Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk

Abstract

Breast cancer is the most common solid organ malignancy and the most frequent cause of cancer death among women worldwide. Previous research has yielded insights into its genetic etiology, but there remains a gap in the understanding of genetic factors that contribute to risk, and particularly in the biological mechanisms by which genetic variation modulates risk. The National Cancer Institute’s “Up for a Challenge” (U4C) competition provided an opportunity to further elucidate the genetic basis of the disease. Our group leveraged the seven datasets made available by the U4C organizers and data from the publicly available UK Biobank cohort to examine associations between imputed gene expression and breast cancer risk. In particular, we used reference datasets describing the breast tissue and whole blood transcriptomes to impute expression levels in breast cancer cases and controls. In trans-ethnic meta-analyses of U4C and UK Biobank data, we found significant associations between breast cancer risk and the expression of RCCD1 (joint p-value: 3.6x10-06) and DHODH (p-value: 7.1x10-06) in breast tissue, as well as a suggestive association for ANKLE1 (p-value: 9.3x10-05). Expression of RCCD1 in whole blood was also suggestively associated with disease risk (p-value: 1.2x10-05), as were expression of ACAP1 (p-value: 1.9x10-05) and LRRC25 (p-value: 5.2x10-05). While genome-wide association studies (GWAS) have implicated RCCD1 and ANKLE1 in breast cancer risk, they have not identified the remaining three genes. Among the genetic variants that contributed to the predicted expression of the five genes, we found 23 nominally (p-value < 0.05) associated with breast cancer risk, among which 15 are not in high linkage disequilibrium with risk variants previously identified by GWAS. In summary, we used a transcriptome-based approach to investigate the genetic underpinnings of breast carcinogenesis. This approach provided an avenue for deciphering the functional relevance of genes and genetic variants involved in breast cancer.

Exome sequencing and case–control analyses identify RCC1 as a candidate breast cancer susceptibility gene

“…[19][20][21] By contrast with low-penetrance variants at the RCCD1 locus, the RCC1 mutation described here is a truncating mutation. Consistent with a genetic predisposition, the mutation was mainly detected in familial cases, where it accounted for some 5% of the hitherto unexplained cases.…”

“…RCC1 has not previously been implicated in cancer risk, although a homolog of RCC1, RCCD1, is encoded near one of the breast cancer susceptibility loci identified through genome-wide association studies. [19][20][21] By contrast with low-penetrance variants at the RCCD1 locus, the RCC1 mutation described here is a truncating mutation. Owing to the absence of this mutation in controls, the effect size could not be determined but it is likely to be high.…”

Integrative analysis of rare variants and pathway information shows convergent results between immune pathways, drug targets and epilepsy genes

“…Recently, methods which use annotation/expression information to impute more risk genes have been actively developed for common variants [51][52][53] . These methods have been successfully used to prioritize risk genes, and elucidate biological pathways for schizophrenia, bipolar 24,54 and breast cancer 55 . gTADA might be the first tool using this approach for rare variants.…”

Cross-cancer pleiotropic associations with lung cancer risk in African Americans

“…Mutations within DHODH have been linked with Miller Syndrome, a recessive disorder characterized by malformations of the limbs and eyes, among other symptoms (54)(55)(56)(57). DHODH has also been investigated for a role in cancer, including melanoma (58) and acute myeloid leukemia (59) and decreased expression of DHODH was associated with breast cancer risk (60).…”