Evolutionary dynamics of BRCA1 alterations in breast tumorigenesis

Abstract

Cancer results from the accumulation of alterations in oncogenes and tumor suppressor genes. Tumor suppressors are classically defined as genes which contribute to tumorigenesis if their function is lost. Genetic or epigenetic alterations inactivating such genes may arise during somatic cell divisions or alternatively may be inherited from a parent. One notable exception to this rule is the BRCA1 tumor suppressor that predisposes to hereditary breast cancer when lost. Genetic alterations of this gene are hardly ever observed in sporadic breast cancer, while individuals harboring a germline mutation readily accumulate a second alteration inactivating the remaining allele--a finding which represents a conundrum in cancer genetics. In this paper, we present a novel mathematical framework of sporadic and hereditary breast tumorigenesis. We study the dynamics of genetic alterations driving breast tumorigenesis and explore those scenarios which can explain the absence of somatic BRCA1 alterations while replicating all other disease statistics. Our results support the existence of a heterozygous phenotype of BRCA1 and suggest that the loss of one BRCA1 allele may suppress the fitness advantage caused by the inactivation of other tumor suppressor genes. This paper contributes to the mathematical investigation of breast tumorigenesis.