We propose a probabilistic method, CancerLocator, which exploits the diagnostic potential of cell-free DNA by determining not only the presence but also the location of tumors. CancerLocator simultaneously infers the proportions and the tissue-of-origin of tumor-derived cell-free DNA in a blood sample using genome-wide DNA methylation data. CancerLocator outperforms two established multi-class classification methods on simulations and real data, even with the low proportion of tumor-derived DNA in the cell-free DNA scenarios. CancerLocator also achieves promising results on patient plasma samples with low DNA methylation sequencing coverage.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1191-5) contains supplementary material, which is available to authorized users.

Learning tasks are typically thought to be either hippocampal-dependent (impaired by hippocampal lesions) or hippocampal-independent (indifferent to hippocampal lesions). Here, we show that conditioned taste aversion (CTA) learning fits into neither of these categories. Rats were trained to avoid two taste stimuli, one novel and one familiar. Muscimol infused through surgically implanted intracranial cannulae temporarily inactivated the dorsal hippocampus during familiarization, subsequent CTA training, or both. As shown previously, hippocampal inactivation during familiarization enhanced the effect of that familiarization on learning (i.e., hippocampal inactivation enhanced latent inhibition of CTA); more novel and surprising, however, was the finding that hippocampal inactivation during training sessions strongly enhanced CTA learning itself. These phenomena were not caused by specific aspects of our infusion technique-muscimol infusions into the hippocampus during familiarization sessions did not cause CTAs, muscimol infusions into gustatory cortex caused the expected attenuation of CTA, and hippocampal inactivation caused the expected attenuation of spatial learning. Thus, we suggest that hippocampal memory processes interfere with the specific learning mechanisms underlying CTA, and more generally that multiple memory systems do not operate independently.

Epithelial cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may escape immune surveillance and progress to invasive cancer; however, the mutational landscape that may predict progression has not been determined. Knowledge of premalignant lesion composition and the associated microenvironment is critical for understanding tumorigenesis and the development of effective preventive and interception strategies. To identify somatic mutations and the extent of immune cell infiltration in adenomatous premalignancy and associated lung adenocarcinomas, we sequenced exomes from 41 lung cancer resection specimens, including 89 premalignant atypical adenomatous hyperplasia lesions, 15 adenocarcinomas in situ, and 55 invasive adenocarcinomas and their adjacent normal lung tissues. We defined nonsynonymous somatic mutations occurring in both premalignancy and the associated tumor as progression-associated mutations whose predicted neoantigens were highly correlated with infiltration of CD8 þ and CD4 þ T cells as well as upregulation of PD-L1 in premalignant lesions, suggesting the presence of an adaptive immune response to these neoantigens. Each patient had a unique repertoire of somatic mutations and associated neoantigens. Collectively, these results provide evidence for mutational heterogeneity, pathway dysregulation, and immune recognition in pulmonary premalignancy. Significance: These findings identify progression-associated somatic mutations, oncogenic pathways, and association between the mutational landscape and adaptive immune responses in adenomatous premalignancy. See related commentary by Merrick, p. 4811

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Each year, more than 1 million persons worldwide are found to have a lung nodule that carries a risk of being malignant. In reality, the vast majority of lung nodules are benign, whether identified by screening or incidentally. The consequences of delaying or missing the diagnosis of lung cancer can be substantial, as can be the consequences of invasive procedures on patients with benign lung nodules. The challenge for the clinician caring for these patients is to differentiate between benign and malignant nodules with the least harm possible. In this review, we will discuss management strategies of the indeterminate pulmonary nodule and will review recent advances and harm-reduction strategies.

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Lung cancer is the leading cause of cancer death in the US and in the world. Over the past 30 years, the five-year survival rate for lung cancer has increased by only 5%. With the widespread implementation of screening programs, detection of premalignant and early stage disease is increasing. A better understanding of genomic alterations and the microenvironment along the spectrum of early disease could lead to identification of progression-associated mutations (PAMs), defined as those shared between premalignant lesions and invasive cancer, and their neoepitopes. Unleashing the immune response against pulmonary premalignancy could transform therapy and outcomes. FFPE tissue blocks from patients with resected lung adenocarcinoma (ADC) were obtained from the UCLA Lung Cancer Tissue Repository. For each patient, the following regions were dissected from distal airways utilizing Laser Capture Microdissection: a) normal airway epithelial cells (1-3 regions), b) premalignant atypical adenomatous hyperplasia (AAH, 2-4 regions), c) adenocarcinoma in situ (AIS, when present) and d) ADC, 1-3 regions followed by whole exome sequencing. Forty-one complete cases have been sequenced to date. Our data suggest that premalignant lesions from the same patient may a) have different mutational profiles and b) bear progression-associated mutations, common with the primary lung tumor. This inter-lesion heterogeneity suggests that a progression-associated mutational landscape could be defined in longitudinal studies of pulmonary premalignancy which will be the focus of future investigations. Next, utilizing the mutational data, we performed in silico neoantigen analysis to identify potential neoepitopes among the genes mutated in premalignant lesions. The neoantigen analysis demonstrated that among the top 11 peptides with high binding avidity for autologous MHC, 9 were derived from PAMs. This suggests that neoepitopes exist in premalignancy that could serve as targets for development of future vaccines. Finally, we performed the quantitative immunohistochemical (IHC) and immunofluorescence (IF) staining for Granzyme B, PD-1, PDL-1, CD4+, CD8+ and FOXP3 to evaluate cell-mediated immunity on the same samples that were utilized for WES. We found both infiltration of T effector cells as well as upregulation of checkpoints in premalignancy and detected a significant inter-lesional heterogeneity. Our studies lay the ground work for identification of neoepitopes that can be targeted before the development of invasive lung cancer, thus shifting the approach to disease interception through immunoprevention and treatment of the very earliest phase of the disease. Citation Format: Kostyantyn Krysan, Linh M. Tran, Brandon S. Grimes, Tonya C. Walser, William D. Wallace, Steven M. Dubinett. Evaluation of progression associated neoepitopes and immune contexture in pulmonary premalignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1016. doi:10.1158/1538-7445.AM2017-1016