Transcriptional analysis of immune modulatory genes in melanoma treated with PD-1 blockade

Song, Hyojin; Lee, Sungyoung; Lee, Se‐Hoon; Lee, Sang Yup; Yoon, Sung-Soo; Yun, Hongseok; Koh, Youngil

doi:10.1101/2020.12.20.397000

Cited by 3 publications

(4 citation statements)

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“…5c ). Furthermore, we measured the transcriptional score (TS), a gene-wide measurement that sums up all the gene expression correlation coefficients between 38 immune checkpoint modulatory genes within a group (see Methods ) 25 , across three groups: (i) PAH carrier in PCAWG-TCGA Lung-SCC, (ii) PAH non-carrier in PCAWG-TCGA Lung-SCC, and (iii) normal lung samples from GTEx 26 . PAH pathogenic germline variant carriers ( N = 15, median TS = 19.14) showed significantly increased TS compared to PAH non-carrier ( N = 478; median TS = 14.69, P = 1.05 × 10 −3 by Wilcoxon rank sum test) and normal lung samples from GTEx ( N = 578; median TS = 9.25, P = 6.14 × 10 −8 by Wilcoxon rank sum test, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…we measured the transcriptional score (TS), a gene-wide measurement that sums up all the gene expression correlation coefficients between 38 immune checkpoint modulatory genes within a group (see Methods) 25 which shows high response rates to immune checkpoint inhibitors 27 . Additionally, we checked the mutational signatures present based on the somatic mutation patterns, but we did not observe any differences in the type of signatures or frequencies of each signature between the PAH carrier and non-carrier group (Supplementary Fig.…”

Section: Methods)mentioning

confidence: 99%

“…GSEA 59 was performed using the java GSEA application version 4.1.0 to evaluate the functional enrichment in Cancer Hallmark with 1,000 permutations. Furthermore, we calculated the transcriptional score (TS) 25 which is defined as an absolute number of summed gene expression correlation coefficient values using 38 immune checkpoint modulatory genes 27 . We compared TS values among three groups of samples (1) PAH carrier in Lung-SCC, (2) PAH non-carrier in Lung-SCC, and (3) normal lung samples in GTEx 26 .…”

Section: Functional Analysis With Pahmentioning

confidence: 99%

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Systematic analysis of disease-linked rare germline variants reveals new classes of cancer predisposing genes

Song

Koh

Kim

et al. 2023

Preprint

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Despite recent insights into cancer predisposition genes (CPGs), the contribution of rare germline variants to carcinogenesis remains unclear. Here, we examine the enrichment of rare germline variants in Mendelian disease-associated genes using PCAWG and the 1,000 Genomes Project. Using an integrative approach that considers disease classes, cellular pathways, and tissue expression profiles, we find that subsets of Online Mendelian Inheritance in Man (OMIM) genes are strong candidate CPGs. These genes were classified into five clusters suggesting diverse mechanisms underlie tumor progression. We further analyzed PAH gene which shows the strongest prevalence of rare germline variants in cancers (2.2%) compared to controls (0.7%). This enrichment was validated in two independent cancer cohorts and present the possibility of tumorigenesis by contributing immune-associated pathways. Our data argue that rare germline variants of Mendelian disease-associated genes contribute to cancer progression and suggest new CPG classifications that may underlie diverse tumorigenesis mechanisms.

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Section: Resultsmentioning

confidence: 99%

Section: Methods)mentioning

confidence: 99%

Section: Functional Analysis With Pahmentioning

confidence: 99%

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Systematic analysis of disease-linked rare germline variants reveals new classes of cancer predisposing genes

Song

Koh

Kim

et al. 2023

Preprint

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“…Relevantes infiltrados imunes, principalmente linfócitos CD8+, e 3. A carga mutacional do tumor, que tende a ser refletida na presença de neoantígenos (59)(60)(61). Apesar de mais bem aceitos, esses marcadores ainda são questionáveis, principalmente se levarmos em conta os benefícios da terapia a longo prazo.…”

Section: O Anti-pd-1 Como Imunoterapia No Melanomaunclassified

O papel do receptor NLRP1 na resposta imune e progressão do melanoma: uma abordagem >i<in vivo>/i< e >i<in sílico>/i<

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Agradeço a meus pais, Rômulo e Néjela, por tudo o que fizeram por mim desde que me conheço por gente e por seu suporte inabalável em toda a minha caminhada. Por todos os conselhos e motivações, pelas caronas aos fins de semana para a USP (sempre dizendo que tinham algo pra fazer por lá, apenas para que eu não me sentisse culpado) e por sempre estarem ao meu lado. Nunca caberia em uma folha descrever como sou grato. Agradeço também a meus Irmãos, Natália, Heloísa e João, por sempre acreditarem em mim e me aguentarem de mau humor diversas vezes.Agradeço a meu orientador Niels. Boss, chefinho, obrigado por tudo, de verdade! Cada vez tenho mais certeza de que não poderia ter escolhido um orientador melhor para o mestrado. Agradeço toda a atenção e calma, todo o suporte e liberdade que me deu. Pela sua consciência do momento em que foi desenvolvido o mestrado e como ele se desenrolou, por entender as dificuldades da pandemia e por estar sempre lá quando precisei. Agradeço acima disso, pelo exemplo de pessoa que você é e pelo que pude aprender com isso durante esses anos. (E também por todos os doces que já levou pro Lab) Aos companheiros de Lab LIT, que fizeram dessa jornada mais agradável e menos maluca. Em especial a minha coorientadora Cris, por todos os ensinamentos e conversas, e ao Hedden e a Raquel, por todas as conversas e risadas, e por sempre estarem disponíveis para me ajudar nos experimentos quando precisei.Ao Igor e Denny, pelos conselhos e por todas as conversas sobre o futuro e bioinformática. Esse trabalho não estaria do jeito que está sem o suporte de vocês. Mais do que isso, agradeço pela amizade de vocês.Aos meus amigos, de longa e breve data. As amizades que fiz no ensino médio e continuam fortes até hoje, a todos os meus amigos de ambas as graduações. Vocês são muito importantes pra mim, e eu seria muito menos do que sou hoje sem vocês.Ao CHAOS DPTO, pelos RPGs pelas conversas e pela amizade, por sempre jogarem uma luz nos períodos sombrios da pandemia.A todos os funcionários do ICB e da USP, a todos os porteiros, funcionários do bandeijão, funcionários do biotério, a equipe de limpeza e diversos outros. Muito obrigado por fazerem possível esse trabalho.A todos os camundongos que usei. Muito obrigado. Esse trabalho também é dedicado a vocês.

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Systematic analysis of Mendelian disease-associated gene variants reveals new classes of cancer-predisposing genes

Song,

Koh,

Kim

et al. 2023

Genome Med

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Background Despite the acceleration of somatic driver gene discovery facilitated by recent large-scale tumor sequencing data, the contribution of inherited variants remains largely unexplored, primarily focusing on previously known cancer predisposition genes (CPGs) due to the low statistical power associated with detecting rare pathogenic variant-phenotype associations. Methods Here, we introduce a generalized log-regression model to measure the excess of pathogenic variants within genes in cancer patients compared to control samples. It aims to measure gene-level cancer risk enrichment by collapsing rare pathogenic variants after controlling the population differences across samples. Results In this study, we investigate whether pathogenic variants in Mendelian disease-associated genes (OMIM genes) are enriched in cancer patients compared to controls. Utilizing data from PCAWG and the 1,000 Genomes Project, we identify 103 OMIM genes demonstrating significant enrichment of pathogenic variants in cancer samples (FDR 20%). Through an integrative approach considering three distinct properties, we classify these CPG-like OMIM genes into four clusters, indicating potential diverse mechanisms underlying tumor progression. Further, we explore the function of PAH (a key metabolic enzyme associated with Phenylketonuria), the gene exhibiting the highest prevalence of pathogenic variants in a pan-cancer (1.8%) compared to controls (0.6%). Conclusions Our findings suggest a possible cancer progression mechanism through metabolic profile alterations. Overall, our data indicates that pathogenic OMIM gene variants contribute to cancer progression and introduces new CPG classifications potentially underpinning diverse tumorigenesis mechanisms.

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Transcriptional analysis of immune modulatory genes in melanoma treated with PD-1 blockade

Cited by 3 publications

References 88 publications

Systematic analysis of disease-linked rare germline variants reveals new classes of cancer predisposing genes

Systematic analysis of disease-linked rare germline variants reveals new classes of cancer predisposing genes

O papel do receptor NLRP1 na resposta imune e progressão do melanoma: uma abordagem >i<in vivo>/i< e >i<in sílico>/i<

Systematic analysis of Mendelian disease-associated gene variants reveals new classes of cancer-predisposing genes

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