P1.09-17 CTNNB1 (Beta-Catenin) Mutations in Non-Small Cell Lung Carcinoma: A Clinicopathological Study of 18 Cases

Abstract

Background: Beta-catenin, encoded by the CTNNB1 gene, plays an important role in a signaling pathway of progenitor cell proliferation and differentiation. Mutations of CTNNB1 are oncogenic in several tumor types and are often associated with a nuclear abnormal expression. However, such mutations have only rarely been reported in non-small cell lung carcinomas and their clinical signification is not well described. Otherwise, beta-catenin expression by immuno-histochemistry has been described as a prognostic factor in non-small cell lung carcinomas. Method: Our study was conducted on 18 CTNNB1-mutated non-small cell lung carcinomas. Tumors were routinely tested by next generation sequencing for mutations in exon 3 of CTNNB1 gene. Fifteen cases (2.6%) were from a series of 568 consecutive and contributive analyses performed between January 2017 and March 2018, on 417 adenocarcinomas, 60 squamous cell carcinomas and 91 large cell carcinomas. The 3 other cases dated from before this series. The hospital files of the 18 patients and pathological data from surgical samples (n¼11), small biopsies (n¼3) and trans-bronchial fine needle aspirations (n¼4) were reviewed. Immuno-histochemistry was performed with an anti-beta-catenin antibody. Result: There were 6 female and 12 male patients aged 54 to 83 (mean ¼ 66). Six of the 18 patients were non-smokers (< 5 pack-years). There were 17 adenocarcinomas and 1 squamous cell carcinoma. Most adenocarcinomas were TTF1-positive (16/17) and had a papillary component accounting for more than 30% of their volume (n¼11). Eight cases (44%) with CTNNB1 mutations showed associated EGFR mutations including exon 19 deletion (n¼5) and L858R (n¼2). Oncogenic KRAS mutations were only found in 3 cases (17%). The frequency of CTNNB1 mutations among EGFR mutated adenocarcinomas was 9% (7/79). The most frequent CTNNB1 mutations were S37F (n¼7) and S45P (n¼4). Immuno-histochemistry showed normal membrane expression with no nuclear or cytoplasmic abnormal expression in all cases. Conclusion: Our study shows that CTNNB1 mutations are rare in non-small cell lung carcinomas and mostly occur in TTF1-positive adenocarcinomas with a papillary pattern. These mutations are similar to those observed in other tumor types but they probably do not play the same oncogenic role. Furthermore, in lung carcinomas, CTNNB1 mutations were often associated with EGFR mutations and may interfere in the mechanism of resistance to tyrosine kinase inhibitors. This should be thoroughly investigated in larges series evaluating the degree of response to EGFR tyrosine kinase inhibitors.