Genetic Ancestry Linked to Differences in Molecular Features

People of different ancestral backgrounds can have different DNA methylation, mRNA, and microRNA expression levels, which in turn may affect how cancer manifests in patients from different populations and influence how it is treated, a new study has found.

Using data from The Cancer Genome Atlas, researchers from the Broad Institute and elsewhere examined ancestry-mediated effects on normal and tumor tissue. As they reported in Cancer Cell on Monday, the scientists found tissue-specific differences associated with ancestry, some of which are related to cancer, such as increased FBXW7 mutations in patients of African ancestry, and decreased immune activity in bladder cancer among patients of East Asian ancestry.

"This comprehensive analysis of molecular features associated with ancestry across a range of tumor types has implications for both cancer and normal tissue, given the limited prior analyses available," the Broad's Rameen Beroukhim and his colleagues wrote in their paper.

The researchers determined the genetic ancestry of TCGA patients to generate a dataset of 8,836 individuals of primarily European, 669 individuals of primarily East Asian, and 651 individuals of primarily African ancestry as well as 41 people of Native or Latin American ancestry, 27 individuals of South Asian ancestry, and 454 individuals of admixed ancestry. The cohort included patients with 33 different cancer types.

Across cancers within their cohort, the researchers uncovered a number of somatic alterations that varied by ancestry. More TP53 mutations were found among patients of African ancestry, as compared to patients of European ancestry, while PIK3CA mutations were more common among patients of European ancestry, as compared to patients of African ancestry. But after correcting for cancer subtype, only increased FBXW7 mutations among patients of African ancestry remained significant. Data from other cohorts likewise supported this association.

They also noted differences at the individual cancer type level. Kidney clear-cell carcinoma cancers from African-ancestry patients lacked VHL and PBRM1 mutations, while East Asian-ancestry patients with bladder had higher levels of HRAS mutations and East Asian-ancestry patients with esophageal cancers had higher levels of NFE2L2 mutations. 

They further noted that chromosome 3p loss, which includes both the VHL and PBRM1 genes, was more common in kidney clear-cell carcinoma patients with European ancestry than those with African ancestry, indicating that genes are biallelically inactivated more often among European-ancestry patients. This suggested to the researchers that kidney clear-cell carcinomas without any mutations affecting VHL — which are more common among African-ancestry patients — may represent a different cancer subtype.

The researchers, meanwhile, also uncovered differences in DNA methylation among cancer patients of different genetic ancestries as well as differences in mRNA and miRNA expression. Some of these differences, they added, are shared by normal tissues.

Based on mRNA expression levels, the researchers noted that bladder cancers from East Asian-ancestry patients exhibited fewer immune infiltrates than such cancers from European-ancestry patients. A pathway-level analysis likewise found high activity of immune-linked features among European-ancestry patients. Additionally, as mRNA expression of CD274, the gene encoding PD-L1, was lower among East Asian-ancestry patients as compared to European and African-ancestry patients, the researchers suspected that this could mean East Asian patients may respond differently to immunotherapies.

"[These] differences between African, European, and East Asian groups in renal and bladder cancers suggest that ancestry should be taken into account when considering routes to disease and response to immunotherapies," the researchers wrote.

They further added that their findings underscore the need for better-characterized tumor samples from non-European ancestry patients.