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PubMed2025

Continuous DNA Methylation Deconvolution-Based Surrogate for B-Cell Differentiation State in CLL.

Chronic Lymphocytic Leukemia (CLL) is clinically divided into IGHV mutated (M-CLL) and IGHV unmutated (U-CLL) subtypes, which are thought to arise from distinct cells of origin along the B-cell differentiation pathway. We measured genome-scale DNA methylation in purified CLL samples ( n = 89) and utilized reference-based cell deconvolution techniques to develop a continuous metric of epigenetic similarity across a B-naive-like to B-memory-like scale (B-Index). B-Index accurately classifies CLL into clinical subtypes (98.8%), has a stronger epigenetic signal than IGHV gene percent identity, and demonstrates additional epigenetic signal within the M-CLL subgroup. We demonstrate that U-CLL is epigenetically more similar to B-memory than B-naive cells and reconcile previous reports of a B-naive-like epigenetic signal. The B-memory-like program of U-CLL is enriched for binding sites of transcription factors related to the germinal center activation pathway. Our findings provide epigenetic evidence for discerning CLL mechanisms of initiation and cell of origin. We also identified an epigenetic signal associated with tumor burden, which may have some relation to viral infections such as Epstein-Barr-Virus. Our cell-type deconvolution-based approach to developing a continuous metric for CLL epigenetic differentiation state can be applied to other tumors with multiple subtypes across differentiation stages.

B-memory-like↗

PubMed2005

The XPC poly-AT polymorphism in non-melanoma skin cancer.

Signature UV-DNA lesions, cyclobutane dimers and 6-4 photoproducts, are repaired via the nucleotide excision repair pathway. NER may be subdivided into transcription-coupled repair and global genome repair, and the XPC protein is specific to this latter repair pathway recognizing helix distorting lesions and initiating their repair. Inactivating XPC mutations are associated with xeroderma pigmentosa and an extremely high risk of skin cancer. A common polymorphism in intron 9 of the XPC gene has been associated with both reduced repair of UV-DNA damage (using the host-cell reactivation assay) and increased risk of squamous cell head and neck cancer. Here, we have tested the hypothesis that the XPC PAT+ polymorphism is associated with non-melanoma skin cancer using a population-based case control study of skin cancer in New Hampshire (n=1917). Overall, there was a modest decreased risk of squamous cell carcinoma (SCC) among those with the homozygous variant PAT+/+ genotype (OR 0.8, 95% CI 0.5-1.1) that was most evident among tanners (OR 0.4, 95% CI 0.1-1.1), however, these trends failed to reach statistical significance. There was no association of the PAT+/+ genotype and basal cell carcinoma (OR 1.0, 95% CO 0.7-1.3), however there was a modest, non-statistically significant, decreased risk among those with the heterozygous genotype (OR 0.8, 95% CI 0.7-1.1). We did not detect gene environment interactions for either SCC or BCC between the XPC PAT genotype and average hours of UV exposure per week, painful sunburn history, nor ionizing radiation therapy. These results suggest that the XPC PAT+polymorphism does not play a major role in non-melanoma skin cancer, but that it may slightly modify the risk of SCC among individuals with a phenotype which results in low UV-DNA adduct burdens. These results require further confirmation.

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