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K. He
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.08 - Lung Cancer Patients with Germline Mutation: A Retrospective Study (ID 8670)
16:30 - 16:35 | Author(s): K. He
- Abstract
- Presentation
Background:
Genetic testing for alterations of oncogenic driver genes has become essential and standard in clinical practice. Germline mutations predisposing to lung cancer are rare, but there have been reports regarding germline mutations in EGFR, HER2, BRCA2, CDKN2A, BAP1, SFTPA2, and PARK2. Next generation sequencing is being introduced to clinical practice of lung cancer, enabling investigation of multiple oncogenic driver genes simultaneously. In addition, liquid biopsy, which analyzes cell free DNA in blood, increases the opportunity to detect germline mutations in lung cancer patients. We examined the frequency and characteristics of lung cancer patients with germline mutations.
Method:
Between February 2012 and January 2017, 3,869 patients with a diagnosis of lung cancer were seen by Division of Medical Oncology in Ohio State University. Of these, seven were found to have germline mutations. The patient characteristics and treatment outcomes were retrospectively investigated.
Result:
Table 1 shows characteristics and treatment outcomes of the seven lung cancer patients with germline mutations. Median age was 50 (range, 34-72). Three had BRCA2 germline mutations, two had germline TP53 mutations(of which one patient also had a PARK2 mutation), one had a BRCA1 mutation, and one had an EGFR mutation. Testing for other oncogenic drivers were done in five patients, and interestingly, four patients had oncogenic driver mutations. The frequency of detecting germline mutations in lung cancer patients has been increasing in recent years, but is often unrecognized by providers. In our series, one patient was found to have a germline mutation by Foundation ONE, and another was found to have a germline mutation by Foundation ACT.Year Age Sex Histology Stage Smoking hisory Other cancer Germline mutation Other somatic gene alteration Targeted therapy Respnse 2014 37 F Ad IA former smoker (2py) No BRCA2 not evaluated － － 2014 72 F Ad IV former smoker breast cancer, lung cancer EGFR T790M EGFR G719S rociletinib SD 2015 69 F Ad IIIA former smoker breast cancer, uterine cancer BRCA2 EGFR L858R － － 2015 50 F SCLC IA never smoker breast cancer TP53 Y236*, PARK2 Q347* FGFR2 amplification － － 2016 34 F Ad IV former smoker No BRCA2 L3061* MET 3028+2T>C crizotinib PR 2016 44 F Ad IV never smoker orbital rhabdomyosarcoma TP53 ALK fusion crizotinib PR 2017 62 F SCLC IV former smoker breast cancer BRCA1 not evaluated － －
Conclusion:
Introduction of next generation sequencing technology and liquid biopsies to clinical practice can raise the probability of detecting germline mutations in lung cancer patients. Clinicians should be alert to the potential existence and importance of germline mutations in their lung cancer patients.
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OA 18 - Lung Cancer Pathology and Genetics (ID 687)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:George R. Simon, Yoon-La Choi
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 316
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OA 18.02 - The Landscape of Alteration of DNA Integrity-Related Genes and Their Association with Tumor Mutation Burden in Non-Small Cell Lung Cancer (ID 10440)
14:40 - 14:50 | Author(s): K. He
- Abstract
- Presentation
Background:
A key hallmark of cancer cells is the ability to proliferate despite remarkable levels of DNA damage. Non-small cell lung cancers (NSCLC) tend to have high mutation rates, frequently related to smoking. While many genes have been functionally implicated in maintaining the integrity of the genome, for the majority of these genes there remains a lack of evidence of a direct relationship between loss-of-function and increased tumor mutation burden (TMB). Recent studies suggested an association between high TMB and cancer response to immunotherapies. The aim of this study was to comprehensively analyze the relationship between DNA integrity-related genes and TMB in NSCLC.
Method:
Whole exome DNA sequencing and copy number array data were downloaded from TCGA lung adenocarcinoma (LAC) and squamous cell carcinoma (LSCC) datasets, and mutation burdens were calculated for each of 974 tumors. We identified 150 genes across 7 pathways and 9 groups known to be involved in repairing or compensating for DNA damage. To test each gene, tumors were placed into one of three groups according to the gene’s mutation status; wild-type, homozygous deleted or mutated with loss-of-function, and non-synonymous missense mutated. We then compared the average mutation burden in each of these groups. This workflow was then repeated with pathways instead of genes.
Result:
Our comprehensive analysis demonstrates a landscape of significant alterations to genes and pathways responsible for maintaining DNA integrity in NSCLC. A loss of function mutation or homozygous deletion in at least one signature gene occurred in 49% of LAC and 59% of LSCC. We searched for genes in this signature associated with significantly higher tumor mutation burdens (one sided t-test, p < 0.05) and found 4 in LAC (RRM1 1%, TP53 17%, FANCE 1%, and MLH1 2%) and 8 in LSCC (NEIL1 0.5%, POLE 4%, POLG 0.5%, FANCE 3%, GEN1 1%, MLH1 4%, MSH6 1%, and RPA1 2%) datasets. Of note, tumors with nonsense mutations, indels, or homozygous deletions in the FANCE or MLH1 genes have significantly higher TMB in both LAC and LSCC. We repeat this process to find pathways significantly associated with increased TMB.
Conclusion:
We present a comprehensive study of the association between genes responsible for maintaining DNA integrity and TMB in NSCLC. These findings are important to the search for potential predictive biomarkers for immunotherapy.
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P3.13 - Radiology/Staging/Screening (ID 729)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.13-033 - DNA Methylation of PTGER4 and SHOX2 in Liquid Biopsies Facilitates the Diagnosis of Lung Malignancy After Chest CT-Scan (ID 10202)
09:30 - 09:30 | Author(s): K. He
- Abstract
Background:
Lung Cancer (LC) is the leading cause of cancer-related death worldwide. The Lung Cancer Screening Trial screened 26,723 patients via Low-Dose chest CT-scan. Screening results were positive in 24.2%, however 96.4% were false positive. Therefore, a biomarker helping to discriminate false positive from true positive screening results will limit unnecessary interventions. The aim of this study was to analyze the feasibility of the DNA methylation markers prostaglandin E receptor 4 gene (PTGER4) and short stature homeobox 2 gene (SHOX2) as potential biomarkers in liquid biopsies additional to CT-scan findings suspicious for LC.
Method:
A total of 73 patients with a chest CT-scan suspicious for stage I-IIIA LC were included in this study. LC was histologically confirmed in 50 patients. In the remaining 23 patients benign diagnoses were established. Circulating cell-free DNA was extracted, bisulfite converted and purified from 3.5 ml plasma, using a commercially available kit. Triplicates of bisulfited DNA were assayed with a 45-cycle rtPCR assay detecting methylated DNA of SHOX2, PTGER4 and ACTB as reference assay. Assay result was called positive for PTGER4 if at least two out of three PCR results had cycle threshold (Ct) values below 45; for SHOX2 if the Ct value was below 35.
Result:
PCR-results were valid in 18 (4 organising pneumonias, 5 pneumonias, 3 post-pneumonic residues, 3 hamartochondroma, 1 mycosis, 1 coal-workers pneumoconiosis, 1 aspergilloma) of 23 benign samples (control), and in 43 of 50 LC samples. PTGER4 results were negative in all controls and positive for 18 of 43 LC. These results translate into a specificity of 100 % and a sensitivity of 41.86% for LC detection via PTGER4. The SHOX2 assay was negative in all controls and positive in 9 LC patients, resulting in a specificity of 100 % and a sensitivity of 20.93% for SHOX2. Overall 21 of 43 LC samples were positive in either PTGER4 or SHOX2 and all controls were negative for both measurements. In combination both markers showed a specificity of 100% and a sensitivity of 48.84%. This specificity would imply a positive predictive value of 100%, further validation in a larger cohort is required.
Conclusion:
DNA methylation of PTGER4 and SHOX2 was highly specific for patients with chest CT-scan findings suspicious for LC. This could help to identify high-risk patients, who should be directly transferred to tissue-based diagnostics, surgery or stereotactic radiation. In the other cases the next diagnostic step should be decided clinically.
