P2-06-02: FOXO3a Genotype Predicts Age of Breast Cancer Onset and Correlates with Lymph Node Involvement.
Authors: Brouwers B , Lambrechts D , Hatse S , Dieudonné A-S , Remmerie C , Neven P , Smeets A , Paridaens R , Wildiers H 
Published: June 2012

Background: Ageing mechanisms and genetic traits underlying the aging process are intimately linked with mechanisms that protect against cancer. FOXO3a genotype might be an important clue in this regard, as single nucleotide polymorphisms in this gene have been related to longevity, but also to differences in cancer susceptibility. FOXO3a is thought to work as a cellular ‘switch', by either promoting apoptosis or halting proliferation and protecting from oxidative stress.

We have assessed FOXO3a genotype in a cohort of breast cancer patients to investigate possible associations with patient and/or breast tumor characteristics.

Patients and methods: Eligible subjects were all early breast cancer patients with upfront surgery, diagnosed at our center between 2000 till 2010, from which germline DNA (peripheral blood) was available. 2 SNP's in the FOXO3a gene, known to correlate with ageing or age associated diseases were assessed by Sequenom (rs 9400239 and rs 6911407).

Results: 2047 patients were included in the study. Age at diagnosis was found to be lower for patients homozygous for the minor allele at position rs6911407 (genotype A/A) (median age at diagnosis 52 years; P=0.001;95% C.I. 50.7−53.3). Patients homozygous for the wild type allele (genotype C/C) at this position had a median age at diagnosis 55.0 years; 95% C.I. 54.0−56.0. After correction for possible confounding variables BMI at diagnosis and parity, the association between age at diagnosis still remained significant (P=0.025, N=1348). We also assessed the relationship of the specific genotypes with tumor characteristics. We found that rs6911407 is positively correlated with lymph node status. This finding remains significant after correction for possible confounding variables ER, PR, Her-2, tumor size and tumor grade (OR=1.224 for homozygous mutants versus wild type; P=0.014;95% C.I. 1.042−1.437).

Conclusion: In our cohort of primary breast cancers, we found that patients homozygous for the minor allele at position rs 6911407 in the FOXO3a gene, develop breast cancer at younger age, and have more lymph node involvement compared to patients homozygous for the wild type allele. SNP's in nearly complete linkage disequilibrium with rs6911407 have previously been correlated with healthy longevity. At first sight, this seems contradictory with our current findings. However, our results are in accordance with the trade-off that has been described to exist between longevity and risk of cancer. It is generally assumed that FOXO3a and p53 function are oppositely controlled by common regulation systems, such that changes in FOXO activation would always be counterbalanced by an inverse change in p53 activation. If FOXO3a is strongly activated in order to protect against DNA damage (i.e. longevity function), p53-mediated cancer protection will concomitantly be diminished. This mechanism reconciles the apparent paradox between the longevity phenotype that has previously been linked with rs 6911407 on the one hand, and, on the other hand, our current findings of earlier breast cancer onset and increased lymph node metastasis. Further research on the function of FOXO3a in both aging and cancer is required to shed more light on the molecular mechanisms underlying these observations.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-06-02.