It is demonstrated that somatic rather than germline risk predominates in middle-aged healthy adults and the VAF-haplotype-sharing analysis framework provides a scalable framework for variant classification in large-scale population genomics.
Abstract
Pathogenic variants in TP53, the key tumour-suppressor gene underlying Li-Fraumeni syndrome (LFS), are among the best-established causes of inherited cancer predisposition. However, large-scale sequencing has revealed that many apparently pathogenic TP53 variants detected in blood are the result of somatic clonal expansions, complicating risk interpretation. Using blood-derived whole-exome data from 469,391 UK Biobank participants, we combined variant allele fraction (VAF) with haplotype-sharing analysis to distinguish germline and somatic TP53 variants. Germline variants were concentrated at sites linked to partial loss of p53 function and lower disease penetrance, whereas classic LFS alleles appeared almost entirely somatic. High-VAF carriers of classic LFS alleles conferred markedly increased risk of haematological malignancy but not solid tumours, consistent with large TP53-mutant clonal expansions. The prevalence of somatic clonal expansion also correlated with missense variant pathogenicity, suggesting that somatic activity provides an informative in vivo proxy for functional impact. These results provide new insights into TP53-associated cancer risk at the population level, demonstrate that somatic rather than germline risk predominates in middle-aged healthy adults and provide a scalable framework for variant classification in large-scale population genomics.
Germline and somatic cancer variants in tumor suppressor genes (TSGs) share loss of function mechanisms, but studies of a few genes (DICER1, CEBPA) demonstrated differences in variant consequence and location. To systematically assess whether TSGs display distinct mutational patterns we leveraged large public genetic databases and compared 32,941 high-quality pathogenic/likely pathogenic (P/LP) germline variants in ClinVar, with 12,907 oncogenic/likely oncogenic (O/LO) somatic tumor variants from cBioPortal across 40 TSGs. Only 3,863 (9.2%) variants were shared. Eighteen TSGs showed significantly different distributions of variant occurrences by molecular consequence replicated with non-overlapping somatic data from the COSMIC database (chi-squared tests, false discovery rate=5%). DICER1, TP53, and SMAD4 displayed excess somatic missense events, while nine TSGs (e.g., RB1, APC) contained excess somatic stop-gain events throughout the coding sequence. Analysis by tumor type revealed excess stop-gain events in tissues exposed to environmental mutagens with corresponding mutation signatures. For several TSGs (WT1), germline variants predispose to tumors (Wilms Tumor) distinct from the majority source of somatic data (myeloid leukemia). Germline and somatic events also distributed unevenly across cDNA location with 103 regions of preferential clustering in 39 TSGs (78 somatic, 25 germline). Twenty somatic clusters contained recurring frameshifts in homopolymer runs, many in tumors with microsatellite instability. Germline clusters contain more germline-exclusive variants, some driving non-cancer phenotypes reflecting genetic pleiotropy. Altogether, germline and somatic variants of TSGs represent unique sets with substantially different patterns shaped by selection pressures from gene-specific and somatic mutational mechanisms. Characterizing these distinctions enables more accurate clinical interpretation of TSG variants.
Suhasini D. Lulla, D. Ritter, C. Kesserwan et al.· American Journal of Human Ge...· 0 citations
Pathogenic variants in the tumor suppressor gene NF1 cause neurofibromatosis type 1 (NF1), one of the most common hereditary cancer predisposition syndromes. Pathogenic NF1 variants have been associated with an increased risk of several cancers; however, the relationship between NF1 variation and colon cancer remains underreported. We report a 41-year-old woman with a mosaic monoallelic germline pathogenic NF1 variant, NM_000267.3:c.1756_1759del (p.Thr586Valfs*18), previously detected on germline multigene panel testing in saliva at a variant allele frequency of approximately 35%. She later presented with fatigue, dyspnea on exertion, and iron-deficiency anemia. Computed tomography, colonoscopy, biopsy, mismatch repair immunohistochemistry, surgical pathology, and tumor next-generation sequencing led to the diagnosis of right-sided colon adenocarcinoma that was mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H). She underwent right hemicolectomy, recovered postoperatively, and entered standard surveillance; at the time of manuscript development, she was also receiving systemic therapy. This case highlights the co-occurrence of an NF1 variant and dMMR colorectal cancer and underscores the need for further studies to determine whether this represents a coincidental finding or a biologically meaningful association.
Feras Alsabagh, Karam M. Chaaban, M. Girardo et al.· Exploration of Neuroscience· 0 citations
High-risk and early-onset PCa is associated with rare germline DDR alterations, and expanded germline testing in younger patients is supported and potential relevance for precision oncology approaches is suggested.
Rawaz Rizgar, Hassan, Abdulkarim Y Karim et al.· Galen medical journal· 0 citations
While pathogenic germline CHEK2 variants are known to increase cancer risk, there is currently insufficient evidence regarding the precise risk of developing malignant neoplasms associated with specific missense variants or variants of uncertain significance. As a result, no clear clinical guidelines exist regarding consultation, monitoring and specific treatment options for those patients. For the first time in Russia, clinical data and whole-genome sequencing (WGS) results were analyzed for 3150 patients with cancer and suspected hereditary cancer syndromes (HCS) and 5163 healthy individuals. This dataset formed the basis for assessing the role of germline CHEK2 variants in the development of different cancer types. The chromosomal coordinates and coding sequence coordinates are given in accordance with the GRCh38 (hg38) genome assembly and the NM_007194.4 transcript. Pathogenic (P) and likely pathogenic (LP) variants of CHEK2 significantly increased the risk of breast cancer (OR = 2.015 [95% CI: 1.27–3.21]; p = 0.0031), but the association with colorectal cancer was not statistically significant (OR = 1.354 [95% CI: 0.42–4.42]; p = 0.616). A moderate increase in cancer risk was identified for the c.1100del variant (OR = 2.263 [95% CI: 1.19–4.32]; p = 0.0132) and for the common P/LP variants c.1100del, c.444+1G>A and c.433C>T (OR = 2.219 [95% CI: 1.40–3.51]; p = 0.0007). Notably, our study confirmed that CHEK2 c.470T>C (p.Ile157Thr) is the most common variant in the patient group, identified in 3.8% of cases (120/3150), compared with 3.0% in the control group (155/5163). Although the association between the most common CHEK2 variant c.470T>C and cancer risk reached nominal statistical significance (OR = 1.279 [95% CI: 1.00–1.63]; p = 0.0463), the effect size was minimal, suggesting that the contribution of this variant to hereditary cancer risk in the Russian population is modest. Additional studies are required before this variant can be definitively excluded from clinical interpretation.
M. Nemtsova, M. Makarova, Anastasiia Danishevich et al.· International Journal of Mol...· 0 citations
Clonal hematopoiesis (CH), an aging-related expansion of hematopoietic stem cell (HSC) clones, is associated with hematologic malignancy, cardiovascular disease, and mortality. Most clonal expansions, however, occur in the absence of known driver mutations. Passenger mutations reveal positive selection in HSCs and provide a quantitative, driver-agnostic phenotype that increases statistical power over dichotomized driver-based definitions. We used somatic passenger mutation burden as a quantitative phenotype to map the genetic, phenotypic, and geographic correlates of CH across 791,067 blood whole-genome sequences from UK Biobank (UKB) and the All of Us Research Program (AoU). Multi-ancestry meta-analysis of genome-wide association studies in both cohorts identified 81 loci associated with passenger mutation burden, including 42 novel loci. Rare-variant analyses additionally implicated MBD2, PRKACB, PUF60, and related epigenetic and transcriptional regulators of clonal fitness. Together, common and rare germline associations converged with canonical CH drivers on shared pathways regulating DNA methylation, chromatin, RNA splicing, and genome maintenance. Sex and ancestry stratified analyses revealed the shared and population-specific determinants of CH, including loci undetected in the pooled analysis. Associated variants were concentrated in regulatory elements active in hematopoietic stem and progenitor cells, linking germline associations to relevant cell states and lineages. Phenome-wide analyses revealed distinct consequences of inherited CH liability and observed passenger burden, with passenger burden strongly associated with incident hematologic malignancy and mortality and germline risk showing additional nonhematologic associations. Finally, spatial modelling of passenger mutation burden across U.S. regions revealed persistent geographic heterogeneity incompletely explained by income, air quality, or chemotherapy prevalence, pointing to additional unmeasured environmental exposures. Overall, through parallel analyses of two population-scale biobanks, we characterize the multi-ancestry genetic architecture of CH and reveal convergence of germline and somatic variation on shared pathways governing clonal expansion in aging blood.
P. S. Reddy, K. Conneely, J. Weinstock· medRxiv· 0 citations
Suggestive evidence supporting associations between rare germline variants in eight hereditary cancer genes and lung cancer were obtained from two large independent datasets.
Sierra R. Broad, Jun Wei, Keri L. Denson et al.· Annals of Thoracic Surgery· 0 citations
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