Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer

Cancers progress when the immune system fails to identify and eliminate malignant cells. Recognition of this, combined with advances in tumor immunology, has allowed development of therapies that induce effective anti-tumor immune responses. For incompletely-understood reasons, effective responses to immunotherapy occur in some patients and not others. Head and neck squamous cell carcinomas (HNSCC) are a common cancer type that can be divided into two subsets based on human papillomavirus (HPV) status. HPV status is a strong predictor of positive clinical outcome. Expression of exogenous viral antigens by HPV+, but not HPV-, HNSCC allows direct comparison of the immune status (immune cell presence and characteristics) between these two otherwise anatomically-similar tumors. Using TCGA data, we compared the immune landscape between HPV+ and HPV- treatment-naïve HNSCC. As compared to HPV- samples, HPV+ HNSCC exhibited a strong Th1 response characterized by increased infiltration with multiple types of immune cells and expression of their effector molecules. HPV+ HNSCC also expressed higher levels of CD39 and multiple T-cell exhaustion markers including LAG3, PD1, TIGIT, and TIM3 compared to HPV- HNSCC. Importantly, patients with higher expression of these exhaustion markers–indicative of a T-cell-inflamed tumor–correlated with markedly improved survival in HPV+, but not HPV-, HNSCC. Thus, profound differences exist between the immune landscape of HPV+ and HPV- HNSCC. These results suggest that immune checkpoint inhibitor therapy is a promising treatment strategy for HPV+ HNSCC, and that expression of immune checkpoint molecules could serve as a predictive biomarker of patient outcome in HPV+ HNSCC.

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“…19 However, no significant differences were detected between the overall leukocyte fraction of HPV+ versus HPV- HNSCC (Supplementary Figure 1).…”

Section: Resultsmentioning

confidence: 91%

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

et al. 2018

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“…Pan-cancer efforts by The Cancer Genome Atlas (TCGA) and others have shown that cancers originating from different tissues share similar genomic signatures (Bailey et al, 2018; Hoadley et al, 2018). Certain breast and bladder cancers display a basal-like molecular profile characterized by p63 activation and the expression of specific basal cell cytokeratins (Damrauer et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers

et al. 2018

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Cancer progression to an aggressive phenotype often co-opts aspects of stem cell biology. Here, we developed gene signatures for normal human stem cell populations to understand the relationship between epithelial cancers and stem cell transcriptional programs. Using a pan-cancer approach, we reveal that aggressive epithelial cancers are enriched for a transcriptional signature shared by epithelial adult stem cells. The adult stem cell signature selected for epithelial cancers with worse overall survival and alterations of oncogenic drivers. Lethal small cell neuroendocrine lung, prostate, and bladder cancers transcriptionally converged onto the adult stem cell signature and not other stem cell signatures tested. We found that DNA methyltransferase expression correlated with adult stem cell signature status and was enriched in small cell neuroendocrine cancers. DNA methylation analysis uncovered a shared epigenomic profile between small cell neuroendocrine cancers. These pan-cancer findings establish a molecular link between human adult stem cells and aggressive epithelial cancers.

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“…extended the reclassifications to additional tumour types, but essentially confirmed their findings of the original study. However, similar to their previous work, detailed histomorphological properties of the analysed tumours were not accounted for in their molecular classification, and reclassification of tumours relied only on top‐level histotypes …”

Section: Discussionmentioning

confidence: 84%

Histomorphological and molecular profiling: friends not foes! Morpho‐molecular analysis reveals agreement between histological and molecular profiling

et al. 2019

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Aims Whereas current cancer diagnosis largely relies on the well‐established organ and tissue typing of tumours, partially complemented by molecular properties, the comprehensive molecular profiling efforts of recent years have stimulated proposals for molecular reclassifications of tumours independently of anatomical origin. Proposals based only on mutational profiles show the least concordance with histotypes, whereas greater concordance is achieved when various genomic and proteomic data are included. Methods and results The most comprehensive molecular reclassification of tumours, by Hoadley et al (Cell, 158, 2014; 929) and Hoadley et al (Cell, 173, 2018; 291), integrated multi‐omics data, and proposes novel molecular tumour classes. To investigate the relationship between the proposed molecular classes and the original histological tumour types, we re‐examined the histomorphology of molecularly reclassified cases. Our results show that the claimed molecular reclassification is associated with and explainable by specific histological subtypes in 70% of the reclassified cases. Conclusion Therefore, in contrast to the proclaimed reclassification and independence of molecular and histological tumour types, our analysis demonstrates that comprehensive molecular profiling, which includes gene expression and methylation as well as proteomic profiling in addition to mutational analyses, is largely consistent with histomorphological tumour properties.

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Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer

Cited by 1,396 publications

References 52 publications

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers

Histomorphological and molecular profiling: friends not foes! Morpho‐molecular analysis reveals agreement between histological and molecular profiling

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