Signet Ring Cell Carcinoma (SRCC) is a rare, aggressive cancer. While many cancers are sporadic, SRCC can have a hereditary component, influencing risk assessment and management.
Understanding Signet Ring Cell Carcinoma
SRCC is characterized by its cells’ unique appearance under a microscope: a large, mucin-filled vacuole pushes the nucleus to the periphery, resembling a signet ring. As an adenocarcinoma subtype, SRCC develops from glandular cells lining various organs.
It most commonly originates in the stomach (approximately 90% of cases), but can also arise in other glandular organs, including the colon, rectum, breast, bladder, and pancreas. Unlike solid tumors, SRCC often grows in diffuse sheets, making early detection challenging and contributing to its aggressive nature.
The Hereditary Link
While most SRCC cases are not inherited, a notable subset has a hereditary basis. This genetic predisposition significantly increases an individual’s risk, often leading to earlier onset than sporadic cases.
The primary genetic mutation linked to hereditary SRCC, especially gastric SRCC, is in the CDH1 gene, associated with Hereditary Diffuse Gastric Cancer (HDGC) syndrome. The CDH1 gene produces E-cadherin, a protein crucial for cell adhesion. A mutated CDH1 gene disrupts this adhesion, allowing cells to detach and spread, contributing to its diffuse growth. Individuals with a pathogenic CDH1 variant face a substantial lifetime risk of diffuse gastric cancer (56-70%). Females also have an increased lifetime risk of lobular breast cancer (23-68%).
SRCC in the colon or rectum can also be associated with Lynch syndrome (Hereditary Non-Polyposis Colorectal Cancer or HNPCC). Lynch syndrome results from mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, EPCAM). These genes correct DNA replication errors; their dysfunction leads to mutation accumulation and increased cancer risk. While less common than CDH1 for gastric SRCC, Lynch syndrome can contribute to colorectal SRCC.
Identifying Hereditary Risk
Identifying hereditary SRCC risk involves assessing personal and family medical history. Patterns of certain cancers across generations, especially early-onset diagnoses, can indicate genetic predisposition, such as multiple family members with diffuse gastric, lobular breast, or colorectal cancer, or specific combinations.
Genetic counseling is central. A genetic counselor collects detailed family health information, often constructing a three-generation family tree to evaluate genetic risk factors. They discuss the likelihood of an inherited cancer condition, explaining genetic testing’s benefits, risks, and limitations.
If family history suggests hereditary risk, genetic testing may be recommended. This involves analyzing blood or saliva for mutations in genes like CDH1 or Lynch syndrome-associated genes. Testing is guided by medical guidelines, focusing on individuals and families with inherited cancer syndrome patterns. Results provide crucial information for personalized risk management.
Implications of a Hereditary Diagnosis
A confirmed hereditary SRCC diagnosis has significant implications for individuals and their families. This knowledge enables proactive measures for early detection and risk reduction. Enhanced surveillance strategies are key to managing this elevated risk.
For CDH1 gene mutation carriers, regular endoscopic surveillance monitors for early gastric cancer. Due to SRCC’s diffuse nature, which infiltrates the stomach lining without a distinct mass, traditional endoscopy can be challenging, though specialized techniques and extensive biopsy protocols improve detection. Women with a CDH1 mutation also require enhanced breast cancer screening, including earlier, more frequent mammograms and breast MRIs.
For many CDH1 mutation carriers, especially those with a strong family history of gastric cancer, prophylactic total gastrectomy (surgical removal of the entire stomach) is recommended to prevent diffuse gastric cancer. This life-altering procedure is considered the most effective way to eliminate gastric SRCC risk in high-risk individuals.
For those with Lynch syndrome, surveillance primarily involves regular colonoscopies, often starting younger and performed more frequently, to detect and remove precancerous polyps. Surveillance for other Lynch syndrome-associated cancers, like endometrial and ovarian cancers, may also be recommended.
Implications extend to family members, who may also risk inheriting the mutation. Genetic counseling is crucial for relatives to understand their potential risk and consider genetic testing. This family-wide approach allows informed decision-making regarding surveillance, prophylactic measures, and personalized cancer management, potentially preventing cancer or detecting it early.