Role of Genetics in Neuroendocrine Cancer
Genetics plays an important role in understanding how and why neuroendocrine cancers develop. While most NETs occur sporadically, a smaller but significant proportion arise due to inherited genetic mutations. These inherited changes can increase an individual’s lifetime risk of developing NETs and other tumours and cysts. By identifying the genes involved, clinicians can better diagnose, treat, and monitor patients, while also providing valuable information to family members who may share genetic risk factors.
Hereditary NETs are typically caused by germline mutations, which are passed from parents to children and present in all cells of the body. Understanding whether a tumour is hereditary or sporadic helps determine whether family members might benefit from screening or genetic testing themselves. Learn more via our factsheet.
Genetic insights also inform treatment decisions. For example, certain gene mutations can predict how a tumour will behave or respond to specific therapies. As research advances, genetic testing is becoming a central tool in personalised medicine for NET patients, improving outcomes through targeted and preventative care.
NeuroEndocrine Cancer Australia (NECA), is dedicated to assisting individuals diagnosed with NETs and their loved ones. NECA offers a wealth of resources, educational programs, and advocacy efforts aimed at deepening the understanding of NETs, improving patient care, and encouraging research advancements. Patients can engage with NECA’s comprehensive support and information by calling the NET nurse line.
When genetic testing Is recommended
Genetic testing is not necessary for every patient diagnosed with a neuroendocrine cancer. It is generally recommended when there is reason to suspect an inherited component or when the tumour characteristics suggest a known hereditary syndrome.
Doctors may suggest testing if:
- The NET appears at a young age
- There are multiple primary tumours
- There is a family history of NETs or related endocrine cancers
- The patient presents with clinical features of specific syndromes such as Multiple Endocrine Neoplasia (MEN) or Von Hippel–Lindau (VHL) disease
Testing can also be considered for patients whose tumours have specific genetic markers discovered through molecular profiling. In these cases, identifying the mutation may guide targeted therapies or determine eligibility for clinical trials.
Currently the only neuroendocrine cancers that require routine genetic counselling and testing are; those with a confirmed diagnosis of Phaeochromocytoma, Paraganglioma or Medullary Thyroid Cancer.
Others that should be considered are gastrinoma or multifocal gastroenteropancreatic neuroendocrine cancer (GEP-NET) at any age; patients with a GEP-NET before age 40 years; and patients with a bronchial or thymic NET at any age for MEN1.
Before testing, patients usually meet with a genetic counsellor who explains the potential benefits, limitations, and implications of genetic testing. Counselling ensures that individuals make informed decisions and understand the possible impact of the results on themselves and their families.
Common genetic syndromes linked to NETs
A number of inherited syndromes are known to increase the risk of developing neuroendocrine cancers. These syndromes involve mutations in specific genes that regulate cell growth, hormone production, and tumour suppression.
Multiple Endocrine Neoplasia Type 1 (MEN1)
MEN1 is one of the most well-known hereditary conditions linked to NETs. It is caused by mutations in the MEN1 gene, which procedures the protein menin, a tumour suppressor. People with MEN1 often develop multiple tumours in the parathyroid glands, pancreas, and pituitary gland. Refer to our fact sheet for more information. Pancreatic NETs are especially common in this group, including gastrinomas and insulinomas. MEN-1 should be considered in those with a gastrinoma or multifocal gastroenteropancreatic neuroendocrine cancer (GEP-NET) at any age; patients with a GEP-NET before age 40 years; and patients with a bronchial or thymic NET at any age.
Multiple Endocrine Neoplasia Type 2 (MEN2)
MEN2 is associated with mutations in the RET gene, which affect cell signalling pathways. This condition primarily increases the risk of medullary thyroid carcinoma and phaeochromocytoma and may also be associated with parathyroid disease which causes hyperparathyroidism leading to elevated parathyroid hormone and calcium levels in the blood. Identifying RET mutations allows for proactive management, including preventive thyroid surgery in at-risk individuals.
Von Hippel–Lindau (VHL) Disease
VHL is caused by mutations in the VHL tumour suppressor gene. It predisposes individuals to a range of cysts and tumours, including gastrointestinal and pancreatic NETs, phaeochromocytomas, inner ear tumours, kidney/renal tumours, and haemangioblastomas of the brain,spinal cord and retina. Genetic testing for VHL is recommended when these tumours appear in young patients or those with a family history of related lesions.
Other relevant inherited conditions
Other rare genetic syndromes linked to neuroendocrine cancer include Neurofibromatosis Type 1 (NF1) and Tuberous Sclerosis (TS). A fault with a succinate dehydrogenase (SDHA/SDHB/SDHC/SDHD) gene can also increase the risk of developing phaeochromocytomas, paragangliomas, kidney cancers, pituitary NETs and gastrointestinal stromal tumours (GIST). These conditions also involve tumour-suppressor gene defects, which increase the likelihood of neuroendocrine or related neoplasms. Although less common, identifying these mutations helps clinicians tailor surveillance and treatment strategies for patients and their relatives.
Genetic Testing Methods
Modern genetic testing called genomic profiling uses advanced laboratory techniques to identify mutations in specific genes associated with NETs. These tests are usually performed on a blood sample, though tumour tissue may also be analysed for somatic mutations that develop after birth.
Blood and tissue-based DNA testing
DNA from blood cells is tested to identify germline mutations that can be inherited. Tissue samples taken during a biopsy or surgery can reveal gene changes specific to the tumour. Analysing both germline and tumour DNA can provide a comprehensive picture of the genetic factors influencing a patient’s disease.
Next-generation sequencing (NGS)
Next-generation sequencing is a powerful tool that allows for the simultaneous analysis of many genes. This technology can detect known mutations, as well as novel or rare variants, helping researchers uncover previously unrecognised genetic causes of NETs.
NGS panels for NETs often include genes such as:
- MEN1
- RET
- VHL
- TSC1
- TSC2
- NF1
Comprehensive genetic testing is becoming more widely available, though interpretation of results requires expert input from geneticists and oncologists to ensure accurate and clinically meaningful conclusions.
Implications of test results
The outcomes of genetic testing can significantly influence patient care and family management. A positive test result confirms the presence of a hereditary mutation and may lead to increased surveillance or preventive measures. For example, regular imaging and biochemical testing can detect tumours at earlier, more treatable stages.
Testing can also identify family members who carry the same mutation. Predictive testing allows relatives to understand their risk and take proactive steps in monitoring or prevention. Conversely, a negative test result can provide reassurance to family members, indicating that they are unlikely to inherit the increased risk.
For patients with confirmed hereditary NET syndromes, treatment may be personalised based on their genetic profile. Some gene mutations predict sensitivity or resistance to certain therapies, helping clinicians choose the most effective treatment strategy.
Ethical and psychosocial considerations
Genetic testing carries emotional, ethical, and social implications that extend beyond the patient. The knowledge of an inherited mutation can cause anxiety, guilt, or concern for family members. Genetic counselling is therefore an essential component before and after testing to help patients understand and manage the results.
Privacy and consent are critical. Patients must decide whether and how to share genetic information with relatives. While this knowledge can empower families to make health-conscious decisions, it may also lead to difficult conversations about risk and responsibility.
There are also broader considerations regarding insurance and employment, though in Australia, anti-discrimination laws provide some protection against the misuse of genetic information. Nevertheless, patients are encouraged to seek advice before disclosing results outside medical contexts.
Future directions in genetic research
The field of genetics in neuroendocrine cancer is rapidly evolving. Researchers continue to identify new mutations that contribute to NET formation and progression. Advances in whole-genome and epigenetic studies are deepening our understanding of how gene regulation and cellular pathways interact in tumour development.
Future genetic testing may go beyond diagnosis and risk prediction, paving the way for truly personalised treatment. By linking genetic mutations to drug responses, clinicians can design precision therapies that target the specific molecular changes driving each patient’s cancer. This approach holds promise for improving survival and quality of life for people living with NETs.
As knowledge expands, large-scale databases and international collaborations will be vital for identifying patterns across populations. The integration of genetic testing into routine clinical care will help detect at-risk individuals earlier, refine treatment, and contribute to the broader goal of reducing the global burden of Neuroendocrine Cancer.
Further information and support for people diagnosed with NETs is available by calling the NECAÂ NET nurse line
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