Distinct inherited metastasis susceptibility exists for different breast cancer subtypes: a prognosis study.
BACKGROUND
Previous studies in mouse models and pilot epidemiology studies have demonstrated that inherited polymorphisms are associated with inherited risk of tumor progression and poor outcome in human breast cancer. To extend these studies and gain better understanding of the function of inherited polymorphism in breast cancer progression, a validation prognosis study was performed in a large independent breast cancer patient population.


METHODS
The study population consisted of 1863 Dutch patients with operable primary breast cancer from Rotterdam, The Netherlands. Genomic DNA was genotyped for the missense Pro436Leu RRP1B single nucleotide polymorphism (SNP) rs9306160 and the intronic SIPA1 SNP rs2448490 by SNP-specific PCR.


RESULTS
A significant association of variants in RRP1B with metastasis-free survival was observed (P = 0.012), validating the role of RRP1B with inherited metastatic susceptibility. Stratification of patients revealed that association with patients' survival was found to be specifically restricted to estrogen receptor positive, lymph node-negative (ER+/LN-) patients (P = 0.011). The specific association with metastasis-free survival only in ER+/LN- patients was replicated for SIPA1, a second metastasis susceptibility gene known to physically interact with RRP1B (P = 0.006). Combining the genotypes of these two genes resulted in the significant ability to discriminate patients with poor metastasis-free survival (HR: 0.40, 95% CI: 0.24 to 0.68, P = 0.001).


CONCLUSIONS
These results validate SIPA1 and RRP1B as metastasis susceptibility genes and suggest that genotyping assays may be a useful supplement to other clinical and molecular indicators of prognosis. The results also suggest that lymphatic and hematogeneous metastases are genetically distinct that may involve different mechanisms. If true, these results suggest that metastatic disease, like primary breast cancer, may be multiple diseases and that stratification of late stage patients may therefore be required to fully understand breast cancer progression and metastasis.
Hsieh
Szu-Min
SM
Laboratory of Cancer Biology and Genetics, NCI, NIH, Room 5046, 37 Convent Drive, Bethesda, Maryland 20892-4264, USA. hsiehsz@mail.nih.gov
Look
Maxime P
MP
Sieuwerts
Anieta M
AM
Foekens
John A
JA
Hunter
Kent W
KW
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011960:Receptors, Estrogen / Q000096:biosynthesis
D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C107468:RRP1 protein, human; D011960:Receptors, Estrogen; C490403:SIPA1 protein, human