Neuroendocrine cancer (NEC) is a group of rare cancers originating from neuroendocrine cells, found throughout the body. These specialized cells exhibit characteristics of both nerve and hormone-producing endocrine cells, making NEC a diverse and complex disease. NEC can affect various organs, including the stomach, bowel, pancreas, and lungs. A common question is whether neuroendocrine cancer is linked to genetics.
The Role of Genetics in Neuroendocrine Cancer
A portion of neuroendocrine cancers are associated with inherited genetic factors. These involve germline mutations, which are DNA alterations present in every cell of the body and can be passed down from parents to their children. Individuals inheriting these mutations have an increased likelihood of developing NEC.
Multiple Endocrine Neoplasia type 1 (MEN1) is a genetic syndrome caused by mutations in the MEN1 tumor suppressor gene. This syndrome predisposes individuals to tumors in endocrine tissues, including pancreatic neuroendocrine tumors (PanNETs), pituitary tumors, and parathyroid tumors. Pancreatic NETs occur in 30-90% of MEN1 patients. MEN1 can also lead to bronchial, gastrointestinal, and thymic carcinoid tumors.
Von Hippel-Lindau (VHL) syndrome is another autosomal dominant disorder linked to neuroendocrine cancer, resulting from inherited mutations in the VHL tumor suppressor gene. VHL disease increases the risk for various tumors, including pancreatic neuroendocrine tumors and pheochromocytomas, which are tumors of the adrenal glands. Pancreatic lesions, such as cysts, serous cysts, and PanNETs, are common in VHL patients, with PanNETs occurring in 11-17% of cases. Pheochromocytomas in VHL can be bilateral in up to 60% of cases.
Neurofibromatosis type 1 (NF1) is caused by loss-of-function mutations in the NF1 gene, which encodes the tumor suppressor protein neurofibromin. NF1 is clinically characterized by features such as café-au-lait spots and neurofibromas. Individuals with NF1 have an increased lifetime risk of developing pheochromocytomas (1-5%) and, less commonly, duodenal carcinoids (somatostatinomas).
Tuberous Sclerosis Complex (TSC) is an autosomal dominant multisystem disorder caused by mutations in the TSC1 and TSC2 tumor suppressor genes. These genes encode hamartin and tuberin, respectively, which are proteins involved in regulating cell growth pathways. While TSC is known for causing hamartomas in multiple organs, it has a rare association with pancreatic neuroendocrine tumors, particularly insulinomas. Pancreatic NETs occur in 1.5-1.8% of TSC patients.
Understanding Sporadic Neuroendocrine Cancer
While genetic syndromes account for a subset of neuroendocrine cancers, most cases are sporadic. Sporadic neuroendocrine cancers are not inherited from parents but arise from acquired genetic changes, known as somatic mutations, that occur during an individual’s lifetime. These mutations are present only in certain cells and are not passed on to offspring.
Somatic mutations in sporadic neuroendocrine tumors can involve various genes. For instance, in sporadic pancreatic neuroendocrine tumors (PanNETs), mutations in genes like MEN1, DAXX, and ATRX are frequently observed. DAXX and ATRX mutations are found in nearly half of sporadic PanNETs.
These acquired genetic alterations can result from random errors during cell division, which naturally accumulate over time as part of the aging process. Environmental factors may also contribute to the development of somatic mutations. Somatic mutations reflect changes that develop in specific cells, leading to tumor formation without a direct familial inheritance pattern.
Genetic Testing and Family Risk Assessment
Understanding the genetic basis of neuroendocrine cancer has practical implications, particularly for genetic testing and family risk assessment. Genetic testing is recommended for individuals with a family history of neuroendocrine tumors, especially if hereditary conditions like MEN1 or VHL are suspected. Testing is also considered for younger patients, generally those under 40 years of age, and in cases of specific tumor types like gastrinomas or high-grade neuroendocrine carcinomas.
Genetic testing involves analyzing a blood or saliva sample to identify specific gene mutations. Before undergoing testing, genetic counseling is important to help individuals understand the potential benefits, risks, and limitations of the tests. Genetic counselors also provide guidance on interpreting results and discuss the implications for the individual and their family members.
A positive test result for an inherited genetic predisposition can lead to enhanced surveillance strategies for the affected individual, such as regular imaging and blood work to monitor for tumor development. This proactive monitoring aims for earlier diagnosis, which can improve treatment outcomes. For family members, a positive result may prompt cascade testing, where other relatives are screened for the same genetic mutation. This allows for early screening and the implementation of risk reduction strategies for at-risk family members, supporting personalized care and management plans.