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Updated: Jul 24, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Homologous recombination pathway gene variants identified by tumor-only sequencing assays in lung carcinoma patients
Ju-Yoon Yoon1,2, Jacquelyn J Roth1,3, Chase A Rushton3
1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Background:
The homologous recombination (HR) repair pathway plays a key role in double-stranded DNA break repair, and germline HR pathway gene variants are associated with increased risk of several cancers, including breast and ovarian cancer. HR deficiency is also a therapeutically targetable phenotype.
Methods:
Somatic (tumour-only) sequencing was performed on 1,109 cases of lung tumors, and the pathological data were reviewed to filter for lung primary carcinomas. Cases were filtered for variants (disease-associated or of uncertain significance) in 14 HR pathway genes, including BRCA1, BRCA2, and ATM. The clinical, pathological and molecular data were reviewed.
Results:
Sixty-one HR pathway gene variants in 56 patients with primary lung cancer were identified. Further filtering by variant allele fraction (VAF) of ≥30% identified 17 HR pathway gene variants in 17 patients. ATM gene variants were most the commonly identified (9/17), including two patients with c.7271T>G (p.V2424G), a variant in the germline that is associated with increased familial cancer risk. Four (4/17) patients had a family history of lung cancer, among which three patients had ATM gene variants suspected to be germline in origin. In three other patients with BRCA1/2 or PALB2 gene variants who had undergone germline testing, the variants were confirmed to be germline; lung cancer was the sentinel cancer in two of these patients with a BRCA1 or PALB2 variant.
Conclusions:
Genomic variants in the HR repair pathway identified in tumor-only sequencing and occurring at higher VAFs (i.e., ≥30%) may suggest a germline origin. Correlating with personal and family history, a subset of these variants is also suggested to be associated with familial cancer risks. Patient age, smoking history and driver mutation status are expected to be a poor screening tool in identifying these patients. Finally, the relative enrichment for ATM variants in our cohort suggests a possible association between ATM mutation and lung cancer risk.
Insights
Germline variants in homologous recombination (HR) repair genes, identified in lung tumors, may indicate familial cancer risk. ATM variants were most common, suggesting a link to lung cancer susceptibility.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The homologous recombination (HR) repair pathway is crucial for DNA double-strand break repair.
- Germline variants in HR pathway genes increase the risk of breast, ovarian, and other cancers.
- HR deficiency presents a therapeutically targetable phenotype in cancer.
Purpose of the Study:
- To identify homologous recombination (HR) pathway gene variants in primary lung cancer using tumor-only sequencing.
- To assess the potential germline origin and familial cancer risk associated with these variants.
Main Methods:
- Somatic sequencing of 1,109 lung tumors.
- Filtering for primary lung carcinomas and variants in 14 HR pathway genes (e.g., BRCA1, BRCA2, ATM).
- Review of clinical, pathological, and molecular data, with filtering for variants with variant allele fraction (VAF) ≥30%.
Main Results:
- Sixty-one HR pathway gene variants were found in 56 patients; 17 variants (in 17 patients) had VAF ≥30%.
- ATM variants were most frequent (9/17), including two with a known germline cancer risk variant.
- Four patients had a family history of lung cancer, with three having suspected germline ATM variants. BRCA1/2 and PALB2 variants were confirmed as germline in three patients.
Conclusions:
- High VAF HR pathway variants in tumor-only sequencing may indicate germline origin and familial cancer risk.
- ATM variants were enriched in this cohort, suggesting a potential association with lung cancer risk.
- Patient age, smoking history, and driver mutation status are poor indicators for identifying patients with these variants.
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