The RET gene is a proto-oncogene that plays a role in cellular communication and development. It is fundamental for the orderly growth and differentiation of cells throughout the body. Mutations within this gene can lead to various health conditions, disrupting its normal function.
The Normal Role of the RET Gene
The RET gene provides instructions for creating a receptor tyrosine kinase protein. This protein, located on the outer membrane of cells, receives and transmits signals from outside the cell. The RET protein is activated when specific molecules, such as growth factors, bind to its external portion.
This binding initiates a series of chemical reactions inside the cell, guiding it to perform actions like dividing, growing, or developing into specialized cell types. The RET protein is involved in the formation of several types of nerve cells during embryonic development, including those in the enteric nervous system, which controls digestion. It also contributes to the proper formation of the kidneys and parts of the autonomic nervous system, which regulates involuntary bodily functions.
How RET Mutations Impact Cellular Function
When a mutation occurs in the RET gene, it can alter the function of the RET protein. These changes generally fall into two main categories: gain-of-function mutations and loss-of-function mutations.
Gain-of-function mutations cause the RET protein to become overactive or constantly “on,” even without external signals. This uncontrolled activation can lead to unchecked cell growth and division. Such overactivity often contributes to the formation of tumors.
Conversely, loss-of-function mutations result in a RET protein that is non-functional or has significantly reduced activity. This prevents cells from receiving necessary signals. The absence or impairment of RET protein signaling can disrupt normal developmental processes, particularly those involving nerve cell formation.
Diseases Associated with RET Mutations
Mutations in the RET gene are linked to a spectrum of human diseases, each arising from either a gain or loss of the protein’s normal function. Understanding the specific type of RET mutation helps in predicting and managing these conditions.
Gain-of-function mutations in the RET gene are primarily associated with various cancers, where the protein’s constant activity drives uncontrolled cell proliferation. One notable example is Multiple Endocrine Neoplasia type 2 (MEN2), a hereditary cancer syndrome. MEN2 is categorized into subtypes, including MEN2A and MEN2B. Both MEN2A and MEN2B involve medullary thyroid carcinoma (MTC), a type of thyroid cancer originating from C cells.
MEN2A typically presents with pheochromocytoma, tumors of the adrenal glands, and may include hyperparathyroidism, which affects the parathyroid glands. MEN2B, a rarer form, is characterized by an earlier onset of MTC and pheochromocytoma, often accompanied by distinct physical features like mucosal neuromas and a marfanoid body habitus.
Familial medullary thyroid carcinoma (FMTC) is another condition caused by gain-of-function RET mutations, primarily involving MTC without the other endocrine tumors seen in MEN2A or MEN2B. Beyond endocrine cancers, gain-of-function RET alterations, specifically RET gene fusions, are recognized as drivers in a subset of non-small cell lung cancer (NSCLC), accounting for about 1-2% of cases. These fusions involve the RET gene joining with another gene, creating an abnormal protein that promotes cancer growth.
In contrast, loss-of-function mutations in the RET gene are the most common genetic cause of Hirschsprung’s disease. This condition is characterized by the absence of nerve cells (ganglion cells) in segments of the intestine, particularly in the colon and rectum. The lack of functional RET protein signaling during development prevents these nerve cells from migrating and maturing properly. Without these nerves, the affected intestinal segments cannot perform the coordinated muscle contractions necessary for moving stool, leading to severe constipation and intestinal obstruction.
Identifying and Managing RET Mutations
Detecting RET mutations is a key step in diagnosing and managing associated conditions. Genetic testing, primarily through DNA sequencing, is used to identify specific RET gene alterations in individuals. This testing can confirm a diagnosis, assess the risk for family members, and guide personalized treatment strategies.
For conditions driven by gain-of-function RET mutations, such as MTC and RET-driven NSCLC, targeted therapies known as RET inhibitors have improved treatment approaches. These medications, like selpercatinib and pralsetinib, are designed to specifically block the overactive RET protein, halting uncontrolled cell growth. Unlike traditional chemotherapy, which affects both healthy and cancerous cells, RET inhibitors offer a more precise treatment by focusing on the underlying genetic driver of the cancer, potentially leading to fewer side effects.
These inhibitors are often considered first-line treatment options for advanced RET fusion-positive NSCLC. Management strategies for tumors caused by RET mutations also include surgical removal. For Hirschsprung’s disease, caused by loss-of-function mutations, management typically involves surgical removal of the affected, nerve-deficient section of the intestine to restore normal bowel function.