Alex's Lemonade Stand Foundation for Childhood Cancer

At diagnosis, the burning question parents often have is “What caused my child’s cancer?” Not only is childhood cancer rare, but children simply haven’t lived long enough to have collected the risk factors that come with environmental and lifestyle exposures. While researchers do not have a full answer to that question, they do know that up to 18%158 of childhood cancers are driven by predisposition.

Predisposition means that an individual has a genetic mutation that makes them more likely to develop cancer. These mutations can be inherited from a parent but can also form spontaneously without a familial link. Mutations can exist on their own, like in the case of RB1 and retinoblastoma, or be linked to a syndrome, which can come with both cancer predisposition and additional symptoms in the body.

Common Predisposition Types:

1. Neurofibromatosis-driven cancers:¹⁶⁰
   Neurofibromatosis type 1 (NF1) is a condition caused by a mutation in the NF1 gene that leads to the development of tumors that are mostly benign but also have the potential to become malignant.¹⁶¹ NF1 primarily leads to the formation of malignant peripheral nerve sheath tumor (MPNST), but also leads to the increased risk of other tumors, such as gliomas, juvenile myelomonocytic leukemia, or other malignancies.¹⁶² Neurofibromatosis type 2 (NF2) is similar to NF1; however, malignant tumor formation is less common than what is observed in NF1. The most common type of tumors developed in NF2 are tumors of the brain and spine, such as ependymoma.

2. Li-Fraumeni Syndrome: Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome caused by a mutation in a tumor suppressor gene called TP53. When TP53 is mutated, a large variety of different cancers may form, and patients with this syndrome undergo frequent cancer prevention screening tests.¹⁶⁴ LFS is rare, occurring in 1 in 5,000 to 1 in 20,000 people worldwide.¹⁶⁵ The types of pediatric cancers that LFS patients are more likely to develop are soft-tissue sarcomas, osteosarcomas, brain tumors, and acute leukemias.¹⁶⁶ There are no direct treatment options for patients with LFS, rather enhanced cancer screening protocols are used, along with treatment of the cancer that may have formed from this condition.¹⁶⁷
3. Beckwith-Wiedemann Syndrome: Beckwith-Wiedemann Syndrome (BWS) is a cancer predisposition syndrome that is caused by a mutation in a gene called CDKN1C that leads to the overgrowth of cells and organs and subsequent predisposition to certain types of pediatric cancer, namely Wilms tumor and hepatoblastoma.^168,169 BWS, like LFS, does not have any direct treatment options to treat the syndrome, but rather requires enhanced surveillance to help find and treat associated diseases.¹⁷⁰