ECHDC1 – Breast Cancer

The association between ECHDC1 (HGNC:21489) and breast cancer (MONDO_0007254) was initially identified in a three‐phase genome‑wide association study of Ashkenazi Jewish individuals, where a risk locus on chromosome 6q22.33 was significantly associated with disease (p = 2.9 x 10(-8) [PMID:18326623]). This signal, which encompassed candidate genes including ECHDC1, suggested an allelic contribution to breast cancer predisposition in this population.

A follow‑up study directly screened the coding regions of ECHDC1 in a cohort of 105 high‑risk individuals, identifying an intronic sequence alteration in 4 probands ([PMID:19517271]). Although these findings hint at a potential role for non‑coding variation in modulating risk, the absence of robust segregation data and recurrent pathogenic coding variants limits the strength of the genetic evidence.

The inheritance pattern in familial breast cancer is generally autosomal dominant. However, in the context of ECHDC1, the current evidence does not show clear segregation of variants with disease, as no additional affected relatives have been documented to carry the alteration.

Functional data directly linking ECHDC1 to breast cancer are lacking. While separate functional studies have investigated ECHDC1 in metabolic contexts (e.g., its role in ethylmalonic aciduria; [PMID:33973257]), such results are not directly applicable to breast cancer pathology. This represents a significant gap in our understanding of the gene’s pathogenic mechanism in breast cancer.

In summary, the genetic evidence for ECHDC1 in breast cancer is limited. Although genome‑wide significance was achieved in the initial association study and an intronic alteration was reported in familial cases, the lack of clear segregation and functional validation precludes a definitive conclusion. Further targeted functional assays and rigorous segregation analyses are needed to clarify ECHDC1’s contribution to breast cancer risk.

Key Take‑home: Current evidence suggests a potential but limited role for ECHDC1 in breast cancer susceptibility, underscoring the need for further studies to validate its clinical utility.

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
• Familial cancer • 2009 • The RNF146 and ECHDC1 genes as candidates for inherited breast and ovarian cancer in Jewish Ashkenazi women PMID:19517271

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