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M. Foll
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.05 - A Case-Control Study to Test the Use of ctDNA in the Early Detection of SCLC Reveals TP53 Mutations in Non-Cancer Controls (ID 4915)
14:50 - 14:56 | Author(s): M. Foll
- Abstract
- Presentation
Background:
Circulating-tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays universal inactivation of TP53 (Peifer and Fernandez-Cuesta et al., Nat Genet 2012; George et al., Nature 2015).
Methods:
We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. The results were further validated in an independent series of 102 non-cancer controls. We identified mutations using Needlestack (Delhomme et al., in preparation; https://github.com/IARCbioinfo/needlestack), a pipeline specifically designed to accurately detect variants at very low allelic fractions (AF).
Results:
We detected TP53 mutations in the cfDNA of 49% of the SCLC patients (35.7% of the stage I-II). While statistically significant in cases versus controls (p-value=6x10[-9]), TP53 mutations were also detected in the cfDNA of 11.4% of the non-cancer controls, and these results were confirmed in the replication series (10.8%). The presence of TP53 mutations in controls was not correlated with age, smoking, or alcohol-intake status. There was a statistically significant difference between the mutational patterns found in cases versus controls (p-value=0.008): within controls the fraction of nonsense, indel, or splicing mutations was lower than in cases. The median AF of the TP53 mutations detected in the five stage I-II SCLC (0.9%) was not significantly different from that found in controls (1.2%; p-value=0.64), while it differed from the median AF of stage III-IV SCLC tumors (8.2%; p-value=2x10[-6]). Finally, we sequenced the DNA extracted from the white-blood cells (WBC) of 39 cfDNA TP53-positive patients, from which material was available (19 cases and 20 controls). Four cfDNA TP53 mutations (1 case and 3 controls) were detected in the WBC DNA, with similar AFs to those found in the cfDNA. These AFs, below 11%, are consistent with a somatic origin in both cfDNA and WBC DNA.
Conclusion:
The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests for the early diagnosis of cancer (Fernandez-Cuesta, Perdomo, and Avogbe et al., EBioMedicine 2016). We will discuss these results as well as follow-up analyses in retrospective and prospective series.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-015 - BAP1 is Inactivated by Copy Number Loss, Mutation, and/or Loss of Expression in More Than 70% Malignant Peritoneal Mesotheliomas (ID 4575)
14:30 - 14:30 | Author(s): M. Foll
- Abstract
Background:
Breast cancer type 1 susceptibility associated protein (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes and acts as a tumor suppressor gene. Malignant mesothelioma is a deadly disease strongly associated with asbestos exposure. Most of the cases (70%) are pleural mesotheliomas while peritoneal and pericardial mesotheliomas account for 25% and 5%, respectively. Germ-line and somatic inactivation of BAP1 has been recurrently reported in pleural mesothelioma. However, due to its rarity and challenging diagnosis, little is known about the BAP1 status in peritoneal mesothelioma, with the largest series so far sequenced including only 12 tumors.
Methods:
Taking advantage of the extensive French national networks MESOPATH and RENAPE, we collected biological material and clinical and epidemiological data for 46 peritoneal mesothelioma patients. In order to determine the status of BAP1 in these samples, three different levels were evaluated: copy number changes by comparative genomic hybridization arrays (Chirac et al., Human Path 2016), mutations by next-generation sequencing, and protein expression by immunohistochemistry.
Results:
We detected copy number losses, mutations, and/or loss of expression of BAP1 in 42.2%, 33.3%, and 56.8% of the malignant peritoneal mesotheliomas analyzed, respectively. In most of the cases with additional data available (13/16), the loss of BAP1 expression was explained by co-occurring copy number loss and/or mutation. Overall, 73.2% of the malignant peritoneal mesotheliomas analyzed carried an inactivated BAP1 gene. In addition, BAP1 mutations were exclusively detected in males and a better overall survival was observed for patients with loss of BAP1 expression independently of age, sex, smoking and asbestos exposures (p=0.03).
Conclusion:
Inactivation of BAP1 seems to have a key role in the development of both pleural and peritoneal mesotheliomas. In addition, we found that loss of BAP1 expression in peritoneal mesotheliomas was mostly explained by copy number losses and mutations, and was associated with a better overall survival.
