In a UK retrospective cohort study reported in The Lancet Oncology, Whitworth et al analyzed the frequency of germline genetic variants in patients with cancer in the 100,000 Genomes Project.
Study Details
The study included data from 14,765 individuals with cancer entered into the 100,000 Genomes Project between November 2016 and February 2020. A total of 109 cancer predisposition genes were curated to include those for which pathogenic variants were consistent with neoplasia as a primary presenting feature.
Key Findings
Among the 14,765 patients with cancer, 56% were female; the ancestry designation was European in 90%; the most common cancer types were breast (20%), colorectal (18%), and lung (10%); and mean age at diagnosis was 62.9 years.
In total, 711 participants (5%) were found to have a cancer predisposition gene variant assessed as pathogenic or likely pathogenic, with a total of 727 pathogenic or likely pathogenic variants identified. The genes with the most frequently detected pathogenic or likely pathogenic variants were CHEK2 (121 participants, 0.82%, 10 unique variants), BRCA2 (110 participants, 0.75%, 80 unique variants), ATM (49 participants, 0.33%, 39 unique variants), BRCA1 (42 participants, 0.28%, 33 unique variants), and PALB2 (36 participants, 0.24%, 23 unique variants).
Of the 727 pathogenic or likely pathogenic variants identified, 326 (45%) were observed in individuals diagnosed with a cancer consistent with the predisposition profile, with proportions varying among genes. For a total of 395 variants (54%), no such association was found between the tumor and the affected gene. Among tumor types for which there were > 50 diagnoses, ovarian cancer had the highest proportion of cases associated with variants (53 [9%] of 610 cases).
The investigators concluded, “Understanding the frequency and nature of variants in cancer predisposition genes is important for planning of clinical services. Our analysis highlights the implications of more expansive genetic testing and the variant interpretation considerations necessary to yield benefit and avoid harm (eg, unnecessary surveillance) for patients.”
James Whitworth, PhD, of the Department of Genomic Medicine, University of Cambridge, Cambridge Biomedical Campus, is the corresponding author for The Lancet Oncology article.
DISCLOSURE: The study was funded by the UK National Institute for Health and Care Research Cambridge Biomedical Research Centre. For full disclosures of the study authors, visit thelancet.com.
