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AURKA – Breast Cancer Susceptibility

AURKA (HGNC:11393) has been evaluated as a low-penetrance breast cancer susceptibility gene through multiple population-based association studies. In a case–control series of 941 incident breast cancer cases and 830 controls, the c.91T>A (p.Phe31Ile) polymorphism showed an odds ratio (OR) of 1.54 (95% CI 0.96–2.47) for Ile/Ile homozygotes versus Phe/Phe homozygotes (n = 941) (PMID:15271853). A meta-analysis of 15 studies comprising 9,549 cancer cases and 8,326 controls confirmed an elevated risk for T+91A homozygotes across cancers (OR 1.40; 95% CI 1.22–1.59) and heterozygotes (OR 1.10; 95% CI 1.03–1.18) (PMID:15802297).

However, subsequent analyses failed to replicate this association in BRCA1/2 mutation carriers (HR 0.91; 95% CI 0.77–1.06) (PMID:17627006) and in British women with two primary breast cancers (OR 0.79; 95% CI 0.58–1.06) (PMID:16849685). The inconsistency across populations and modest effect sizes support a classification as a limited association rather than a Mendelian risk allele.

Functional assays demonstrate that the Ile31 variant has increased transforming activity in Rat1 cells, preferential amplification in tumors, altered binding to the ubiquitin-conjugating enzyme UBE2N, and promotes aneuploidy, consistent with a gain-of-function mechanism (PMID:12881723). These data provide moderate functional evidence but do not overcome the inconsistent epidemiology.

References

  • Carcinogenesis • 2004 • STK15 polymorphism and breast cancer risk in a population-based study. PMID:15271853
  • Carcinogenesis • 2005 • Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. PMID:15802297
  • Cancer Epidemiology, Biomarkers & Prevention • 2007 • AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 study. PMID:17627006
  • Journal of the National Cancer Institute • 2006 • Inconsistent association between the STK15 F31I genetic polymorphism and breast cancer risk. PMID:16849685
  • Nature Genetics • 2003 • Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. PMID:12881723

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Low-penetrance risk allele with modest ORs in case–control and meta-analyses, inconsistent replication across studies

Genetic Evidence

Limited

Association of AURKA c.91T>A (p.Phe31Ile) in 941 cases and 830 controls (OR 1.54) [PMID:15271853], meta-analysis of 9,549 cases (OR 1.40) [PMID:15802297]; failure to replicate in BRCA1/2 carriers and other cohorts

Functional Evidence

Moderate

Ile31 variant shows increased transforming ability, preferential amplification, altered UBE2N binding, and induces aneuploidy [PMID:12881723]