Abstract 3413: CRIPAK genomic alterations are associated with indolent lung adenocarcinoma and predicts longer survival

Abstract Background: Multiple lung screening studies have shown a beneficial reduction in cancers specific mortality with annual low-dose computed tomography (LDCT) screening in high risk patients and resulted in a much improved probability of early stage disease at diagnosis. Nonetheless, still ~30% of such patients have a recurrence within 5 years following surgical resection. This begs the question what are the molecular determinants of cancer behavior between indolent and aggressive tumors. Methods: A targeted deep sequencing was performed on the DNA samples of 21 adenocarcinoma in situ (AIS), 27 minimally invasive adenocarcinoma (MIA) and 54 fully invasive adenocarcinoma. These cancers were classified based on the tumor size (1.5 cm) as indolent (n=42) and aggressive (n=60) tumors. We analyzed the association between tumor aggressiveness and genomic alterations of these targeted genes including frequency of gene mutations, copy number changes, mutation signatures, tumor clonality as well as overall survival. Results: Copy number loss of CRIPAK (chr4p16) and copy number gain of NOTCH1 were enriched in indolent tumors and chromosome 19q13 deletion was enriched in aggressive tumors. CRIPAK alterations including both mutations and copy number loss together were further significantly enriched in a subset of indolent tumors (16/25) that only consists of AIS/MIA. CRIPAK alterations were associated with longer survival in all population, after adjusting for histology and age (P=0.02). Interestingly, we found higher CRIPAK mRNA level was also significantly associated with better survival in a combined seven public lung adcarcinoma datasets (n=673, HR=0.37, P=1.1e-05), after adjusting for stage, gender and smoking history. In addition, both APOBEC and MMR mutation signatures were correlated with indolent tumors. Known driver genes such as KRAS, EGFR or TP53 mutations were not distinct between indolent and aggressive tumors, indicating an early role for these genes in the development of lung adenocarcinoma. Finally, we found that mutations of NCOR1, USP9X and NF1 were enriched in indolent tumors while mutations in GNAS and ATM were enriched in aggressive tumors. Conclusion: Our study suggests the genomic alterations of the chromosome 4p16 harboring a novel cancer gene CRIPAK’s deletions and mutations are predictive of indolent behavior, a finding that warrants further validation. This work was supported by UO1CA196405. Citation Format: Jun Qian, Heidi Chen, Yong Zou, Pierre Massion. CRIPAK genomic alterations are associated with indolent lung adenocarcinoma and predicts longer survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3413.