PKNOX1 and Plasma Cell Myeloma

PKNOX1 has emerged as a candidate gene associated with plasma cell myeloma, particularly in the context of bortezomib-induced peripheral neuropathy. Two independent genome-wide association studies (GWAS) have identified significant risk alleles in PKNOX1 that correlate with an increased likelihood of developing severe neuropathic pain in myeloma patients (PMID:27060151, PMID:37194045).

The genetic evidence includes a primary analysis in an exploratory cohort of 469 patients followed by replication in an independent group of 114 patients (PMID:27060151). In an additional study, targeted Sanger sequencing in 88 patients revealed that the homozygous state of the PKNOX1 risk SNP (rs2839629) is significantly enriched in individuals with painful neuropathy (PMID:37194045). Although the studies reported SNP identifiers rather than explicit HGVS-coded variants, these findings indicate a reproducible association between PKNOX1 and the observed neuropathic symptoms in plasma cell myeloma.

The mode of inheritance in these observations appears to be complex, attributable to common risk alleles in a multifactorial setting rather than a straightforward Mendelian pattern. As such, the contribution of PKNOX1 variants reflects a genetic predisposition modulated by other genetic and environmental factors. No family-based segregation analyses were reported, and no affected relatives have been specifically documented.

Functional evidence supporting this association is emerging. Expression quantitative trait loci (eQTL) analyses have demonstrated that the risk alleles (notably rs2839629) are correlated with altered PKNOX1 expression in peripheral nerve tissue, suggesting a potential mechanism for increased susceptibility to bortezomib-induced neurotoxicity. However, direct experimental studies linking PKNOX1 function to plasma cell myeloma pathogenesis remain limited.

In summary, the genetic findings from sizeable patient cohorts along with supportive eQTL data provide a moderate level of evidence for the involvement of PKNOX1 in plasma cell myeloma, especially regarding treatment-associated peripheral neuropathy. While robust familial segregation data and direct functional assays are lacking, the independent replication across studies reinforces PKNOX1 as a biomarker candidate.

This integrated data supports the clinical utility of PKNOX1 risk assessment as part of personalized treatment planning in plasma cell myeloma, ultimately informing decisions to mitigate bortezomib-induced neuropathy.

Key take‑home: PKNOX1 variants represent a promising biomarker for predicting treatment-related neuropathy in plasma cell myeloma, with potential for tailoring therapeutic approaches.

References

• Clinical cancer research • 2016 • A Genome‑Wide Association Study Identifies a Novel Locus for Bortezomib‑Induced Peripheral Neuropathy in European Patients with Multiple Myeloma PMID:27060151
• Biomarker research • 2023 • Bortezomib induced peripheral neuropathy and single nucleotide polymorphisms in PKNOX1 PMID:37194045

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