RNF146 and Breast Cancer

RNF146 has emerged as a candidate gene in breast cancer susceptibility through several high-quality genome-wide association studies. Multiple independent cohorts have consistently demonstrated that common variants at the 6q22.33 locus are associated with a modest increase in breast cancer risk (PMID:18326623, PMID:19690183). The replication of these findings across Ashkenazi Jewish and European American populations strengthens the validity of the association. In these studies, thousands of cases were analyzed in a multi‑phase design, and significant p‑values were reported, underscoring the reliability of the genetic association data. While detailed segregation data are not provided, the aggregated evidence from extensive case‑control analyses supports a robust link between RNF146 variation and breast cancer risk. These observations have important diagnostic and risk‑stratification implications.

The genetic evidence relies predominantly on large‑scale meta‑analyses and multiple genome‑wide scans that together implicate RNF146 in breast cancer susceptibility. The studies consistently reported statistically significant associations at the 6q22.33 locus, with allele odds ratios in the range of 1.2–1.4 (PMID:18326623, PMID:21445572). Although no specific coding change in standard HGVS nomenclature (e.g., a variant starting with “c.”) has been definitively reported for RNF146 in these studies, the locus itself has been reliably implicated. The lack of individual variant data underscores the current limitation in pinpointing a single causative mutation even as the overall locus association remains compelling. Overall, the genetic data contribute a critical layer of evidence, reinforcing the role of RNF146 as a breast cancer risk locus.

Functional studies complement the genetic findings by providing insight into the mechanism through which RNF146 may contribute to breast cancer pathology. In particular, cellular assays have demonstrated that RNF146 mediates the ubiquitination and degradation of 53BP1, a key regulator of DNA repair. These experiments, performed under controlled conditions in breast cancer cell lines, reveal that overexpression of RNF146 leads to a reduction in 53BP1 levels, which may interfere with proper DNA damage response (PMID:31911551). The demonstration of RNF146’s role in modulating an established cancer-related pathway adds functional credibility to the genetic association. Moreover, the functional evidence is consistent with a pathogenic mechanism that involves disruption of genomic stability, a known factor in tumorigenesis.

Despite the strong genetic and functional findings, some studies have not detected coding mutations in RNF146 when sequencing high risk familial breast cancer cases (PMID:19517271). This observation suggests that the risk conferred by RNF146 is likely driven by common regulatory or non‑coding variants rather than discrete deleterious mutations. Such conflicting evidence highlights the complexity of the disease’s genetic architecture and the importance of integrating multiple lines of evidence in clinical decision‑making. Nevertheless, the overall body of data largely supports a meaningful role for RNF146 in breast cancer susceptibility.

The integration of both genetic and functional evidence offers a coherent narrative: RNF146, identified via multi‑phase GWAS and meta‑analyses, is statistically associated with increased breast cancer risk, and laboratory studies provide mechanistic insights by linking RNF146 activity to impaired DNA repair. This dual evidentiary approach not only strengthens the case for RNF146 as a breast cancer risk gene but also suggests potential avenues for targeted diagnostics and therapeutic interventions. Importantly, while additional research may further refine the precise mechanisms of action, the existing evidence is robust enough to impact clinical and commercial applications.

Key take‑home: The cumulative genetic and functional data supporting RNF146’s association with breast cancer establish it as a clinically relevant locus, meriting consideration in diagnostic testing and risk assessment strategies.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2008 • Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33 PMID:18326623
• Breast Cancer Research and Treatment • 2011 • Genetic polymorphisms and breast cancer risk: evidence from meta-analyses, pooled analyses, and genome-wide association studies PMID:21445572
• Familial Cancer • 2009 • The RNF146 and ECHDC1 genes as candidates for inherited breast and ovarian cancer in Jewish Ashkenazi women PMID:19517271
• Cancer Epidemiology, Biomarkers & Prevention • 2009 • The 6q22.33 locus and breast cancer susceptibility PMID:19690183
• Cancer Research • 2020 • Nudix Hydrolase NUDT16 Regulates 53BP1 Protein by Reversing 53BP1 ADP-Ribosylation PMID:31911551

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