Homologous Recombination Defects Prevalent in African-American Cancer Patients

Lung cancer, the second most common cancer in the USA and the leading cause of cancer-related death, has persistent disparities in both incidence and mortality African-Americans have the highest lung cancer incidence and mortality rates compared with other racial or ethnic groups.

Scientists from the National Cancer Institute (Bethesda, MD, USA) and their associates 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.

DNA was extracted from fresh, frozen micro-dissected primary lung tumor tissues using the Qiagen DNeasy Blood and Tissue kit spin column procedure (Qiagen, Hilden, Germany). Isolated primary lung tumor DNA was initially quantified using a DS-11 spectrophotometer (DeNovix, Wilmington, DE, USA). Subsequent Qubit fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) analyses were performed to assess DNA integrity and ensure the presence of intact double-stranded DNA in all samples.

The team estimated the tumors' genomic instability by determining the portion of their genomes that harbored a non-diploid copy number. They found that lung squamous cell carcinomas from African-Americans 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.

The team 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. 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.

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 scientists noted, they have been shown in some studies to be effective in combination with chemotherapy. The study was published on January 13, 2020 in the journal Nature Cancer.

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National Cancer Institute
Qiagen
DeNovix
Thermo Fisher Scientific