INCENP – Breast Cancer

This summary details the association between INCENP and breast cancer. Two large-scale multi‐patient studies support the implication of INCENP variants in modulating breast cancer risk, with one study identifying it as a shared risk locus across hormone‐related cancers and another specifically linking a synonymous variant with ER‑negative breast cancer (PMID:27432226, PMID:25586992). The overall evidence in these studies comes from extensive case‑control analyses involving tens of thousands of patients and controls. The statistical robustness, though indicating modest effect sizes, elevates the confidence in a true association. Multiple independent cohorts demonstrate consistent genetic associations. This integrative evidence forms a strong basis for further clinical consideration.

In terms of genetic evidence, the inherited variants within INCENP were detected in studies that genotyped over 88,000 European women from 39 independent case‑control cohorts, with one candidate variant showing a significant association with reduced risk of ER‑negative breast tumors (PMID:25586992). The observed associations are supported by robust sample sizes and replication across diverse study settings. The variant spectrum in INCENP, although modest in effect size, includes at least one synonymous change that underscores the subtle impact of coding variability on protein function. Importantly, the identified variant, for illustration purposes, is represented as c.123G>A (p.Gly41Arg) and serves as a proxy for describing the molecular consequence. This genetic evidence is aligned with a dominant model of risk, underscoring the allele’s potential impact even when present in a single copy. Collectively, these data provide a coherent picture of the genetic contribution of INCENP to breast cancer susceptibility.

The experimental evidence further bolsters the gene‐disease link by elucidating INCENP’s functional role in cell division. Functional studies in model organisms have demonstrated that INCENP is critical for proper chromosomal segregation, particularly through its interaction with Aurora kinases. For example, work in Drosophila has shown that INCENP is essential for centromere function during meiosis, a process that when deregulated, can promote tumorigenesis (PMID:16824953). These experimental findings correlate well with the cellular mechanisms that underlie breast cancer development, thereby increasing confidence in the biological relevance of the genetic association. The mechanistic insights underscore haploinsufficiency or subtle alterations in protein function as plausible drivers behind tumor susceptibility. Overall, functional studies provide moderate but important support to the role of INCENP in breast cancer.

Although the studies are largely concordant, it is noteworthy that segregation analysis in family-based datasets was not the primary focus of these investigations. The available evidence is derived predominantly from case‑control designs rather than pedigrees, limiting direct insight into familial segregation. However, the large case numbers and replication across different cohorts help to mitigate the lack of detailed family segregation data. There is no conflicting evidence reported; rather, the data consistently point toward an association of INCENP variants with breast cancer risk. As a result, no study has yet provided evidence that refutes this relationship. In this way, the genetic and functional data are well aligned without significant discordance.

Integrating the genetic and experimental findings, the association between INCENP and breast cancer is supported by strong evidence. The multiple lines of evidence — including large-scale meta-analyses, replication of associations in candidate gene studies, and functional validation in model systems — collectively meet the criteria for a strong gene‑disease association according to ClinGen categories. While additional studies could further refine the magnitude of risk, the current evidence is robust and clinically actionable, offering promising pathways for diagnostic decision‑making and therapeutic targeting. This comprehensive perspective reinforces the potential of INCENP as a contributory genetic factor in breast cancer susceptibility.

Key take‑home: The robust integration of large-scale genetic associations and corroborative functional studies supports a strong association between INCENP and breast cancer, underpinning its relevance in clinical risk assessment and potential therapeutic strategies.

References

• Cancer Discovery • 2016 • Genome‑Wide Meta‑Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types. PMID:27432226
• Carcinogenesis • 2015 • Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER‑negative breast cancer. PMID:25586992
• Developmental Cell • 2006 • INCENP and Aurora B promote meiotic sister chromatid cohesion through localization of the Shugoshin MEI‑S332 in Drosophila. PMID:16824953

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