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Understanding susceptibility to breast cancer metastasis: the genetic approach.

ABSTRACT: Metastasis is a complex phenotype that is not discrete, is polygenic, varies in range over the entire population and follows non-Mendelian inheritance. Recent evidence indicates that inherited susceptibility affects not only the development of the primary tumor, but is also an important factor in progression and metastasis. Since metastasis accounts for the majority of breast cancer deaths, identification and understanding of the genetic modifiers of metastasis underlies success of personalized therapy. Studies from our laboratory and others have now characterized several metastasis susceptibility factors. While an important step forward, these certainly do not describe the entire metastatic phenomenon and efforts continue to expand this knowledge. Here we review the complex metastatic process and current knowledge on the genetics of breast cancer metastasis, including germline polymorphisms that have been associated with the disease.

SUBMITTER: Shukla A

PROVIDER: S-EPMC4157690 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Understanding susceptibility to breast cancer metastasis: the genetic approach.

Shukla Anjali A Alsarraj Jude J Hunter Kent K

Breast cancer management 20140301 2

Metastasis is a complex phenotype that is not discrete, is polygenic, varies in range over the entire population and follows non-Mendelian inheritance. Recent evidence indicates that inherited susceptibility affects not only the development of the primary tumor, but is also an important factor in progression and metastasis. Since metastasis accounts for the majority of breast cancer deaths, identification and understanding of the genetic modifiers of metastasis underlies success of personalized ...[more]

PMID: 25214894

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Project description:IntroductionPrevious 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.MethodsThe 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.ResultsA 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).ConclusionsThese 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.

Dataset Information

Understanding susceptibility to breast cancer metastasis: the genetic approach.

Publications

Understanding susceptibility to breast cancer metastasis: the genetic approach.

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