The interplay between genes harboring single nucleotide polymorphisms (SNPs) is vital to better understand underlying contributions to the etiology of
breast cancer. Much attention has been paid to epistasis between nuclear genes or mutations in the mitochondrial genome. However, there is limited understanding about the epistatic effects of genetic variants in the nuclear and mitochondrial genomes jointly on
breast cancer. We tested the interaction of germline SNPs in the mitochondrial (mtSNPs) and nuclear (nuSNPs) genomes of female
breast cancer patients in The
Cancer Genome Atlas (TCGA) for association with morphological features extracted from
hematoxylin and
eosin (H&E)-stained pathology images. We identified 115 significant (q-value < 0.05) mito-nuclear interactions that increased nuclei size by as much as 12%. One interaction between nuSNP rs17320521 in an intron of the WSC Domain Containing 2 (WSCD2) gene and mtSNP rs869096886, a synonymous variant mapped to the mitochondrially-encoded
NADH dehydrogenase 4 (MT-ND4) gene, was confirmed in an independent
breast cancer data set from the Molecular Taxonomy of
Breast Cancer International Consortium (METABRIC). None of the 10 mito-nuclear interactions identified from non-diseased female breast tissues from the Genotype-Expression (GTEx) project resulted in an increase in nuclei size. Comparisons of gene expression data from the TCGA
breast cancer patients with the genotype homozygous for the minor alleles of the SNPs in WSCD2 and MT-ND4 versus the other genotypes revealed core transcriptional regulator interactions and an association with
insulin. Finally, a Cox proportional hazards ratio = 1.7 (C.I. 0.98-2.9, p-value = 0.042) and Kaplan-Meier plot suggest that the TCGA female
breast cancer patients with low gene expression of WSCD2 coupled with large nuclei have an increased risk of mortality. The intergenomic dependency between the two variants may constitute an inherent susceptibility of a more severe form of
breast cancer and points to genetic targets for further investigation of additional determinants of the disease.