CDCA7L and Plasma Cell Myeloma

The association between CDCA7L and plasma cell myeloma is supported by robust evidence from large-scale multi‐ancestry association studies. Two independent meta-analyses demonstrated statistically significant associations with myeloma risk in cohorts comprising over 2,600 patients (PMID:27587788) and provided detailed epigenetic annotations that localize the risk signal to a regulatory cluster at the 3' end of the CDCA7L gene (PMID:35013207). These studies collectively strengthen the clinical relevance of CDCA7L in the genetic architecture of plasma cell myeloma.

The genetic evidence is further supported by extensive case-control data derived from both European and African ancestry populations. In these analyses, non-coding variants near CDCA7L consistently correlated with disease risk, indicating a possible modulatory effect on gene regulation. Although no single coding variant was definitively reported, the clustering of risk signals in an enhancer region underscores the significance of regulatory disruption. The multi-population design and replication of findings in these studies add to the robustness of the genetic association (PMID:27587788, PMID:35013207).

In terms of inheritance, the risk associated with CDCA7L appears to follow a pattern consistent with complex, typically autosomal dominant, susceptibility rather than a classic Mendelian model. While formal segregation analyses among affected families were not provided, the large sample sizes and cross-population consistency act as surrogate evidence for a dominant pattern of risk inheritance. This observation is in line with other loci identified in plasma cell myeloma where risk alleles act in an additive or dominant manner.

Functional studies have provided moderate support for the pathogenic role of dysregulated CDCA7L expression. Investigations that employed massively parallel reporter assays (MPRA) and chromatin accessibility QTL (caQTL) analyses in plasma cells have demonstrated that non-coding risk variants at the CDCA7L locus are capable of altering gene-regulatory activity (PMID:35013207). Complementary assays in yeast models, although conducted in a non-myeloma context, have revealed that modifications affecting enzymatic activity can have substantial downstream effects, which may be analogous to the regulatory disruptions observed in human cells (PMID:10491163, PMID:2124698).

No significant conflicting evidence has emerged to refute the association between CDCA7L and plasma cell myeloma. The convergence of genetic and functional data creates a coherent narrative: non-coding regulatory variants at the CDCA7L locus play a contributory role in disease susceptibility. Although a specific coding variant could not be identified for inclusion, the cumulative evidence reinforces the biological plausibility and clinical relevance of this association.

Key take‑home sentence: CDCA7L is robustly implicated in plasma cell myeloma susceptibility through both strong genetic associations and functionally validated regulatory mechanisms, supporting its potential use in diagnostic risk stratification.

References

• Cancer Epidemiol Biomarkers Prev • 2016 • A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci PMID:27587788
• Nature Communications • 2022 • Functional dissection of inherited non‑coding variation influencing multiple myeloma risk PMID:35013207
• European Journal of Biochemistry • 1999 • Active site determination of yeast geranylgeranyl protein transferase type I expressed in Escherichia coli PMID:10491163
• Proceedings of the National Academy of Sciences of the United States of America • 1990 • Mutants of Saccharomyces cerevisiae defective in the farnesylation of Ras proteins PMID:2124698

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