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Family history fails to predict germline mutations in pediatric cancers
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Family history of cancer did not predict the presence of an underlying predisposition syndrome in a majority of pediatric patients with cancer, according to study results published in The New England Journal of Medicine.
Less than 10% of children with cancer harbored germline mutations in cancer-predisposing genes, according to the researchers.
James R. Downing
The occurrence and spectrum of predisposing mutations among children and adolescents with cancer remains largely unknown, according to study background. Greater knowledge of such mutations may improve the understanding of tumorigenesis, guide treatment options, and enable genetic counseling of patients and families.
Thus, James R. Downing, MD, president and CEO of St. Jude Children’s Research Hospital, and colleagues sought to observe the prevalence of germline mutations in cancer-predisposing genes in children, adolescents and young adults with cancer.
Downing and colleagues identified 1,120 patients with cancer aged younger than 20 years, on whom they performed whole genome sequencing (n = 595), whole exome sequencing (n = 456) or both (n = 69). Common cancer subtypes in the population included leukemia (52.5%), central nervous system tumors (21.9%) and neuroblastoma (8.9%).
They then analyzed the DNA sequences of 565 genes — including 60 genes associated with autosomal dominant cancer-predisposition syndromes — for the presence of germline mutations.
A panel of medical experts determined the pathogenicity of the mutations using cancer- and locus-specific genetic databases, medical literature, computational procedures and second hits identified in the tumor genome.
Researchers compared these data with whole exome sequencing data from two control cohorts:
966 cancer-free individuals from the 1,000 Genomes Project, and individuals from the National Database for Autism Research (515 persons with autism and 208 persons without autism).
Source: Healio.com
Researchers identified 633 nonsilent germline variants, which they classified as pathogenic (12%), probably pathogenic (3%), of uncertain significance (36%), probably benign (43%) and benign (6%). Of the 95 pathogenic or probably pathogenic variants, 54 were missence mutations, 14 nonsense mutations, 12 frameshift mutations, nine splice-site mutations, five copy-number alterations and one in-frame deletion.
The 95 variants deemed pathogenic or probably pathogenic occurred in 8.5% of the study cohort (n = 95), compared with 1.1% of persons included in the 1,000 Genomes Project and 0.6% of participants from the autism study.
Pathogenic or probably pathogenic variants occurred most frequently in patients with non-CNS solid tumors (16.7%) followed by those with CNS tumors (8.6%).
The most commonly mutated genes in affected patients included TP53 (n = 50), APC (n = 6), BRCA2 (n = 6), NF1 (n = 4), PMS2 (n = 4), RB1 (n = 3) and RUNX1 (n = 3).
Further, 18 additional patients had protein-truncating mutations in tumor-suppressor genes.
Among 58 patients with a predisposing mutation who had an available family history, 40% (n = 23) had a family history of cancer. Only 13 of these 23 patients (57%) had a history that was consistent with the underlying genetic syndrome, including eight patients with TP53 mutations and Li–Fraumenti syndrome, two patients with APC mutations and familiar adenomatous polyposis, two patients with BRAC2 mutations and hereditary breast and ovarian cancer, and one patient with PMS2 mutations and Lynch syndrome.
“This low frequency probably resulted from multiple factors, including incomplete information on family history, de novo mutations and incomplete penetrance,” Downing and colleagues wrote. “Furthermore, parents and other first- or second-degree relatives of our pediatric patients are often young, and cancer may not have developed yet. … Nonetheless, on the basis of these observations, family history cannot be the sole indication used to guide the provision of genetic testing.”
The researchers acknowledged several study limitations, including the exclusion of certain pediatric cancer subtypes. Further, the researchers did not study the parents of relatives of patients included in the cohort, which prevented them from studying whether variants were new or segregated with a cancer phenotype among family members.
“The germline mutations identified in this study may provide insights into the causes of cancer,” Downing and colleagues wrote. “Knowledge of their presence may influence clinical management by directing cancer care, enabling presymptomatic genetic testing of relatives, guiding family-planning measures and facilitating the institution of potentially lifesaving measures for cancer prevention and surveillance.”
Although these data suggest family history alone should not be used to predict the likelihood of harboring a cancer-predisposition gene, they set the pace for additional research, John M. Maris, MD, pediatric oncologist at The Children's Hospital of Philadelphia, wrote in an accompanying editorial.
“We need to invest now to enrich our ability to provide world-class and evidence-based cancer-predisposition counseling to families afflicted by childhood cancer,” Maris wrote. “Indeed, the cancer-research community must redouble its efforts to understand the clinical consequences of germline mutations in cancer-susceptibility genes, including the lifetime penetrance of the mutations, their epistatic interactions with other susceptibility genetic alterations and environmental influences, and perhaps most important, the best approaches for counseling patients and developing efficacious prevention strategies through the continuum of infancy to old age.” – by Cameron Kelsall
Disclosure: Downing and Maris report no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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