Breast cancer (BC) is the preponderant malignancy among women worldwide and exacts the highest annual toll of cancer deaths in Chile (15.7/100,000 women). Unfortunately, national incidence is climbing in both younger and older populations [1]. Risk factors include gender, age, hormonal factors, and, most significantly, family history. Although genetic predisposition plays an important role in the etiology of this disease, the major susceptibility genes BRCA1 and BRCA2 only account for about 16% of diagnoses. Moderate- and low-penetrance genes are likely responsible for a significant percentage of familial BC in BRCA1/2-negative families. Many new hereditary BC (HBC) susceptibility genes were discovered between 2012 and 2015. However, all known BC susceptibility genes account for about half of hereditary BRCA1/2-negative BC cases, leaving much of the genetic risk unexplained.

Cancer is fundamentally a genomic disease. While numerous somatic mutations accumulate during tumorigenesis, the majority of these variants are neutral “passenger” mutations. Those variations that do contribute to tumorigenesis are known as “driver” mutations [2]. A tumor typically contains 2–8 driver mutations that initiate carcinogenesis [3,4,5]. The driver mutations and mutational processes operative in BC have not yet been comprehensively defined [6].

Several studies have used next-generation sequencing (NGS) to identify potential driver mutations [6,7,8,9]. Various relevant genes have been identified in sporadic breast tumors: ARID1B, CASP8, MAP3K1, MAP3K13, NCOR1, SAMRCD1, CDKN1B, AKT2, and TBX3. However, there has been scant research into the possibility that these driver genes contain inherited variants that influence the development of cancer [10]. In one of these few studies, Göhler et al. [10] investigated whether known driver genes contain heritable variants that influence risk and/or survival in Swedish BC patients. That group evaluated selected single-nucleotide polymorphisms (SNPs) located in 15 genes that have consistently been classified as BC driver genes by NGS. Five genes were associated with BC risk: TBX3 (rs2242442) was associated with decreased risk; TTN (10497520) and MAP3K1 (rs702688 and rs72758040) were associated with increased risk; MLL2 (rs11168827) was associated with increased overall risk, positive hormone receptor status, and low-grade tumors; and SF3B1 (rs4688) had a protective effect and was associated with negative lymph node findings, metastasis, and hormone receptor status [11]. Considering that variations in these novel driver genes had not been assessed in any Latin American population, our group performed an association study on germline variations in BC driver genes in a Chilean population. We evaluated associations between SNPs in the driver genes TTN (rs10497520), TBX3 (rs2242442), MLL2 (rs11168827), and MAP3K1 (rs702688 and rs702689) with BC risk in BRCA1/2-negative Chilean families. The results did not support an association between rs702688:A > G (MAP3K1) or rs702689:G > A (MAP3K1) and risk. The rs10497520 (TTN) T allele was associated with decreased risk in patients with a family history of BC or early-onset BC (OR = 0.6, p < 0.0001 and OR = 0.7, p = 0.05, respectively), and rs2242442-G (TBX3) also demonstrated a protective effect (OR = 0.6, p = 0.02). On the other hand, rs11168827-C (MLL2) was linked to increased risk in families with a strong history of BC (OR = 1.4, p = 0.05) [12].

The SF3B1 gene encodes subunit 1 of the splicing factor 3b protein complex. Several studies have identified SF3B1 mutations in solid tumors, including 9.7% of uveal melanomas, 4% of pancreatic cancers, and 1.8% of BC [13]. The T-box 3 gene (TBX3) is a member of the T-box gene family. Functional analysis has shown that T-box family members are transcription factors with a highly-conserved DNA binding domain known as the T-box and a nuclear localization signal. These proteins can activate and/or repress target genes by binding to T-elements [14]. TBX3 is a critical developmental regulator of several structures but has no known function in adult tissue. Nevertheless, TBX3 is frequently overexpressed in several cancers, such as colon cancer, hepatocarcinoma, melanoma, chondrosarcoma, and BC. The identification of TBX3 mutations in breast tumors samples suggests that TBX3 is a driver gene in BC [15]. The protein MAP3K1, on the other hand, acts within the MAP-signaling pathway, which triggers expression of genes important for angiogenesis, proliferation, and cell migration [6]. Moreover, there is evidence to suggest that MAP3K1 is a potential driver gene in BC [6]. On the other hand, post-translational modifications of TBX3 include phosphorylation of 29 sites in which some MAP kinase proteins are involved. Therefore, it is very important to determine whether inherited genetic variants in SF3B1, TBX3, and MAP3K1 genes affect BC risk.

The present study evaluates the association between specific SNPs and SNP-SNP interactions in the driver genes SF3B1, TBX3, and MAP3K1 with familial and early-onset sporadic BC, studying cases and controls from Chilean families who are negative for BRCA1/2 point mutations. A case–control design was used to explore the relationship between BC susceptibility and the following SNPs: rs4685 (SF3B1), rs12366395 (TBX3), rs72758040 (MAP3K1), rs8853 (TBX3), and rs1061651 (TBX3). Moreover, we assessed the SNP-SNP interaction for rs12366395 and rs72758040 to evaluate their combined effect on BC risk. The SNPs selected in this study were chosen based on their genetic location and their possible consequence within the gene. In addition, it is important to replicate the previous association studies of these SNPs in other populations in order to confirm their effect on BC risk.