.004). Expression of LKB1 was significantly lower in EA tumors compared to normal esophagus (p=0.002) in the Kim Esophagus dataset in Oncomine. IHC analysis for LKB1 showed reduced LKB1 protein expression in both EA (Figure 1E, F; 24 out of 29; 82%) and dysplastic BE (Figure 1C, D; 10/16; 62%). Expression of LKB1 was observable in non-dysplastic BE (Figure 1A, B; n=3). Conclusions: Analysis of TCGA EA dataset and our EA TMA suggest that inactivation of LKB1 frequently occurs in EA. Based upon the reported oncogenic effects of LKB1 inactivation, combined with the lack of oncogenic drivers in EA, our data indicates that LKB1 loss may play a significant role in EA tumorigenesis and necessitates future studies.


Figure 1: Representative images of EA TMA. IHC staining of LKB1 in non-dysplastic BE (A), dysplastic BE (C) and EA (E) and hemotoxylin and eosin staining of serial sections (B, D, F). Bar is 200 microns.


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