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. 2022 Nov 14;14(22):5571.
doi: 10.3390/cancers14225571.

Polygenic Risk Scores Associated with Tumor Immune Infiltration in Common Cancers

Jungyoon Choi  1 , Jung Sun Kim  1 , Hwa Jung Sung  1 , Yu-Wei Chen  2 , Zhishan Chen  2 , Wanqing Wen  2 , Xiao-Ou Shu  2 , Xingyi Guo  2   3
Affiliations

Polygenic Risk Scores Associated with Tumor Immune Infiltration in Common Cancers

Jungyoon Choi et al. Cancers (Basel). .

Abstract

It is largely unknown whether genetic susceptibility contributes to tumor immune infiltration in common cancers. We systematically investigated the association between polygenic risk scores (PRSs) and tumor immune infiltration in common cancers. First, we constructed a PRS for common cancers using the risk variants identified in previous genome-wide association studies. Then, we analyzed 139 immune traits predicted by previous studies by examining gene expression data in tumor tissues from The Cancer Genome Atlas (TCGA). We applied regression analyses to evaluate the associations between PRS and immune traits for each cancer overall and stratified by stage, including 2160 pathologically confirmed cases of breast, colorectal, lung, ovarian, pancreatic, and prostate cancers in the White population. At a nominal (p < 0.05) significance level, we identified 31 significant associations between PRS and immune traits. In the analyses stratified by stage for breast, colorectal, lung adenocarcinoma, and lung squamous cell carcinoma, we identified 65 significant associations, including 56 associations that were undetected by the overall analysis. This study provides evidence for genetic risk factors affecting immune infiltration and provides novel insights into the role of genetic susceptibility in immune responses, underlying cancer development, prognosis, and the potential role of an early diagnostic or therapeutic targeting strategy.

Keywords: cancer genetic susceptibility; genome-wide association study; polygenic risk score; tumor immune infiltration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overall associations between polygenic risk scores (PRSs) for cancers and immune traits. (A) Overall workflow for assessing the effect of PRSs for cancers on immune traits. (B) Overall proportion of cancer types in each immune module (nominal p < 0.05). The thickness of line indicates −log10 P. (C) Overall associations between PRSs for cancers and immune traits (nominal p < 0.05.) Immune traits were presented when a nominal p < 0.05 against at least one type of cancer was observed. The bottom figure represents the stratified analyses by intrinsic molecular subtypes of breast cancer between the PRSs for breast cancer and immune traits. Abbreviations: BRCA, breast cancer; COREAD, colorectal cancer; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; OV, ovarian cancer; PAAD, pancreatic cancer; PRAD, prostate cancer.
Figure 2
Figure 2
Stratified analyses by stage (early and advanced stages) between PRSs for cancers and immune traits. Immune traits were presented when a nominal p < 0.05. against at least one type of cancer, was observed. In the figure below, forest plots are presented when a nominal p < 0.02 in advanced stages of breast cancer and early stages of colorectal cancer, which were the most representative of the data. Abbreviations: BRCA, breast cancer; COREAD, colorectal cancer; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PRS, polygenic risk score.
Figure 3
Figure 3
Summary of stratified analyses by stage and immune subtype. (A) Overall proportion of cancer types in each immune module (nominal p < 0.05). (B) Specific proportion by cancer stage in each immune module (nominal p < 0.05). (C) Absolute number of associations by cancer stage in each immune module (nominal p < 0.05). (D) Mechanisms of immune traits. Tregs attenuate the activity of CD4+ and CD8+ T cells to maintain self-tolerance through the secretion of immunosuppressive cytokines including IL-2. M2 macrophages are characterized by the expression of anti-inflammatory cytokines, such as IL-4 and chemokines, which suppress CD8+ T-cell activation, promote the recruitment of Tregs, and contribute to tumor immune evasion. CD8+ T cells play a central role in inducing an antitumor immune response through the release of cytolytic factors and induction of apoptosis in tumor cells. CTLA-4 on T cells leads to a pro-tumoral immunosuppressive phenotype. Stromal components can contribute to immune evasion and resistance to immune checkpoint inhibitors. High rates of angiogenesis in the tumor microenvironment, resultant abnormal vasculature, and high interstitial pressure within the tumor can impair the infiltration of immune cells and penetration of checkpoint inhibitors. (E) Representative immune traits by PRS in the cancer groups. The PRS group was classified into “low PRS” and “high PRS” based on the median PRS for each cancer. White dots represent the median values. The thick black bars in the center represent interquartile ranges. The thin gray line represents the rest of the distribution, except for the points that were determined to be outliers. (F) Immune subtype analyses. The numbers in the matrix indicate the sample size for each group. Abbreviations: BRCA, breast cancer; COREAD, colorectal cancer; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IL, interleukin; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; OV, ovarian cancer; PAAD, pancreatic cancer; PRAD, prostate cancer; PRS, polygenic risk score; Treg, regulatory T cells.
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