602 Cyclin D1 and retinoblastoma susceptibility gene alterations in non-small cell lung cancer

18065 Background: The abundant expression of the epidermal growth factor receptor (EGFR) in a variety of solid tumors including non-small cell lung cancer (NSCLC), head and neck, breast, colon and brain has made it an attractive target for various selective molecular therapeutics, including the tyrosine kinase inhibitor gefitinib. The recent evidence of activating mutations in EGFR combined with clinical - demographic features has suggested that subgroups of patients with NSCLC are most likely to respond to selective therapies. We sought to determine whether the integration of clinical variables, tumor morphometry and quantitative protein profiles using support vector machines could identify a set of features which predicts overall survival in patients with NSCLC treated with gefitinib. Methods: We analyzed tumor samples from 109 patients with advanced refractory NSCLC treated with gefitinib. Formalin fixed, paraffin embedded tissue samples were evaluated with the following assays: Hematoxylin and Eosin image morphometry, EGFR DNA mutation analysis, EGFR protein immunohistochemistry and quantitative immunofluorescence with the following antibodies: CK18, Ki67, Caspase 3 activated, cd34, EGFR, phosphorylated-EGFR, phosphorylated-ERK, phosphorylated-AKT, PTEN, Cyclin D1, phosphorylated-m-TOR, PI3-K, VEGF, KDR (VEGFR2) and phosphorylated KDR. A predictive model was developed using support vector regression for censored data. Results: 4 of 87 patients had tyrosine kinase domain mutations in exons 19, 20 or 21. Utilizing 51 patients with complete data profiles (i.e. clinical, image morphometry and immunofluorescence), a model predicting overall survival was developed with a concordance index of 0.74. Poor performance status, poorly differentiated histology by morphometry and increased levels of activated caspase 3, phosphorylated KDR (VEGFR2) and cyclin D1 were associated with reduced survival. Conclusion: The integration of clinical, imaging and biomarker data identified a set of features which were associated with a more aggressive disease phenotype and resulted in overall poor survival. [Table: see text]

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Characters of germline mutations in Chinese non-small cell lung cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13542 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13542-e13542

Author(s):

Yuan Qiu ◽

Liping Liu ◽

Qiuhua Deng ◽

Haihong Yang ◽

Hanzhang Chen ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Age Of Onset ◽

Statistical Significance ◽

Susceptibility Gene ◽

Germline Mutations ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients

e13542 Background: Environment factors are associated with lung cancer occurrence. Genetic susceptibility to lung cancer remains unclear. This study assessed germline mutations in Chinese non-small-cell lung cancer (NSCLC) patients. Methods: 506 FFPE samples were collected from 469 patients pathologically confirmed as lung adenocarcinoma. A 508-gene panel including 63 hereditary cancer genes was applied to detect mutations on MGI-seq 2000. Raw data was processed and analyzed. Variation pathogenicity was categorized following ACMG 2015 guideline. Results: 21 patients (4%) carried (likely) pathogenic (P or LP) mutations in 15 cancer predisposition genes. 11 germline variations included MUTYH (1/21), BLM (1/21), BRIP1(2/21), RAD50(1/21), PMS1(1/21), TP53(1/21), BRCA2(1/2), PALB2(1/21), NF1(1/21), CDH1(1/21) and MRE11A (1/21) genes. Nine likely pathogenic mutations were identified in MRE11A, RAD51C, RAD50, ATR, BRCA2, BLM, PMS1 and VHL genes. These mutations are involved in homologous recombination repair, mismatch repair, Fanconi anemia, and Li-Fraumeni syndrome. Germline mutations were commonly occurred in females (female vs Male: 13 vs 7) without statistical significance. No significant correlations of age of onset and TMB were observed between NSCLC patients with germline wild type and mutation. Other clinical characters like histology and clinical stage presented similar results. Somatic mutations with high frequency like EGFR, KRAS were distributed equally in patients with both germline mutation positive and negative. Conclusions: In this study, there is no significant correlation of germline susceptibility gene mutations with clinical and genetic characters of NSCLC patients. Further investigation on germline genetic aberrations of NSCLC is definitely needed to clarify germline impact on the etiology of NSCLC. [Table: see text]

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