Germline Variants Impact Somatic Events during Tumorigenesis

Ramroop, Johnny R.; Gerber, Madelyn M.; Toland, Amanda E.

doi:10.1016/j.tig.2019.04.005

Cited by 42 publications

(41 citation statements)

References 57 publications

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“…A limitation of variant-level GWAS analyses is that variants that are not statistically associated with cancer risk could still contribute to cancer development and mediate heritability through phenotypic convergence at biological process level 13 . In phenotypic convergence, distinct genomic alterations in different members of a biological pathway could lead to the same-or similar-phenotypic effect.…”

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confidence: 99%

Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden

et al. 2020

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Cancers harbor many somatic mutations and germline variants, we hypothesized that the combined effect of germline variants that alter the structure, expression, or function of protein-coding regions of cancer-biology related genes (gHFI) determines which and how many somatic mutations (sM) must occur for malignant transformation. We show that gHFI and sM affect overlapping genes and the average number of gHFI in cancer hallmark genes is higher in patients who develop cancer at a younger age (r = −0.77, P = 0.0051), while the average number of sM increases in increasing age groups (r = 0.92, P = 0.000073). A strong negative correlation exists between average gHFI and average sM burden in increasing age groups (r = −0.70, P = 0.017). In early-onset cancers, the larger gHFI burden in cancer genes suggests a greater contribution of germline alterations to the transformation process while late-onset cancers are more driven by somatic mutations.

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confidence: 99%

Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden

et al. 2020

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“…Our observation of somatic second hit (Figure 2-3) and transcriptional effects (Figure 4) coupled with germline variants also adds on to the current literature on germline-somatic interactions in cancer [45]. While the majority of cancer genomic studies focus exclusively on the germline or somatic genome, pathogenic germline variants are associated with different somatic mutational signatures, allele-specific imbalance, or somatic drivers [11,26,[46][47][48].…”

Section: Discussionmentioning

confidence: 68%

Ancestry-Specific Predisposing Germline Variants in Cancer

Oak

Cherniack

Mashl

et al. 2020

Preprint

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Background: Cancer risk differs across ancestries and these differences may result from differing prevalence of inherited genetic predisposition. Yet, most germline genomic studies performed to date have focused on individuals of European ancestry.Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis for each ancestral group. Here, we investigate potentially germline pathogenic variants in cancer predisposition genes (CPG) and their somatic effects in patients across diverse ancestral backgrounds. Methods:We performed a retrospective analysis of germline genomic data of 9,899 patients from 33 cancer types generated by The Cancer Genome Atlas (TCGA) project along with matching somatic genomic and transcriptomic data. By collapsing pathogenic and likely pathogenic variants to the gene level, we analyzed the association between variants in CPGs and cancer types within each ancestry. We also identified ancestryspecific predisposing variants and their associated somatic two-hit events and gene expression levels.Results: Recent genetic ancestry analysis classified the cohort of 9,899 cancer cases into individuals of primarily European, (N = 8,184 , 82.7%), African (N = 966, 9.8%), East Asian (N = 649, 6.6%), South Asian (N=48, 0.5%), Native/Latin American (N=41, 0.4%), and admixed (N=11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association of BRCA2 in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1-275.6]; FDR = 0.002) along with the previously identified association of BRCA2 in ovarian serous cystadenocarcinoma (OR=8.5 [95% CI, 1.5-47.4];FDR=0.045). Similarly, in the East Asian ancestry, we discovered one previously known association of BRIP1 in stomach adenocarcinoma (OR=12.8 [95% CI, 1.8-90.84];FDR=0.038). Rare variant burden analysis further identified 7 suggestive associations for cancer-gene pairs in African ancestry individuals previously well described in European ancestry including SDHB in pheochromocytoma and paraganglioma, ATM in prostate adenocarcinoma, VHL in kidney renal clear cell carcinoma, FH in kidney renal papillary cell carcinoma, and PTEN in uterine corpus endometrial carcinoma. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from the SDHB or BRCA2 carriers showed simultaneous allelic specific expression and low gene expression of their respective affected genes; and FH splice-site variant carriers showed mis-splicing of FH. Conclusions:While several predisposing genes are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects.Analysis of larger diverse ancestries genomic cohorts are required to pinpoint ancestryspecific genetic predisposition to inform personalized diagnosis and screening strategies.

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“…Comparison with non-urothelial cancer types in WCM cohort. To investigate whether the pDGVs detected in the WCM-UC cohort were present in other WCM cancer cohorts 72 , we selected European and Ashkenazi Jewish patients with prostate cancer (134), kidney cancer (55), glioblastoma (52), colorectal cancer (49), and breast cancer (37). We performed pDGVs enrichment analysis by comparing each WCM cancer cohort with the respective ethnicity-matched SPARK noncancer cohort.…”

Section: Methodsmentioning

confidence: 99%

Common germline-somatic variant interactions in advanced urothelial cancer

et al. 2020

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The prevalence and biological consequences of deleterious germline variants in urothelial cancer (UC) are not fully characterized. We performed whole-exome sequencing (WES) of germline DNA and 157 primary and metastatic tumors from 80 UC patients. We developed a computational framework for identifying putative deleterious germline variants (pDGVs) from WES data. Here, we show that UC patients harbor a high prevalence of pDGVs that truncate tumor suppressor proteins. Deepening somatic loss of heterozygosity in serial tumor samples is observed, suggesting a critical role for these pDGVs in tumor progression. Significant intra-patient heterogeneity in germline-somatic variant interactions results in divergent biological pathway alterations between primary and metastatic tumors. Our results characterize the spectrum of germline variants in UC and highlight their roles in shaping the natural history of the disease. These findings could have broad clinical implications for cancer patients.

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Germline Variants Impact Somatic Events during Tumorigenesis

Cited by 42 publications

References 57 publications

Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden

Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden

Ancestry-Specific Predisposing Germline Variants in Cancer

Common germline-somatic variant interactions in advanced urothelial cancer

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