Individuals carrying a rare pathogenic variant in one of 16 cancer-associated genes were 1.9 times more likely to develop a single cancer and 2.6 times more likely to develop multiple primary cancers, according to the results of a genetic association study published in JAMA Oncology.
These findings highlight a greater need for gene panel testing among patients with multiple primary cancer diagnoses.
“As more patients survive their first cancer, we’re learning that many carry inherited genetic mutations that put them at risk for developing additional cancers,” said senior study author Kathleen Cooney, MD, George Barth Geller Distinguished Professor of Medicine and Chair in the Department of Medicine at Duke University School of Medicine. “Knowing this opens the door to earlier screening, more personalized treatment, and the chance to protect family members through genetic testing.”
Study Methods and Rationale
Previous explorations of rare pathogenic variants and cancer risk have been attained from family-based studies, which may have provided a degree of selection bias or limited sample sizes, explained the study authors. They wanted to look at these associations in a larger population-based study.
The researchers conducted a genetic association study in an unselected population of 183,627 participants from the United Kingdom. All participants were between the ages of 40 and 69 years at enrollment and had released whole-exome sequencing data of 200,000 genomes to the UK Biobank. The study only looked at White participants, as the proportions of patients belonging to other racial and ethnic groups were too small.
The team sequenced a set of 96 previously implicated cancer predisposition genes across 11 common solid tumors (bladder, breast, central nervous system, colorectal, lung, melanoma, ovarian, pancreatic, prostate, renal, and thyroid) and compared the results across two methods.
Key Study Findings
Of the participants, 25,824 individuals received at least one cancer diagnosis by March 2024; 91.8% of these were single-cancer diagnoses and 8.2% were two or more cancer diagnoses.
The median age was 57 (interquartile range [IQR] = 50–63 years) in participants who did not develop cancer vs 62 years (IQR = 56–65 years) in those with at least one cancer diagnosis.
Genetic variants from 16 genes (including ATM, BARD1, BRCA1, BRCA2, BRIP1, CDKN2A, CHEK2, HOXB13, MITF, MLH1, MSH2, MSH6, NF1, PALB2, RAD51C, and RAD51D) were considered significantly associated with at least one cancer of interest, which built upon established associations seen in prior research. The presence of a rare pathogenic variant among these genes was associated a greater risk for having at least one cancer diagnosis (odds ratio [OR] = 1.87; 95% confidence interval [CI] = 1.76–1.98) and for having multiple primary cancers (OR = 2.56; 95% CI = 2.18–2.99).
The study also confirmed that there are associations between BRCA2 and the development of bladder and lung cancers, which have not commonly been linked with this gene.
Carrier rates for rare pathogenic variants were 6.28% among individuals with at least one cancer diagnosis and 8.36% for individuals with multiple cancer diagnoses.
“We’ve now implicated some potential cancers that patients may be at risk for, which is different than what we’re seeing during family-based studies,” said first study author Jeffrey Shevach, MD, Assistant Professor in the Department of Medicine at Duke University School of Medicine, clarifying that population-based studies can help refine risk estimates raised in family-based studies. “As we uncover new gene-cancer associations, it may lead to changes in screening guidelines to reflect this broader understanding of inherited risk.”
Disclosure: Research was funded by the National Institutes of Health. For full disclosures of the study authors, visit jamanetwork.com.