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Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies.

Stoll G, Bindea G, Mlecnik B, Galon J, Zitvogel L, Kroemer G - Oncotarget (2015)

Bottom Line: Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts.Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies.Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders.

View Article: PubMed Central - PubMed

Affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

ABSTRACT
Anticancer immunosurveillance is one of the major endogenous breaks of tumor progression. Here, we analyzed gene expression pattern indicative of the presence of distinct leukocyte subtypes within four cancer types (breast cancer, colorectal carcinoma, melanoma, and non-small cell lung cancer) and 20 different microarray datasets corresponding to a total of 3471 patients. Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts. Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies. The reproducibility of the correlations among immune-relevant metagenes was highest in breast cancer (followed by colorectal cancer, non-small cell lung cancer and melanoma), reflecting the fact that mammary carcinoma has an intrinsically better prognosis than the three other malignancies. Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders. Altogether, this meta-analysis revealed novel organ-specific features of the immune infiltrate in distinct cancer types, as well as a strategy for defining new prognostic biomarkers.

No MeSH data available.


Related in: MedlinePlus

Immune metagene correlations (A-E) and correlation reproducibility p-values (F), in melanoma; reproducible correlations of first dataset (G), identified by hierarchical clustering of reproducibility p-values (H)Heat map representation of metagene correlation matrices, in the 5 datasets of melanoma transcriptome (blue rectangle corresponds to reproducible metagenes of Figure 1). A correlation reproducibility test is applied to the 5 correlation matrices, producing a matrix of p-values. Clustering of correlation reproducibility (H) allows for the identification of a sub-part of correlation matrix (yellow square), represented for the learning dataset (G).
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Figure 2: Immune metagene correlations (A-E) and correlation reproducibility p-values (F), in melanoma; reproducible correlations of first dataset (G), identified by hierarchical clustering of reproducibility p-values (H)Heat map representation of metagene correlation matrices, in the 5 datasets of melanoma transcriptome (blue rectangle corresponds to reproducible metagenes of Figure 1). A correlation reproducibility test is applied to the 5 correlation matrices, producing a matrix of p-values. Clustering of correlation reproducibility (H) allows for the identification of a sub-part of correlation matrix (yellow square), represented for the learning dataset (G).

Mentions: A collection of metagenes that correspond to distinct tumor-infiltrating leukocyte subtypes [11] was analyzed for their reproducibility across distinct cohorts of cancers. For each cancer type (breast cancer, colorectal carcinoma, melanoma and lung adenocarcinoma), we chose the cohort comprising the largest number of patients to establish leukocyte-specific metagenes in which the relative contribution of each individual gene was weighted (Table 1). Then, we determined whether this specific metagene could be confirmed in other four cohorts, calculating the p-value of reproducibility in each case. While the majority of metagenes were highly reproducible (as this applies for instance for the metagenes indicating the presence of T cells, NK cells, macrophages and neutrophils), a minority was not, including for instance those signifying the presence of regulatory T cells, Tregs, or blood vessels in the tumor, because these metagenes are composed of a single gene (gray squares in Figure 1). Metagenes that were considered as reproducible (by visual inspection) are indicated by the blue squares in Figures 1, 2, 3, 4, 5.


Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies.

Stoll G, Bindea G, Mlecnik B, Galon J, Zitvogel L, Kroemer G - Oncotarget (2015)

Immune metagene correlations (A-E) and correlation reproducibility p-values (F), in melanoma; reproducible correlations of first dataset (G), identified by hierarchical clustering of reproducibility p-values (H)Heat map representation of metagene correlation matrices, in the 5 datasets of melanoma transcriptome (blue rectangle corresponds to reproducible metagenes of Figure 1). A correlation reproducibility test is applied to the 5 correlation matrices, producing a matrix of p-values. Clustering of correlation reproducibility (H) allows for the identification of a sub-part of correlation matrix (yellow square), represented for the learning dataset (G).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494912&req=5

Figure 2: Immune metagene correlations (A-E) and correlation reproducibility p-values (F), in melanoma; reproducible correlations of first dataset (G), identified by hierarchical clustering of reproducibility p-values (H)Heat map representation of metagene correlation matrices, in the 5 datasets of melanoma transcriptome (blue rectangle corresponds to reproducible metagenes of Figure 1). A correlation reproducibility test is applied to the 5 correlation matrices, producing a matrix of p-values. Clustering of correlation reproducibility (H) allows for the identification of a sub-part of correlation matrix (yellow square), represented for the learning dataset (G).
Mentions: A collection of metagenes that correspond to distinct tumor-infiltrating leukocyte subtypes [11] was analyzed for their reproducibility across distinct cohorts of cancers. For each cancer type (breast cancer, colorectal carcinoma, melanoma and lung adenocarcinoma), we chose the cohort comprising the largest number of patients to establish leukocyte-specific metagenes in which the relative contribution of each individual gene was weighted (Table 1). Then, we determined whether this specific metagene could be confirmed in other four cohorts, calculating the p-value of reproducibility in each case. While the majority of metagenes were highly reproducible (as this applies for instance for the metagenes indicating the presence of T cells, NK cells, macrophages and neutrophils), a minority was not, including for instance those signifying the presence of regulatory T cells, Tregs, or blood vessels in the tumor, because these metagenes are composed of a single gene (gray squares in Figure 1). Metagenes that were considered as reproducible (by visual inspection) are indicated by the blue squares in Figures 1, 2, 3, 4, 5.

Bottom Line: Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts.Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies.Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders.

View Article: PubMed Central - PubMed

Affiliation: Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

ABSTRACT
Anticancer immunosurveillance is one of the major endogenous breaks of tumor progression. Here, we analyzed gene expression pattern indicative of the presence of distinct leukocyte subtypes within four cancer types (breast cancer, colorectal carcinoma, melanoma, and non-small cell lung cancer) and 20 different microarray datasets corresponding to a total of 3471 patients. Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts. Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies. The reproducibility of the correlations among immune-relevant metagenes was highest in breast cancer (followed by colorectal cancer, non-small cell lung cancer and melanoma), reflecting the fact that mammary carcinoma has an intrinsically better prognosis than the three other malignancies. Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase-1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders. Altogether, this meta-analysis revealed novel organ-specific features of the immune infiltrate in distinct cancer types, as well as a strategy for defining new prognostic biomarkers.

No MeSH data available.


Related in: MedlinePlus