Germline Sequence Variations in People with Central Nervous System Tumors

Most neurologists are familiar with the risk of central nervous system (CNS) tumors in people with well-established genetic syndromes—such as neurofibromatosis (which predisposes to optic pathway gliomas), NF2-related schwannomatosis (which predisposes to ependymomas), and Gorlin (which predisposes to medulloblastomas), Turcot, and Li Fraumeni (which is associated with TP53 sequence variations) syndromes—which are commonly taught and tested in neurology education, but few people with CNS tumors are referred for genetic testing. Global genome-wide association studies of families with ≥2 people with gliomas have found some loci associations but have not highlighted any specific gene for routinely available clinical testing.^1-3 Recent studies have indicated that CNS tumors may be an uncommon manifestation of other described germline tumor predisposition sequence variations. Because preventive care can save lives and improve treatment for germline tumor sequence variations, identifying families that carry these cancer-causing genes is crucial. However, guidelines often have focused on specific syndromes and genes; therefore, few formal recommendations exist regarding which people with CNS tumors should be referred for germline genetic testing.

Incidence of Germline Tumor Predisposition Sequence Variations in Adults and Children with Brain Tumors

In the 100,000 Genomes Project from the United Kingdom, >4% of individuals with low-grade glioma and almost 9% of individuals with glioblastoma had a germline tumor predisposition sequence variation (most commonly BRCA, PALB1, BRIP, RAD51, MSH2, MLH1, POLE, POLD1, or FLCN).⁴ For children or adolescents with CNS tumors, ~20% had a germline tumor predisposition sequence variation.⁵ Among people with medulloblastomas, 6% to 20% had a variant germline tumor predisposition gene (APC, PTCH, SUFU, or ELP1; highest in the sonic hedgehog molecular tumor type), and fewer than half had a family history of cancer to prompt such testing^.6 Atypical teratoid rhabdoid tumors have been associated with germline SMARCB1 and SMARCA4 sequence variations in rhabdoid tumor predisposition syndrome.⁷ Pineoblastomas and pituitary blastomas can be associated with germline sequence variations in RB1 and DICER1 which occur in ~1 of every 5000 individuals in the general population, and a diagnosis of pineoblastoma or pituitary blastoma alone is enough to recommend genetic testing.⁸ Germ cell tumors of the CNS have been associated with germline sequence variations in JMJD1C in ~1 of 6 individuals with these tumors.⁹ As survivorship for people with pediatric CNS tumors has improved, these individuals may continue to see neurologists for care, and referral to medical genetic specialists would be appropriate even if the index diagnosis was decades ago.

Sequence variations associated with Lynch syndrome are probably the most common and underdiagnosed germline tumor predisposition variations. Although mostly associated with colon cancer, several Lynch sequence variations increase risk for many cancers, including brain cancers, which appear to reach a cumulative lifetime risk of 1% to 8% of people with these variations (being highest for MSH2).¹⁰ Many Lynch-associated cancers are more responsive to immunotherapies due to their microsatellite instability causing more antigenic tumor sequence variations.

Guidelines for Testing

The National Comprehensive Cancer Network, American Society of Clinical Oncology, and American College of Medical Genetics recommend genetic testing in certain clinical scenarios, as summarized in the Table.^11-14 More individuals are having detailed genetic testing of their tumors which can suggest the possibility of germline sequence variations. However, tumor variant testing misses 8% to 10% of germline pathogenic sequence variations¹⁵; therefore, tumor testing should not be considered a substitute for germline testing. Panels for germline sequence variations are updated frequently, so at-risk families with previous negative test results or variants of unknown significance should consider repeat testing or consultation every 3 to 5 years.

Summary

Germline sequence variations that predispose to cancer are common and are present in ~2% to 20% of people with CNS tumors. Neurologists should be aware of this risk, take an attentive family history (but understand that a negative family history should not obviate the need for testing), and have a low threshold to refer people with CNS tumors to medical genetics specialists for detailed counseling and consideration of testing.