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A.M. Bowcock
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OA 03 - Mediastinal and Esophageal Tumor: Insight and New Treatment (ID 654)
- Event: WCLC 2017
- Type: Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:M. Chida, Jhingook Kim
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 311 + 312
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OA 03.02 - Comprehensive Characterization of Thymic Epithelial Tumour Subtypes Through an Analysis of Somatic Mutations and Copy Number Alterations (ID 10322)
11:10 - 11:20 | Author(s): A.M. Bowcock
- Abstract
- Presentation
Background:
Thymic epithelial tumours (TETs) are rare and under-researched intrathoracic cancers. So far the only significant finding is a recurrent (43%) missense mutation in GTF2I. In addition to validating this finding, we set out to expand our understanding of the molecular changes underlying TETs through whole exome sequencing (WES) and detection of copy number alterations (CNAs) following SNP genotyping.
Method:
WES was performed on 17 TETs (2AB, 1B1, 3B2, 2B3, 6CA and 3NETT) and matched normal tissue. Somatic single nucleotide variants (SNVs) were identified with the GATK HaplotypeCaller and annotated for impact prediction (SnpEff 3.6b and SnpSift 1.3.4b) and population frequency (SnpSift 1.3.4b). The frequency of the GTF2I mutation was assessed with Sanger sequencing with semi-nested primers on DNA from 144 TETs of all subtypes. SNP genotyping was performed on 100 TETs of all subtypes with matched normal tissue in most cases, to identify somatic CNAs. Analysis was performed with ASCAT (v2.4.4) and copy number segments were annotated with Bedtools (v2.26.0).
Result:
WES confirmed a low mutation burden for TETs. No highly recurrent mutations were found. Hotspot mutations in NRAS and KRAS were seen, as was a hotspot mutation in TP53 in a NETT. A high impact frameshift MSH6 somatic mutation was noted in one of the squamous cell carcinomas (SCCs). Another SCC had a germline BAP1 mutation and a family history of other cancers, suggesting a BAP1 familial cancer predisposition syndrome in this individual. The GTF2I mutation was seen in 48 of 141 evaluable TETs (34%) and was present more commonly in type A (90%) and AB (69%) thymomas. The frequency decreased to 16%, 6% and 13% in B1, B2 and B3 thymomas respectively and was not seen in any squamous (0/12) or neuroendocrine carcinomas (0/6). Overall, the most frequent copy number gains in TETs involved chromosomes 7q (22%), 1q (17%) and 11q (17%). The commonest gain was in a gene not previously found to be amplified in solid tumours. The most frequent copy number losses were in chromosomes 6p (40%), 2q (37%) and 7q (32%). Gains and losses demonstrated distinct patterns between aggressive versus indolent subtypes.
Conclusion:
The mutation in GTF2I remains the single most frequently recurrent mutation in TETs. We are in the process of establishing a clinical use for this finding. Results from WES and CNA through SNP genotyping have provided important insight into other potential key players in the aetiology of this intriguing malignancy.
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P1.17 - Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies (ID 703)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.17-019 - B7-H3 Protein Expression in Thymic Epithelial Tumour Subtypes and Its Association with PD-L1 and Clinical Characteristics (ID 10332)
09:30 - 09:30 | Author(s): A.M. Bowcock
- Abstract
Background:
B7-H3 (CD276) belongs to the B7 immunoregulatory family that includes PD-L1. Its expression is associated with poor overall survival (OS) in a range of solid tumours but its expression in TETs is unknown. Phase II clinical trials with anti-PD-1 inhibitors are on-going and exhibit good efficacy although they are often complicated by severe autoimmune toxicities. We measured the levels of B7-H3 in TETs and associated them with PD-L1 levels, OS and GTF2I status.
Method:
TMA sections from each of 125 TET FFPEs and 18 thymic hyperplasias were stained separately with antibodies to PD-L1 (clone 28-8, Abcam) and B7-H3/ CD276 (clone 6A1, Abcam). CD45 and cytokeratin (MF116) stains were used to differentiate epithelia and lymphocytes. All sections were scored with an H-score, giving a final score range of 0-300. For each antibody scores for each TET subtype were compared to each other with the Mann-Whitney test. Positive staining was defined as any staining above 0. Associations between the antibody scores and clinicopathological variables were determined.
Result:
The histological breakdown of analyzed samples was 17 A, 4 MNT LS, 30 AB, 25 B1, 26 B2, 5 B3, 10 CA, 8 NETT and 18 hyperplasias. B7-H3 protein was detected in the epithelia of 110 of 125 TETs (88%) and in 15 of 17 hyperplasias (88%) (Subtype breakdown in Diagram 1). No link between OS and GTF2I mutations status (previously described) was found. B7-H3 and PD-L1 were co-expressed in 94 of 125 TETs (75%). Only 2 B1 TETs were negative for both. Figure 1
Conclusion:
B7-H3 protein is expressed in the large majority of TETs, being highest in A and AB thymomas followed by squamous and neuroendocrine carcinomas. Trials with anti-B7-H3 monoclonal antibodies are already underway and given these findings, patients with TETs are likely to be good subjects for these trials.
