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H. Zhai
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MA17 - Genetic Drivers (ID 409)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Satouchi, G.R. Simon
- Coordinates: 12/07/2016, 14:20 - 15:50, Lehar 1-2
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MA17.05 - Evolutionary Trajectories of Molecular Progression in Different Subtypes of Primary Lung Adenocarcinomas (ID 5712)
14:50 - 14:56 | Author(s): H. Zhai
- Abstract
- Presentation
Background:
Morphological and genetic heterogeneity predict prognostics, impede continuous responses to systemic regimens and foster inevitable treatment failure. But how morphological and genetic features evolve in tumorigenesis still remains controversial.
Methods:
Single(n=1112) and multiple(n=91) primary adenocarcinoma patients receiving surgeries with specific prominent subtypes were screened. Six patients with mixed ground glass opacities and maximum cross-sections of primary tumors were randomly selected. Intra-tumoral regions with different subtypes and imaging densities related to relative distributions, were resected for target region sequencing and further molecular evolutionary analyses.
Results:
Clinical data revealed certain preferences of driver gene mutations and discrepant survival benefits. Driver gene heterogeneity was higher in multiple primary lung cancers(51.7%, 15/29) than single ones(1.4%, 1/70). Copy number alterations implied more consistence within the same subtype and tended to be higher in lepidic subtype. Somatic nucleotide variants revealed highest homogeneity between different regions within the same tumor lesion. Sequencing data indicated larger fractions of geographically ubiquitous mutations than pathologically ones, and higher mutation frequencies of shared mutations in the lepidic than acinar subtype. Phylogenetic trees exhibited higher geographically private mutation burdens of lepidic than acinar region in lesions with mixed subtypes; while in lesions with the same subtype, the central region bore higher mutation burdens than in the periphery, implying a linear accumulation of genetic mutations. Functional analyses of private mutations verified that lepidic subtypes promoted intracellular organism and structure development, promoting growth and proliferation. Acinar subtypes lead to metabolic and signaling transduction pathway. Preferences of divergent pathway alterations delineated branched evolutions from low to higher grade subtypes. Figure 1
Conclusion:
We propose a model that the same morphological subtype evolves with a linear accumulation and mixed subtypes in branched evolutionary trajectories with preferences to pathway alterations. Couple with relatively geological distributions of different subtypes, tumor microenvironment might contribute more to genetic instability and thus tumor evolutions.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-038 - Typical Morphological Features Revealed Unfavorable Survival Benefits in High-Grade Neuroendocrine Carcinomas (ID 5718)
14:30 - 14:30 | Author(s): H. Zhai
- Abstract
Background:
The 2015 WHO classification of lung cancer has proposed an revision about high-grade neuroendocrine carcinomas(HGNEC). Neuroendocrine(NE) markers are necessary for differentiations in cases lacing in typically morphological features, but their roles in survival benefits remain unclear.
Methods:
A total of 700 consecutive patients diagnosed with pNET were re-diagnosed during 2008 to 2015 and 632 were HGNECs. NE markers, such as Syn(synaptophysin), CgA(chromogranin A) and CD56, were stained by immunohistochemistry(IHC) if morphological features were not enough for diagnoses.
Results:
Four were excluded due to clinical identification of transformation from adenocarcinomas to SCLC. Nine HGNECs were previously diagnosed with AC. TTF1 stained 77.4%(459/593) HGNEC patients, of which 50.6% in LCNEC, 80.9% in SCLC and 62.5% in poorly differentiated HGNEC(P<0.001). Syn staining(94.1%, 571/607) were not statistically significant in three groups(89.1% vs. 94.6% vs. 100.0%, respectively; P=0.30). The same situation was in CgA(52.6%, 319/607), with a frequency of positive staining as 46.9%, 53.6% and 25.0%(P=0.26), respectively in three diagnoses. The number of positive NE markers were generally balanced(P=0.62). Cases with zero to three positive NE markers indicated marginal significant differences of overall survival(OS)(P=0.05). Meanwhile, no differences of mOS existed in positive and negative staining of Syn(14.7 vs. 32.53 mons, P=0.14) or CgA(14.6 vs. 15.9 mons, P=0.82); but patients with typical morphological features for diagnose and thus without IHC staining Syn or CgA (mOS, 9.13mons) bore significantly poorest OS benefits than those with positive(Syn, HR=2.71, 95%CI=1.24-5.86, P=0.01; CgA, HR=2.72, 95%CI=1.25-5.92, P=0.01) or negative(Syn, HR=3.44, 95%CI=1.39-8.52, P<0.01; CgA, HR=2.76, 95%CI=1.26-6.05, P=0.01) staining. The same condition occurred especially inⅠto Ⅲa patients(P<0.01). Figure 1
Conclusion:
The number of positive NE markers were necessary for precise diagnoses but not significant for survival benefits. Typical morphological features of NE tumor cells were unfavorable factors for OS. Further studies are imperative to identify its crucial role in HGNEC patients.
