Heterozygous germline pathogenic variants (PVs) in BRCA1/2 and mismatch repair (MMR) genes contribute to cancer risk in children and adolescents, but with a reduced penetrance compared with that in adults, a new study indicates.
Because of this lower penetrance, the findings do not warrant any changes in current genetic testing or surveillance, according to researchers. They reported these findings in the Journal of the National Cancer Institute.
“Genetic predisposition is a significant cause of cancer, yet little is known about the role of ‘adult cancer predisposition syndromes’ in childhood cancer,” the researchers wrote. “These conditions include BRCA1/2 or PALB2-associated hereditary breast and ovarian cancer (HBOC), susceptibility to breast cancer due to PVs in ATM or CHEK2, among others, and Lynch syndrome, caused by heterozygous PVs in one of the MMR genes.”
To examine the extent to which these variants might contribute to cancer risk in children and adolescents, the researchers conducted a meta-analysis of 11 studies that included comprehensive germline testing.
The researchers compared a cohort of 3975 children and adolescents with cancer to 2 cohorts of cancer-free control patients, consisting of 27,501 patients and 74,023 patients, respectively.
In the cancer cohort, 1.2% of patients carried a heterozygous PV in BRCA1/2 (0.7%) or an MMR gene (0.5%). This compared with 0.3% in the control group of 27,501 patients, in which 0.2% had a PV in BRCA1/2 and 0.1% had a PV in an MMR gene. In the control group of 74,023 patients, 0.6% had a PV in BRCA1/2 (0.4%) or an MMR gene (0.2%).
When comparing the cancer cohort and the control cohort of 27,501 patients, there was a significant association between cancer and PVs in BRCA1/2 (odds ratio [OR], 2.78; 95% CI, 1.69-4.45; P <.001) and in MMR genes (OR, 7.33; 95% CI, 3.64-14.82; P <.001).
When comparing the cancer cohort and the control cohort of 74,023 patients, there was a trend toward a significant association between cancer and PVs in BRCA1/2 (OR, 1.53; 95% CI, 0.99-2.28; P =.05), and there was a significant association between cancer and PVs in MMR genes (OR, 1.96; 95% CI, 1.15-3.15; P =.009).
The associations were most pronounced for brain tumors, followed by other solid tumors. No significant associations were seen for hematologic neoplasms.
In addition, no significant associations were seen for heterozygous germline PVs in ATM, CHEK2, or PALB2.
The researchers validated these results in a group of 1664 children and adolescents with cancer.
“Our results do not implicate changes in the current predictive testing practice, which is to defer predictive testing for heterozygous BRCA1/2 and the MMR gene variants
until adulthood,” the researchers concluded. “Cancer surveillance is not indicated in healthy children carrying PVs in BRCA1/2 or MMR genes.”
“PVs in BRCA1/2 or MMR genes may increase the risk of SNs [subsequent neoplasms] among childhood cancer survivors, and this risk may be further increased by genotoxic treatment elements such as radiation and alkylating agents.”
Kratz CP, Smirnov D, Autry R, et al. Heterozygous BRCA1/2 and mismatch repair gene pathogenic variants in children and adolescents with cancer. J Natl Cancer Inst. Published online August 18, 2022. doi:10.1093/jnci/djac151