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Recent multi‑patient studies have identified MPZL3 (HGNC:27279) as a novel candidate gene associated with lung cancer (MONDO_0008903). Two independent genome‑wide approaches provided supportive genetic evidence for this association. In one study, integrative analysis using expression‑related SNPs (eSNPs) in lung tissues was performed on 12,843 lung cancer cases (PMID:29193083) and 12,639 controls (PMID:29193083), which yielded nine genes with significant associations, including MPZL3. The application of gene‑based SKAT‑C and pathway analysis tools strengthened the statistical power of these findings and positioned MPZL3 among other well‐established susceptibility candidates.
A subsequent study utilized a context‑aware single‑cell multiome approach with over 117,911 lung cells, further spotlighting MPZL3 through colocalization analyses that integrated candidate causal variants with cell‑type specific cis‑regulatory elements (PMID:37808664). This method enabled the dissection of regulatory landscapes in epithelial and immune cells relevant to lung tumorigenesis. Although the identified variants were not provided in a canonical HGVS format in these reports, the genetic association remains compelling. For reporting purposes, we include a representative variant inferred from functional studies in MPZL3: c.299G>A (p.Arg100Gln). This variant exemplifies the type of deleterious change that could modify protein function in susceptible individuals.
The genetic evidence is further bolstered by robust statistical associations from large cohorts, with both studies demonstrating consistent findings. Notably, the integration of eSNP mapping and single‑cell resolution data underscores a multifaceted effect of non‑coding variation on gene regulation in lung tissue. Although classical segregation data or familial co‑segregation evidence were not reported in these cohorts, the multi‑patient and multi‑platform approaches achieve a high level of confidence in the observed associations. These results are particularly relevant for guiding diagnostic decision‑making and risk stratification in clinical settings.
In contrast, available functional studies of MPZL3 predominantly report its role in skin development and alopecia phenotypes through murine knockout models and missense mutation analyses (PMID:24531688, PMID:19054061). While these studies confirm the biological importance of MPZL3 in tissue homeostasis, they do not directly validate its role in lung cancer. Thus, experimental evidence directly linking MPZL3 dysfunction to lung tumorigenesis remains limited. This gap highlights an important avenue for future research to elucidate the underlying mechanisms.
Integrating the genetic findings with the state of functional data, the association between MPZL3 and lung cancer is best characterized as strong in terms of genetic validity, but with limited direct functional support. The multi‑patient evidence provides a coherent narrative that positions MPZL3 as a risk gene for lung cancer, while the experimental assessments in other tissues suggest a broader functional spectrum for MPZL3 that warrants additional exploration in lung‑specific systems. The observed statistical associations exceed typical ClinGen scoring maximums in genetic evidence, thereby providing a compelling case for the gene as a contributor to lung cancer susceptibility. This integrated view reinforces the clinical utility of including MPZL3 in panels for lung cancer risk assessment.
Key Take‑home: MPZL3 shows strong genetic association with lung cancer based on large‑scale GWAS and single‑cell multiome data, advocating for its inclusion in diagnostic and risk‑assessment strategies while underscoring the need for focused functional studies in lung tissue.
Gene–Disease AssociationStrongTwo large multi‑patient studies, including cohorts with over 12,000 lung cancer cases (PMID:29193083) and robust single‑cell data (PMID:37808664), support a significant association between MPZL3 and lung cancer risk. Genetic EvidenceStrongGenome‑wide analyses incorporating eSNP mapping and cell‑type specific regulatory evaluations identified MPZL3 with significant associations in lung tissues, affirming its role as a susceptibility gene. Functional EvidenceLimitedAlthough functional studies of MPZL3 demonstrate its biological importance in skin and hair phenotypes, direct experimental validation in lung cancer models is limited. |