Somatic mutational profiles and germline polygenic risk scores in human cancer

Liu, Yuxi; Gusev, Alexander; Heng, Yujing J.; Alexandrov, Ludmil B.; Kraft, Peter

doi:10.1101/2021.01.28.428663

Cited by 2 publications

(3 citation statements)

References 101 publications

(117 reference statements)

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“…Mounting evidence suggests that somatic variations in tumors can have a germline genetic basis (12,18-23). This germline-somatic relationship has been established at different levels, from the impact of a single germline variant on somatic mutation rate of a cancer gene (e.g., rs25673 at 19p13.3 with PTEN alterations that involved in the mTOR signaling pathway) (20), to the associations between germline polygenic risk scores (PRS) and somatic mutational signatures (e.g., germline PRS of inflammatory bowel disease with APOBEC signatures in breast cancer) (23). Emerging evidence also shows an interactive effect of germline and somatic variations on clinical outcomes (24).…”

Section: Introductionmentioning

confidence: 99%

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Germline cancer gene expression quantitative trait loci influence local and global tumor mutations

Liu

Gusev

Kraft

2022

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Somatic mutations drive cancer development and are relevant to patients' response to treatment. Emerging evidence shows that variations in the somatic genome can be influenced by the germline genetic background. However, the mechanisms underlying these germline-somatic associations remain largely obscure. We hypothesized that germline variants can influence somatic mutations in a nearby cancer gene ("local impact") or a set of recurrently mutated cancer genes across the genome ("global impact") through their regulatory effect on gene expression. We integrated tumor targeted sequencing from 12,413 patients across 11 cancer types in the Dana-Farber Profile cohort with germline cancer gene expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression Project. We identified variants that upregulate ATM expression which are also associated with a decreased risk of having somatic ATM mutations across 8 cancer types (P = 3.43 &#215 10−5). We also identified GLI2, WRN, and CBFB eQTL that are associated with global tumor mutational burden of cancer genes in ovarian cancer, glioma, and esophagogastric carcinoma, respectively (P < 3.45 &#215 10−6). An EPHA5 eQTL was associated with the number of mutations in cancer genes specific to colorectal cancer, and eQTL associated with expression of APC, WRN, GLI1, FANCA, and TP53 were associated with mutations in genes specific to endometrial cancer (P < 1.73 &#215 10−5). Our findings provide evidence for the germline-somatic associations mediated through expression of specific cancer genes and open new avenues for research on the underlying biological processes, especially those related to immunotherapy responses.

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Section: Introductionmentioning

confidence: 99%

“…Mounting evidence suggests that somatic variations in tumors can have a germline genetic basis (12,(18)(19)(20)(21)(22)(23). This germline-somatic relationship has been established at different levels, from the impact of a single germline variant on somatic mutation rate of a cancer gene (e.g., rs25673 at 19p13.…”

Section: Introductionmentioning

confidence: 99%

Germline cancer gene expression quantitative trait loci influence local and global tumor mutations

Liu

Gusev

Kraft

2022

Preprint

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“…It has also been uncovered that germline variants can associate with different types of somatic mutations, such as copy number alternations (CNAs) and single-nucleotide variants (SNVs) (Ramroop et al 2019). A robust association between somatic mutation profiles and polygenic risk score and an inverse association between germline risk factor and total somatic mutation counts in human cancers have been detected (Zhu et al 2016;Liu et al 2022). In dogs that were studied in this thesis, there seems to be an interaction between germline risk mutation in the TPO gene and driver mutation in the GNAS gene as well, but it is weak as no significant interaction was detected by a Chi-squared test.…”

Section: Interaction Between Germline Risk and Driver Mutationsmentioning

confidence: 99%

Genomics underlying a canine hereditary thyroid follicular cell carcinoma

Yu¹

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Yu, Y. (2022). Genomics underlying a canine thyroid follicular cell carcinoma. PhD thesis, Wageningen University, the NetherlandsIntense human selection on domestic dogs over the past ~200 years has created a variety of pure dog breeds, but also resulted in breed-specific predispositions to many hereditary diseases/disorders. The incidence of thyroid cancer (TC) in the Dutch population of German Longhaired Pointer (GLP) dogs has been extremely high over the past approximately 20 years, indicating a population predisposition to TC. To help the breeders to eradicate TCs from Dutch GLPs, I performed a series of analyses to decode TCs that occurred in those Dutch GLPs. Firstly, we determined the histological subtype of identified TCs and revealed that these TCs are a familial disease according to consanguinity of affected GLPs. I investigated the effect of inbreeding on the incidence of the familial TCs in these Dutch GLPs based on both pedigree and genotype data and revealed that inbreeding contributed to the high incidence of the familial TCs in these GLPs. Furthermore, I identified germline risk mutations for familial TC using a combination of a genome-wide association study and homozygosity mapping. The identified germline risk mutation is used in a genetic test that identifies GLPs at a high risk for familial TC. To further understand the molecular mechanism underlying familial TC initiation and development, I profiled the somatic mutation landscape of 7 familial TCs and identified a recurrent missense mutation that very likely drives tumorigenesis. Furthermore, I genetically characterized the GLP breed and identified a specific selection signature that might contribute to hunting performance of GLPs. Lastly, I tested a novel approach to predict driver mutations using prior signaling pathway knowledge. Together I comprehensively decoded the familial TCs in the Dutch GLPs and developed a genetic test to identify dogs at a high risk for familial TCs. ContentsGeneral introduction Familial follicular cell thyroid carcinomas in a large number of Dutch German longhaired pointers Deleterious Mutations in the TPO Gene Associated with Familial Thyroid Follicular Cell Carcinoma in Dutch German Longhaired Pointers A recurrent somatic missense mutation in the GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs Unique genetic signature and selection footprints in Dutch population of German Longhaired Pointer dogs A cancer gene score based on pathways and its application in driver mutation prediction using machine learning approach General discussion Summary Appendices 10 1.1. CancerCancer is a disease in which some of the body's cells grow uncontrollably in a tissue and may spread to other parts of the body (NCI 2021). Cancer is a leading cause of death in humans worldwide. In 2020, more than 19 million new cancer cases appeared and nearly 10 million people died of a variety of cancers (Sung et al. 2021). Cancer can start almost everywhere in the body, such as the brain, bone...

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Somatic mutational profiles and germline polygenic risk scores in human cancer

Cited by 2 publications

References 101 publications

Germline cancer gene expression quantitative trait loci influence local and global tumor mutations

Germline cancer gene expression quantitative trait loci influence local and global tumor mutations

Genomics underlying a canine hereditary thyroid follicular cell carcinoma

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