Neuroendocrine tumours (NETs) are a diverse group of neoplasms that arise from neuroendocrine cells — specialised cells with characteristics of both nerve and hormone-producing (endocrine) cells.
These tumours can develop in various organs, including the pancreas, gastrointestinal tract, and lungs.
Understanding the genetic mutations that drive NET formation and progression is key to improving diagnosis, personalising treatment, and advancing research into new therapies.
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.
Cancer begins when cells acquire mutations that disrupt the normal control mechanisms regulating growth, division, and death.
In NETs, genetic changes can alter signalling pathways, deactivate tumour suppressor genes, or activate genes that promote tumour growth.
These mutations may be inherited (germline mutations) or develop spontaneously over time (somatic mutations), contributing to the formation and behaviour of these complex cancers.
Researchers have identified several genes that are commonly altered leading to various types of NETs. These mutations play a role in tumour development, progression, and response to treatment.
The MEN1 gene encodes a protein called menin, which helps regulate cell growth. When this gene is mutated, it loses its tumour-suppressing function. Mutations in MEN1 are frequently seen in pancreatic and gastrointestinal NETs, and in individuals with multiple endocrine neoplasia type 1 syndrome. These tumours tend to develop at younger ages and can be multiple or recurrent.
Mutations in the DAXX and ATRX genes are associated with changes in chromatin structure, which controls how DNA is packaged and accessed by the cell. These mutations are linked to a process known as alternative lengthening of telomeres (ALT), allowing tumour cells to divide indefinitely. DAXX and ATRX mutations are commonly found in pancreatic NETs.
The mTOR (mechanistic target of rapamycin) pathway plays a critical role in cell growth and metabolism. When genes in this pathway (such as TSC2 or PTEN) are mutated, they can lead to hyperactivation of mTOR signalling. This promotes unchecked cell proliferation and survival. These mutations are relevant to therapeutic strategies, as tumours with activated mTOR pathways may respond to targeted treatments like everolimus.
TP53 and RB1 are two of the most well-known tumour suppressor genes. They play essential roles in controlling the cell cycle and initiating apoptosis (programmed cell death). Mutations in these genes are usually found in high-grade neuroendocrine carcinomas, which are aggressive and poorly differentiated.
The accumulation of genetic mutations can influence how NETs grow, behave, and respond to treatment.
Mutations in tumour suppressor genes like TP53 and RB1 allow cancer cells to bypass normal cell cycle checkpoints and evade apoptosis. This enables them to grow uncontrollably and become resistant to therapies designed to trigger cell death.
Some genetic changes promote the formation of new blood vessels (angiogenesis), supplying the tumour with nutrients and oxygen. Others affect the surrounding cellular environment (microenvironment), helping tumour cells avoid immune detection or invade nearby tissues. Together, these changes make NETs more capable of spreading and more difficult to treat.
It’s important to distinguish between inherited (germline) mutations and acquired (somatic) mutations when evaluating NETs.
Several genetic syndromes are linked to a higher lifetime risk of developing NETs. These include:
Individuals with these syndromes inherit mutations that predispose them to tumour formation, often at a younger age and in multiple organs.
Most NETs, however, are not inherited. They result from random mutations that develop over time, often due to DNA replication errors or environmental exposures. These sporadic NETs account for the majority of cases, especially in older adults.
Advancements in molecular diagnostics have made it easier to detect the mutations that drive NETs.
NGS allows researchers and clinicians to analyse hundreds of genes at once, providing a comprehensive view of a tumour’s genetic profile. This technique can detect both known and novel mutations, making it useful for personalising treatment and identifying patients who may benefit from targeted therapies.
Immunohistochemistry (IHC) uses antibodies to detect specific proteins expressed by mutated genes in tissue samples. It helps identify tumour subtypes and provides clues about potential underlying mutations. Other molecular techniques are also used to detect gene rearrangements or deletions.
Understanding the genetic makeup of a neuroendocrine tumour (NET) has significant implications for both treatment planning and prognosis. As research advances, clinicians are increasingly using molecular profiling to guide personalised treatment strategies and improve patient outcomes.
Some genetic mutations provide insight into which targeted therapies may be most effective.
For example, tumours with alterations in the mTOR pathway (such as mutations in TSC2 or PTEN) may respond well to mTOR inhibitors like everolimus, which help slow tumour growth by blocking this overactive signalling pathway.
Additionally, clinical trials are investigating drugs that target other molecular pathways involved in NET development, including those affecting chromatin remodelling and cell cycle regulation.
As more targeted agents are developed, identifying the genetic alterations driving a patient’s tumour will play a central role in selecting the most appropriate therapy. In future, therapies may be matched to individual mutation profiles in much the same way targeted treatments are used for lung or breast cancers today.
Beyond guiding treatment, mutation profiling can provide valuable information about the likely course of the disease. Mutations in TP53 and RB1, for instance, are frequently found in high-grade neuroendocrine carcinomas (NECs) and are associated with poor prognosis, faster disease progression, and limited treatment response. These patients often require more aggressive or multimodal treatment strategies.
On the other hand, mutations in DAXX and ATRX, often seen in pancreatic NETs, tend to be associated with less aggressive tumours, longer progression-free survival, and better overall outcomes. Identifying these genetic features early can help shape long-term management plans and inform the frequency of surveillance imaging or follow-up care.
Ultimately, mutation profiling is becoming a cornerstone of precision medicine in NETs, helping clinicians better understand tumour behaviour and tailor care to the individual needs of each patient.
Further information and support for people diagnosed with NETs is available by calling the NECA NET nurse line.
DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors
https://pubmed.ncbi.nlm.nih.gov/21252315/PubMed
ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup
https://www.nature.com/articles/s41467-018-06498-2PMC+2Nature+2ResearchGate+2
PTEN expression and mutations in TSC1, TSC2 and MTOR are associated with response to rapalogs in patients with renal cell carcinoma
https://pubmed.ncbi.nlm.nih.gov/31335987/New England Journal of Medicine+10ResearchGate+10PubMed+10PubMed
Alternative lengthening of telomeres and loss of DAXX/ATRX expression predicts metastatic disease and poor survival in patients with pancreatic neuroendocrine tumors
https://pubmed.ncbi.nlm.nih.gov/27407094/MedNexus+1AACR Journals+1
Next generation sequencing of neuroendocrine tumors undergoing trans-arterial embolization reveals DAXX mutation status predicts shorter hepatic progression free survival
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480743/
Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms
https://pubmed.ncbi.nlm.nih.gov/31857137/PMC+1PubMed+1PubMed
Everolimus for advanced pancreatic neuroendocrine tumors
https://www.nejm.org/doi/full/10.1056/NEJMoa1009290
Familial syndromes associated with neuroendocrine tumours
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631294/
Genetic associations with neuroendocrine tumor risk
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151867/PMC+6PMC+6Gut+6
Neuroendocrine tumors: genomics and molecular biomarkers with clinical and therapeutic implications
https://www.mdpi.com/1422-0067/24/2/1418
