SNP variants at the MAP3K1/SETD9 locus 5q11.2 associate with somatic PIK3CA variants in breast cancers

Abstract

Genome-wide association studies have revealed many breast cancer (BC) risk-associated genetic variants that might functionally interact with other molecular determinants of BC. We analysed the association of 21 known risk-associated single-nucleotide variants (SNVs) with recurrent somatic variants in two cohorts of 77 and 754 oestrogen receptor α-positive BCs. Four SNVs located at 5q11.2 were found to be associated with the somatic PIK3CA variant status in the pilot cohort of 77 cases with odds ratio (OR) up to 6.5 indicating strong effects, and were selected for the validation phase. Two of these SNVs, rs252913 and rs331499, located in the MAP3K1/SETD9 gene boundary, were confirmed to be associated with somatic PIK3CA variants in the large cohort with OR 2.97 (1.17-7.75) and 1.76 (1.11-2.77), respectively, notably higher than their BC risk-associated values, both around 1.1. In the presence of the SNV or of somatic PIK3CA variants, cancers express significantly elevated levels of MAP3K1 and SETD9, with synergy of SNV and PIK3CA variants in MAP3K1 gene overexpression, consistent with a preferential PIK3CA-dependent regulation of the variant alleles. European Journal of Human Genetics (2017) 25, 384-387; doi:10.1038/ejhg.2016.179; published online 28 December 2016 INTRODUCTIONLess than 10% of human breast cancers (BCs) show pronounced familiarity that can be explained by high penetrance germline variants, but sporadic BCs are also co-determined by low penetrance variants. 1-3 Genome-wide association studies in BC cohorts compared with the general population have identified almost a 100 singlenucleotide variants (SNVs) associated with BC with odds ratio (OR) below 1.2 for most single SNVs. 4,5 However, differently from high penetrance variants, how SNVs functionally increase BC risk is difficult to establish and mostly unknown.In sporadic BC, next-generation sequencing has revealed a mutational landscape characterised by a large number of somatic variants (SM), but few recurrently mutated genes: PIK3CA (25-35%), TP53 (20-30%), and to a lesser extent MAP3K1, GATA3 and CDH1, with a certain preference for specific BC (sub)types. 6-8 Recurrent somatic variants drive tumour progression, but little is known about what leads to the development of tumours carrying these variants. We reasoned that risk-associated genetic variants might modify driver gene penetrance, and investigated the issue by analysing the association of a small series of known BC risk-associated SNVs with the occurrence of SM in the frequently mutated genes PIK3CA, TP53 and MAP3K1. METHODSTwenty-one SNVs were selected (Supplementary Table S1): 11 from O'Brien et al., 9 rs889312, an expression quantitative trait locus (eQTL) SNV, 10,11 and three further SNVs in high linkage disequilibrium (LD) with the former all located at 5q11.2 (Supplementary Table S2), as well as seven further SNVs were selected from Rhie et al. 12 We preferred SNVs associated with oestrogen receptor α-positive (ER+) BC risk (often higher than for all BC) and close to coding sequenc...

Common genetic variation in the germline influences where and how tumors develop

“…Due to limited sample sizes, our study was better powered to detect associations with some tumor sites and cancer genes than others, and was underpowered to evaluate associations with mutated cancer genes within specific tumor types, a factor that other studies suggest will be important. For example, Puzone and Pfeffer reported germline SNPs associated with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit a (PIK3CA) mutation in estrogen receptor positive breast cancer, 10 whereas our cross-cancer screen did not identify PIK3CA associated loci, suggesting that some associations may only be observable in the correct disease context. Thus we expect that collection of additional data capturing both germline and somatic genotypes and exploration of different study designs will be needed to gain a complete picture of germline's contribution to cancer.…”

Germline Variants Impact Somatic Events during Tumorigenesis

“…In gastric cancer, several germline SNVs associatewith somatic alterations in SOS1and other genes in the PDGF and DNA mismatch repair pathways [50](Table 2). In a cohort of ER-positive breast cancer patients, GxM analysis found associations of two SNVs, rs252913and rs331499(5q11.2)withsomatic PIK3CAvariants(3q26.32) [51](Table 2), which results in MAP3K1gene overexpression. While PIK3CA mutations are frequent in breast cancer, clinical trials of agents targeting this mutationhave produced disappointing results [52].…”

<p>MAP3K1 rs889312 genotypes influence survival outcomes of Chinese gastric cancer patients who received adjuvant chemotherapy based on platinum and fluorouracil regimes</p>

“…SNP variants at the MAP3K1/SETD9 locus 5q11.2 were found to be associated with somatic PIK3CA variants in breast cancers. A direct association between both MAP3K1 and SETD9 overexpression and PIK3CA somatic mutation (SM) status were found 54. The bioinformatics analysis of MAP3K1 rs889312 indicated its potential link with the regulation of the expression of SETD9 in gastric tissue.…”

“…The MAPK finally regulates the effects of downstream signaling on multiple cancer genes 51,52. MAP3K1 rs889312 SNP was first identified in 2007 and confirmed as a susceptibility locus for breast cancer 53,54. The SNP rs889312 is located in the region containing the MAP3K1 gene.…”