Virtual Library
Start Your Search
Elisabeth Brambilla
Author of
-
+
MTE 05 - Neuroendocrine Tumors: Pathology and Genetic Update (Sign Up Required) (ID 554)
- Event: WCLC 2017
- Type: Meet the Expert
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 07:00 - 08:00, Room 313 + 314
-
+
MTE 05.01 - Neuroendocrine Tumors: Pathology and Genetic Update (ID 7780)
07:00 - 08:00 | Presenting Author(s): Elisabeth Brambilla
- Abstract
- Presentation
Abstract:
Pathology In the current WHO 2015 classification[1] neuroendocrine lung tumors are listed in the order of their frequency with SCLC first as it is the most common (15% of lung cancer). Despite the grouping of these tumors together, it is clear that the carcinoids have major clinical, epidemiologic, histologic and genetic differences compared to the high grade SCLC and LCNEC. SCLC and LCNEC have much higher mitotic rates (more than 11 per 2mm2), more necrosis than carcinoids and can show combinations with other lung cancer types including adenocarcinoma or squamous cell carcinoma, which testify of a common progenitor cell derivation, not shared by carcinoid which is never mixed with a non-neuroendocrine (NE) tumor type Immunohistochemistry (IH) / neuroendocrine markers can be very helpful in diagnosing pulmonary NE tumors especially in small biopsies with crushed artefact. Endocrine morphology and neuroendocrine IH markers are both required for the diagnosis of LCNEC. The cases with one missing (Endocrine morphology or NE markers) are considered as large cell carcinoma in the absence of other differentiation marker on resection specimens, and as non- small cell lung carcinoma on small samples. Genomic update Small cell lung carcinoma [2-3] The universal biallelic alteration of both TP53 and RB1 gene was remarkable (100% for P53 and 93% for RB1) by different alterations of each of the 4 alleles. Other significantly mutated genes are KIAA1211 and COL22A1 with unclear functions, as well as RGS7 and FPR1 involved in G-protein-coupled receptor signalling. Locally clustered mutations occurred on CREBBP (15%) and EP300 (13%) genes, inactivating their histone acetylase functions. Notch family genes were recurrently mutated (25%) whereas RNA transcriptome analysis revealed a rate of Notch inactivation of 77% associated with up regulation of neuroendocrine (NE) lineage genes (DLK1 a Notch inhibitor, CHGA (chromogranin A), ASCL1 a master regulator of NE lineage, and GRP (gastrin releasing protein)). Another Notch inhibitor DLL3 was reported to be upregulated in 65% of SCLC[3]. DLL3 is considered as a therapeutic target tested in several clinical trials[4]. The mouse model validated NOTCH as a tumor suppressor and master regulator of NE malignant differentiation in SCLC[ 3]~.~ TP73 gene breaks inducing intragenic fusions and rearrangements, creates the N-terminally truncated transcripts variants lacking a fully competent transactivation domain and exerting dominant negative functions on both wild type p73 and p53. With additional mutations in TP73, 13% SCLC showed alteration in TP73 gene. Somatic copy number alterations (CNA) include focal events on 3p14.3-3p14.2 (FHIT gene) and 3p12.3-3p12.2 (ROBO1) with reduced expression of theses 2 genes. Homozygous deletion of the CDKN2A locus (chromosome 9p) and amplification of the MYC family genes (MYCL1, MYCN, MYC) as well as of FGFR1 (6%) and IRS2 (2%) were recurrent events. The remarkable largely mutually exclusive mutations in the five key genes: CREBBP, EP300, TP73, RBL1, RBL2 (equivalents of RB1 in the mouse model) and Notch suggest they may exert similar pro-tumorigenic functions in the development of SCLC and are candidate drivers[3]~.~ Large cell neuroendocrine carcinoma (LCNEC) TP53 was the most frequently inactivated gene (92%) followed by RB1 (42%) Biallelic inactivation of both TP53 and RB1 (the hallmark of SCLC) was seen in 40%.Mutations in STK11/ LKB1(30%, characteristic of ADC) and KEAP1 (22%, detected in both ADC and SCC but not in SCLC). The mutations were deleterious (nonsense, splice and frameshift mutations) or missense affecting important protein domain mutations in RB1 and STK11/KEAP1 which occurred in a mutually exclusive fashion (p<0.0001). Damaging mutations also occur in chromatin-remodelling genes ARID1A and MEN1/PSP1 in 10% and 7% of LCNEC respectively; Ras family alterations were found in 10% of cases. Overall RAS family, BRAF and NKX2-1 alterations were mutually exclusive with RB1 ( P=0.0049) suggesting again distinct genomic patterns in LCNEC . Analyses of CNA on 60 LCNEC reveals similarities to SCLC[3]. As mutations, the pattern of copy number alterations of LCNEC share characteristics with SCLC, ADC, or SCC. Overall from genomic profiles, while certain alterations (RB1 MYCL1) resemble thoses found in SCLC, others are typical of adenocarcinoma (STK11, NKX2-1, RAS, BRAF) or of squamous cell carcinoma( KEAP1, NFE2L2), showing the heterogeneity of LCNEC which can be divided into molecular subsets by similarities with other major lung cancers. At transcriptional level[5] an unsupervised consensus clustering showed a common cluster including both SCLC and LCNEC characterized by high expression of neuroendocrine lineage transcription factors, as well as high levels of cell cycle regulation and DNA damage response genes, and centrosomal functions. Although LCNEC shared characteristics with ADC and SCC, theses were dissimilar and strongest correlation was being found with SCLC. The transcriptional relationship of LCNEC and SCLC revealed 4 consensus clusters I-IV. Tumors in cluster I exclusively contained LCNECs with STK11 or KEAP1 alterations (type1-LCNEC) characterized by a high level-expression of chromogranin A and synaptophysin. The majority of LCNECS in cluster 2 enriched in cases with RB1 alterations exhibited reduced levels of NE markers and elevated Notch signalling, low expression of ASCL1 and DLL3 an inhibitor of NOTCH signalling pathway (type 2 LCNEC).. Whereas type1-LCNECs harbor STK11 or KEAP1 alterations but share NE expression profiles with SCLC , type2- LCNEC (40% of LCNEC) bear genetic resemblance with SCLC with RB1 alterations ,but profound transcriptional differences with SCLC. Carcinoid Tumors Molecular alterations underlying pathogenesis of this tumor were enlighted only recently[6] Genome/exome sequencing data from 44 tumor/normal pairs, allowed identification of MEN1, ARID1A, and EIF1AX as significantly mutated genes. MEN1, PSIP1(13%) and IRID1A play important roles in chromatin remodelling process showed mutually exclusive frameshifts and truncating mutations. Mutations in histone methyltransferases (SETD1B, SETDB1, NSD1) and demethylases (KDM4, PHF8) as well as members of the polycomb complex 1 and 2 (CBX6 and EZH1) mutations were accompanied with LOH. In total 40% of carcinoids carried mutually exclusive mutations in genes involved in covalent histone modification. Truncating and frameshift mutations occur in ARID1A (6,7%), and other mutations in this SWI/SNF chromatin remodelling complex in 22%. With sister chromatid cohesion affected by reccurrent mutations (COHESIN, STAG1, NIPBL, the microRNA processor DICER and ERCC6L), 51% of carcinoid carried mutations in chromatin remodelling genes. There was no genetic segregation between typical and atypical carcinoid, neither between the expression clusters generated from both subtypes. References Travis WD, Brambilla E, Burke A, Marx A, Nicholson A. WHO Classification of the Tumours of the Lung, Pleura, Thymus and Heart. 4th Edition. Lyon: IARC Press; 2015. Peifer M, Fernandez-Cuesta L, Sos ML, et al. Nat Genet 2012;44:1104-10. George J, Lim JS, Jang SJ, et al. Nature 2015;524:47-53. C.Rudin, M.C. Pietenza, M. Todd et al. Lancet Oncol 2017; 18: 42–51. Georges et al. Nature communication. In press 2017 Fernandez-Cuesta L, Peifer M, Lu X, et al. Nature communications 2014;5:3518.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
