Germline genomic patterns are associated with cancer risk, oncogenic pathways, and clinical outcomes

Abstract

There is an ongoing debate on the importance of genetic factors in cancer development, where gene-centered cancer predisposition seems to show that only 5 to 10% of the cancer cases are inheritable. By conducting a systematic analysis of germline genomes of 9712 cancer patients representing 22 common cancer types along with 16,670 noncancer individuals, we identified seven cancer-associated germline genomic patterns (CGGPs), which summarized trinucleotide mutational spectra of germline genomes. A few CGGPs were consistently enriched in the germline genomes of patients whose tumors had smoking signatures or correlated with oncogenesis- and genome instability–related mutations. Furthermore, subgroups defined by the CGGPs were significantly associated with distinct oncogenic pathways, tumor histological subtypes, and prognosis in 13 common cancer types, suggesting that germline genomic patterns enable to inform treatment and clinical outcomes. These results provided evidence that cancer risk and clinical outcomes could be encoded in germline genomes.

Deciphering of Somatic Mutational Signatures of Cancer

“…only SNVs were used in the SBS signatures we mainly focused on; (2) the read depths covering the mutated sites should be larger than 10; (3) the variant allele frequency (VAF) should be larger than 1%, consistent with our previous research 16 . As a result, 10,088 samples were retained for subsequent analysis.…”

“…We used the ‘maf2vcf perl script (https://github.com/mskcc/vcf2maf) to convert the MAF to VCF files. In addition to the filtration implemented by TCGA, the mutations were further filtered using these criteria: (1) only SNVs were used in the SBS signatures we mainly focused on; (2) the read depths covering the mutated sites should be larger than 10; (3) the variant allele frequency (VAF) should be larger than 1%, consistent with our previous research 16 . As a result, 10,088 samples were retained for subsequent analysis.…”

“…Interestingly, a number of genome-wide association studies (GWAS) have revealed that germline polymorphisms in cholinergic receptor genes, including CHRNA3 22, 23, 24, 25 , CHRNA4 26, 27, 28 , CHRNA5 22, 24, 25, 29, 30 , CHRNB1 28, 31 , and CHRNB4 22, 24, 25 , are indeed associated with tobacco addiction and are also associated with the risk of smoking-related diseases including lung cancer. In our previous study, we introduced the cancer germline genome pattern (CGGP) and found a positive correlation between CGGP_E and SBS4 32 . These findings suggest an interaction between genomic variations and environmental exposure, whereby cholinergic receptor germline polymorphisms are associated with tobacco addiction, and tobacco smoking results in somatic mutations in such genes.…”

Immune Microenvironment and Response in Prostate Cancer Using Large Population Cohorts

“…Germline genome may substantially affect immune capacity in cancer patients at a population level, including the response rate to cancer immunotherapy (42). Xue et al comprehensively analyzed the germline genomes of nearly 20,000 patients in 22 common cancer types and concluded that germline genomic patterns could inform treatment and clinical outcomes (43). Based on the prognosis-related immune terms, we identified IRS model to predict PCa patient survival and immunotherapy response rate.…”

Role of germline variants in the metastasis of breast carcinomas

“…Animal models and epidemiological studies suggest that the risk of developing metastasis after breast cancer diagnosis depends on the characteristics of the tumour and germline gene variants [8,9]. Furthermore, Xu et al, have shown how germline variants of natural killer cells in the tumour immune microenvironment can sway metastasis risk in several cancers [10]; they have also identified germline genomic patterns that contribute to cancer progression and metastasis [11].…”