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Non-Small Cell Lung Cancer Risk Variants Profiled in Han Chinese Population

NEW YORK – A team from Nanjing Medical University and other centers in China has untangled germline risk variants associated with non-small cell lung cancer (NSCLC) susceptibility in individuals of Han Chinese ancestry, using whole-genome sequencing on thousands of individuals with or without lung cancer.

"These findings greatly broaden our understanding of the genetic etiology of lung cancer and will ultimately improve precise prevention of lung cancer," co-senior and co-corresponding authors Hongbing Shen and Zhibin Hu, researchers affiliated with Nanjing Medical University, and their colleagues wrote in Cancer Cell on Thursday.

The researchers tapped into the Nanjing Lung Cancer Cohort (NJLCC) to perform whole-genome sequencing on nearly 3,000 NSCLC patients and more than 3,000 unaffected controls. Together with available array-based SNP genotyping profiles for more than 23,000 NJLCC participants, the sequence data made it possible to put together a haplotype reference panel for finding and interpreting common, low-frequency, and rare germline variants linked to NSCLC risk in individuals with Han Chinese ancestry.

The reference panel was constructed with 6,040 Chinese haplotypes, including more than 34 million single-nucleotide variants and almost 4 million small insertions and deletions, and yielded "substantial improvement for imputation in the Chinese population," the authors noted.

With the help of this reference panel, the team performed single-variant analyses for tracking down new and known lung cancer risk variants in the common to low-frequency range. In addition, gene- or gene region-based analyses led to rare NSCLC-related variants in coding or regulatory regions of genes implicated in the risk of other cancer types. Such associations were verified with testing on another 4,410 NSCLC cases and controls and in an independent prospective cohort that encompassed almost 24,000 individuals with or without NSCLC.

With directly assessed and imputed variant data, the team focused in on 20 common or low-frequency risk variants with apparent ties to NSCLC in the Chinese participants. Five of those variants had not been linked to NSCLC susceptibility in the past.

That prompted a series of follow-up functional analyses, including regulatory clues drawn from chromatin immunoprecipitation sequencing or DNase-seq data. In addition, the researchers gained expression quantitative trait locus insights informed by genotyping and gene expression data from the Genotype-Tissue Expression project and for 116 matched normal samples for Chinese individuals with NSCLC.

On the rare variant side, meanwhile, the researchers found 183 recurrent NSCLC-related, loss-of-function (LOF) variants falling in 19 genes. While just two of those variants had been tied to lung cancer in the past, dozens had been linked to other cancer types or cancer risk syndromes, the researchers noted.

The rare variant results highlighted relationships between NSCLC risk and alterations affecting genes spanning half a dozen DNA damage response (DDR) pathways, including mutations in protein-coding portions of the breast and ovarian cancer-related gene BRCA2 and regulatory sequences and rare enhancer variants impacting a DDR network that involves the Fanconi anemia core complex-associated protein 100 (FAAP100).

"We demonstrate that LOF variants damaging BRCA2 or DDR pathways significantly increase the risk of NSCLC," the authors reported. "Beyond coding variants, our findings provide evidence that non-coding variants of DDR genes, such as promoter variants of BRCA2 and enhancer variants of FAAP100, can confer strong effects on risk of NSCLC."