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Homologous Recombination Defects More Common in Tumors From African-American Cancer Patients

NEW YORK – Tumors from African-American patients are more likely to have homologous recombination deficiencies than tumors from European-American patients, a new study has found.

Researchers from the US National Cancer Institute profiled lung cancer samples from African-American and European-American individuals to find that certain lung tumors from African Americans exhibited a higher degree of genomic instability, which they traced to homologous recombination deficiency. In the US, African Americans have the highest incidence of cancer as well as the lowest survival rates across numerous cancer types, but particularly in lung cancer.

As they reported in Nature Cancer on Monday, the researchers also looked beyond lung cancer to find that other types of tumors from African Americans also have higher genomic instability due to an increased prevalence of germline pathogenic variants affecting homologous recombination genes. 

"This suggests an ancestry-associated disparity in deficiency of the homologous recombination pathway," NCI's Bríd Ryan and her colleagues wrote in their paper. They also noted that their findings suggest African-American cancer patients might be more likely to respond to certain treatment approaches.

The researchers generated and compared genome-wide copy number profiles for 222 non-small cell lung cancer samples obtained from 126 African-American and 96 European-American patients. They estimated the tumors' genomic instability by determining the portion of their genomes that harbored a non-diploid copy number. Lung squamous cell carcinomas from African Americans, they found, had higher genomic instability compared to those from European Americans.

They did not, however, uncover significantly higher genomic instability in lung adenocarcinomas from American Americans, as compared to European Americans.

Still, the researchers proposed that the higher level of genomic instability in lung squamous cell carcinomas could be due to a higher prevalence of homologous recombination deficiencies among patients of African descent. They confirmed this suspicion by measuring the loss of heterozygosity, telomere allelic imbalance, large-scale state transition, and a combination of those three features within the lung cancer samples.

The researchers then extended their analysis to 6,492 tumors from The Cancer Genome Atlas to find that tumors from African-American patients had a higher burden of genomic instability as well as of homologous recombination deficiencies. In particular, 11 of the 17 cancer types analyzed exhibited higher homologous recombination deficiency in African Americans. Additionally, a mutational signature associated with homologous recombination deficiency was more prevalent among these tumors.

To ascertain whether this effect was driven by germline or somatic mutations, the researchers examined the prevalence of pathogenic variants in homologous recombination genes in a TCGA database of 10,389 tumors. In both a pan-cancer analysis and a lung squamous cell carcinoma-specific one, they found that African-American patients had significantly higher germline homologous recombination deficiencies than European-American patients. Pan-cancer, they found pathogenic variants in BRCA2, PALB2, and BARD1, among other genes, to be enriched in African-American patients.

This suggested that pathogenic germline mutations contribute to genomic instability and homologous recombination deficiency among African Americans.

The findings also indicated a potential treatment approach, Ryan and her colleagues noted. Higher homologous recombination deficiency in lung squamous cell carcinoma and other cancers hints that these tumors could potentially respond to poly ADP ribose polymerase (PARP) inhibitors and that African-American patients in particular might be more likely to respond to PARP inhibitor treatments. While PARP inhibitors are not commonly used to treat lung cancer, the researchers noted, they have been shown in some studies to be effective in combination with chemotherapy.

They also wrote that most clinical trials do not report or are not powered to report differences in treatment response by ancestry group. Their findings underscore the need to include underrepresented populations in genomic research, they added.