This association study globally showed that the two independent SNPs, rs13281615 and rs6983267, which modulate the risk of breast and colorectal cancer respectively, have no major influence on the development of distant metastases in colon cancer. However, it unexpectedly revealed that the rs6983267 genotype strongly influences the metastatic risk of an aggressive form of breast cancer, namely inflammatory breast cancer. Because the metastatic risk was found comparable for patients of GT and GG genotypes, the G allele is likely to play a dominant role over the T allele. The absence of the G allele reduced the metastatic risk to a level similar to that of non-IBCs patients. The presence of the G allele in a context of inflammatory tumor might thus potentiate a specific metastatic mechanism that would superimpose to the « standard » metastatic risk of breast cancer. With an odd ratio of 8.3 (CI95: 2.6–33), the prognostic value of the G allele might add to the predictive value derived from the currently limited pre-therapeutic evaluation of IBC patients. It might be interesting to use this feature in prospective studies. For instance, the monitoring of the rs6983267 genotype of IBC patients would enable to focus the analysis on subgroups of patients with comparable risk for metastasis. Because genotypic studies can be done retrospectively, this approach might not only be applicable to future studies but also to past surveys.
The alleles of rs6983267 are known to differentially bind transcription regulating elements such TCF7L2/TCF4 
. The downstream activation of corresponding snpRNAs have also been involved in the phenotypic orientation of prostate cancer 
. We found the presence of a large chromatin-loop bringing the rs6983267 in the vicinity of MYC
in two IBC cell lines SUM149 and SUM190 (unpublished observations done in collaboration with Matthew Freedman) suggesting that the increased metastatic risk of inflammatory tumors might be promoted by a deregulation of the MYC
gene, as it was initially proposed for colon cancer 
. Because IBC is defined by the presence of tumor emboli within dermal lymphatic vessels and as it was recently shown that vessels inflammation could be regulated by beta-catenin-independent signaling pathway involving WNT5A and TNF alpha signaling 
, IBC specificity could be linked to WNT/TCF4/MYC pathway activation in inflammatory lymphatic vessels.
In conclusion, the rs6983267(G) allele, initially described as a low penetrance susceptibility locus for colorectal and prostate cancers, appears to be associated with a high risk for metastasis in inflammatory breast cancer. The implementation of new tools for tumor prognostication, presently based on the histo-clinical factors and somatic mutations, may benefit from the monitoring of specific germline variations of the IBC patients. To date, no candidate gene emerges from expression studies, but MYC
remains a good one as it is able to binds both alleles of rs6983267 through a large chromatin-loop in two IBC cell lines. Further functional studies have thus to delineate this physical link. Although IBC do not exhibit a specific expression profile, they tend to aggregate poor prognosis breast cancer clusters, being commonly of basal-like subtype, showing Her-2 amplification, EGFR overexpression and lacking estrogen and progesterone receptors. Variations in the NFKB1
genes expression linked to HER-2
expression levels might be interesting arguments to propose targeted therapies 
. Finally, other known cancer risk loci could be associated with metastatic risk in subgroups of cancer and new association studies may identify more susceptibility loci to metastasis.