SMAD4 gene testing
SMAD4 gene testing is a diagnostic tool used to identify defects in the SMAD4 gene, which encodes a protein crucial for regulating cell proliferation. Abnormalities in this gene have been linked to conditions such as juvenile polyposis syndrome (JPS) and various cancers, including pancreatic, colorectal, and gastric cancers. JPS is characterized by the presence of multiple gastrointestinal polyps and carries a significant risk for colorectal cancer, with estimates suggesting that 39 to 68 percent of JPS patients may develop this type of cancer.
The testing process involves analyzing DNA from patients to detect short deletions, insertions, and point mutations in the SMAD4 gene, as well as larger deletions. This testing not only aids in diagnosing JPS, facilitating increased surveillance for associated cancers, but also provides critical information for at-risk family members, allowing them to take preventive health measures. Furthermore, understanding one’s SMAD4 status can help tailor recommendations for regular endoscopic evaluations, particularly in individuals with hereditary conditions like JPS and hereditary hemorrhagic telangiectasia (HHT), who may not always be aware of their elevated cancer risks. Overall, SMAD4 gene testing plays a vital role in managing and guiding the health surveillance of individuals with genetic predispositions.
SMAD4 gene testing
SIGNIFICANCE: The SMAD4gene (also known asDPC4 and MADH4) encodes a protein, which in its normal state is involved in regulation of cell proliferation. However, defective SMAD4is seen in juvenile polyposis syndrome (JPS) and several cancers. SMAD4gene testing identifies patients with defective SMAD4 genes, enabling better disease management and clearer information to at-risk family members.
SMAD4 Biology
Many genes that code for proteins that participate in signaling pathways that regulate functions such as cell proliferation promote cancer when altered. SMAD4 codes for a protein that plays a central part in many transforming growth factor β (TGF-β) pathways. Normal function of these pathways is required for inhibition of the growth of many types of cells. When TGF-β pathway participants are defective, this inhibition is lost and malignancy can follow.
Defective SMAD4 genes are seen in various cancers, including pancreatic, colon, lung, breast, ovarian, and endometrial. Defective germ-line SMAD4genes are also seen in some JPS patients and hereditary hemorrhagic telangiectasia (HHT) patients.
Juvenile Polyposis Syndrome
Juvenile polyposis syndrome is a rare autosomal dominant disorder characterized by gastrointestinal (GI) tract polyps, most commonly found in the colon and rectum. JPS usually, but not always, starts in childhood. It is diagnosed when there are more than five colorectal polyps (although there may be many more), any polyps in other GI tract locations, or a family history of JPS. JPS patients commonly suffer from GI bleeding, anemia, diarrhea, and abdominal pain. According to 2022 data published in the journal Best & Research Clinical Gastroenterology, patients with JPS have a 39 to 68 percent risk of developing colorectal cancer and a 21 percent risk of developing upper gastrointestinal cancers such as gastric, pancreatic, and duodenal cancer. The prevalence rate of JPS was believed to be 1 in 100,000 people in 2024.
HHT is another rare autosomal dominant disorder with different symptoms. In HHT, blood vessel malformations lead to frequent episodes of bleeding from a variety of organs, including the GI tract. Sometimes JPS and HHT coexist in the same individual. Germ-line mutations in SMAD4 are not seen in any other disorders.
Testing for Defective SMAD4
Abnormalities of SMAD4 are either short deletions and insertions of a few base pairs and point mutations (about 75 percent) or large deletions (about 24 percent).
DNA sequencing is used to identify and map short abnormalities. SMAD4 DNA, purified from patient genomic DNA, is amplified using the polymerase chain reaction (PCR). The amplified DNA is purified and sequenced, usually with an automated sequencer. Sequences are compared to normal SMAD4 DNA sequences, and differences are noted.
Long deletions can be analyzed by comparative genomic (CGH). Denatured patient genomic DNA is hybridized to a large number of overlapping normal DNA probes of known map position in SMAD4, which are each immobilized on glass. Probes that do not hybridize to patient DNA can locate deletions.
Impact
SMAD4 gene testing aids in the diagnosis of JPS, a difficult-to-diagnose disorder. Diagnosis encourages increased surveillance for colorectal and gastric cancer.
JPS patients with defective SMAD4 are more likely to have noncolorectal GI polyps and gastric cancer, while gastric cancer is unlikely for patients with normal SMAD4. Therefore, knowledge of SMAD4 status can emphasize or deemphasize surveillance at different GI sites.
SMAD4 status of one family member can alert presymptomatic, first-degree relatives to get tested and take appropriate preventive measures or alternatively can eliminate unnecessary procedures. Knowledge of SMAD4 status can improve adherence to recommendations for endoscopy at three-year intervals and make it possible to tailor recommendations.
Patients with JPS-HHT are likely to be primarily under the care of cardiovascular specialists and may not know they have JPS and are at high risk for colorectal and gastric cancers. Knowledge of SMAD4 status advises them about the desirability of preventive endoscopy.
Key Terms
- acquired mutationmutation that arises in an individual after birth
- denatured DNADNA that has been treated (usually by heat) to cause strand separation
- germ linegenetic material passed from parents to offspring
- hybridizeto form double-stranded DNA from single-stranded DNA molecules by mixing them in conditions where base pairs can form
- polymerase chain reaction (PCR)a procedure using enzymes to amplify specific DNA sequences many fold to provide sufficient material, e.g., for sequencing
Bibliography
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Dal Buono, Arianna, et al. "Juvenile Polyposis Syndrome: An Overview." Best Practices & Research Clinical Gastroenterology, vol. 58-59, June-Aug. 2022, doi.org/10.1016/j.bpg.2022.101799. Accessed 11 Sept. 2024.
"Juvenile Polyposis Syndrome." Medline Plus, 1 Oct. 2014, medlineplus.gov/genetics/condition/juvenile-polyposis-syndrome/. Accessed 10 Sept. 2024.
Schneider, Katherine A. Counseling about Cancer: Strategies for Genetic Counseling. 3rd ed. Hoboken: Wiley, 2012. Print.
Schouten, Jan P., Cathal J. McElgunn, Raymond Waaijer, et al. “Relative Quantification of Forty Nucleic Acid Sequences by Multiplex Ligation-Dependent Probe Amplification.” Nucleic Acids Research 30 (2002): e57. Print.
"SMAD4 SMAD Family Member 4." National Center for Biotechnology Information, 27 Aug. 2024, www.ncbi.nlm.nih.gov/gtr/genes/4089/. Accessed 10 Sept. 2024.
Vogelstein, Bert, and Kenneth Kinzler. The Genetic Basis of Human Cancer. 2nd ed. New York: McGraw-Hill, 2002. Print.