Navigating CDH1 and Hereditary Diffuse Gastric Cancer: Evolving Risks, Guidelines, and Counseling Challenges

Hereditary diffuse gastric cancer (HDGC) has long been recognized as one of the most penetrant hereditary cancer syndromes, primarily linked to pathogenic variants in the CDH1 gene.

Early reports painted a sobering picture, with lifetime gastric cancer risks estimated at over 80%, often leading to prophylactic total gastrectomy as the “default” recommendation. But in recent years, the story of CDH1 has shifted. New penetrance data, updated guideline recommendations, and a growing understanding of variable cancer risk are reshaping how clinicians and genetic counselors discuss CDH1 with patients. These changes bring opportunities for more nuanced, individualized care—but also present real challenges in communication, coordination, and decision-making.

In Episode 5 of the CGA-IGC Podcast Series, Josie Baker, MS, CGC, spoke with Maegan Roberts, MS, CGC, a genetic counselor at The Ohio State University specializing in hereditary gastrointestinal cancers. Megan has been deeply involved in CDH1 research and variant interpretation, serving as co-chair of the Gastric Cancer ClinGen Variant Curation Panel and a member of the International Gastric Cancer Linkage Consortium (IGCLC). This conversation explored how evolving evidence is reshaping practice—and what genetic counselors and providers need to know.

From Early Penetrance to Modern Reassessment

The CDH1 gene was first identified in 1998, with penetrance estimates soon following. Initial publications suggested lifetime diffuse gastric cancer risks of 67–83%, later revised to 40–70% in subsequent studies. But those early numbers were heavily influenced by ascertainment bias, since studies often included families with striking gastric cancer histories. With the advent of multi-gene panel testing, CDH1 variants are now identified in broader, less selective populations. This shift has profoundly altered risk estimates, with current estimates as low as 10% lifetime risk in individuals without family history of gastric cancer.

These findings underscore a critical reality: a germline CDH1 pathogenic variant is not a guarantee of gastric cancer development. Instead, penetrance is more heterogeneous, depending heavily on family history and possibly other modifiers. This evolving evidence has forced the field to reconsider one-size-fits-all recommendations and move toward personalized risk management strategies.

NCCN vs. IGCLC: A Tale of Two Guidelines

Management guidelines for CDH1 are in flux, and clinicians often face the challenge of reconciling different recommendations. The International Gastric Cancer Linkage Consortium (IGCLC), with its predominantly European membership, has historically adopted a conservative stance, shaped by strict genetic testing criteria and more severe phenotypes observed in tightly regulated healthcare systems. By contrast, the National Comprehensive Cancer Network (NCCN) has adapted its guidelines to reflect the U.S. clinical landscape. In 2023, NCCN notably moved CDH1 out of the gastric cancer guidelines and into its Detection, Prevention, and Risk Reduction framework, signaling a broader, more flexible approach. Allegedly, the NCCN guidelines currently offer the most relevant reference point for U.S.-based practice, providing options that better match the spectrum of patients now being identified through genetic testing. While future IGCLC updates may relax previous criteria, alignment is not yet complete.

Counseling Challenges: Building Confidence and Consistency

One of the greatest hurdles genetic counselors face is how to communicate nuanced, evolving risks to patients and to collaborating providers. Two key strategies exist:

• Confidence through preparation – Counselors must deeply understand NCCN guidelines, penetrance data, and the clinical significance (or lack thereof) of certain findings in order to guide patients effectively.

• Consistency across the care team – Patients often interact with gastroenterologists, surgeons, and oncologists. Establishing a unified message is critical to avoid confusion or conflicting recommendations.

  This coordination extends beyond patients: genetic counselors should actively share new literature with collaborating physicians and engage in ongoing dialogue about management strategies.

  
  

T1a Signet Ring Cell Carcinomas

A particularly delicate counseling point involves T1a signet ring cell carcinomas. These lesions, often found during endoscopic surveillance or in prophylactic gastrectomy specimens, are technically classified as “cancer” but are confined to the lamina propria and often remain indolent. ,Studies suggest a 90–95% chance of detecting at least one T1a SRCC in gastrectomy specimens of CDH1 carriers. ,Their presence does not equate to inevitable progression to invasive gastric cancer. For patients, hearing the word “carcinoma” on a pathology report can be anxiety-provoking. Anticipatory counseling should be discussed before endoscopy is performed: framing T1a SRCCs as precursor lesions and using visual tools (such as stomach cross-sections) to contextualize their clinical significance. This reframing helps patients avoid undue alarm while still appreciating the rationale for surveillance and surgical considerations.

Shifting Patient Perspectives

Interestingly, while many clinicians feared that lower penetrance estimates might lead to confusion or resistance, Megan’s experience has been the opposite. Patients without a strong family history of gastric cancer often feel relieved to learn that NCCN supports options beyond immediate prophylactic gastrectomy, including endoscopic surveillance. For families with difficult experiences following surgery, this flexibility can be particularly reassuring as younger generations approach testing decisions.

Working with Providers: Collaboration, Skepticism, and Growth

Not all providers adapt to guideline changes at the same pace. Megan acknowledged that some physicians may remain skeptical or resistant. Her approach:

• Engage respectfully but persistently, even if it means “pushing buttons” to encourage thinking beyond the long-standing one-size-fits-all approach.

• Tailor counseling so patients are prepared for differing provider perspectives.

• Maintain dialogue by sharing papers, suggesting team reviews of new guidelines, and keeping conversations ongoing.

Ultimately, long-term collaboration requires openness, humility, and shared commitment to evolving evidence-based care.

Take-Home Messages

As the field of hereditary gastric cancer evolves, so too must our counseling and clinical practices. Three key takeaways:

• Educate yourself and approach counseling with confidence; deep knowledge builds trust.

• Understand the true significance of findings, particularly the limited implications of T1a signet ring carcinomas.

• Know your team and keep the dialogue alive, collaboration with surgeons, gastroenterologists, and oncologists ensures patients receive consistent, well-informed care.

  
  

The story of CDH1 is far from static. As penetrance data, guideline recommendations, and patient experiences continue to evolve, the role of genetic counselors remains pivotal, not only in guiding patients, but also in shaping how multidisciplinary teams respond to new evidence. To hear the full conversation and gain deeper insights, listen to the episode of the CGA-IGC Podcast Series.

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If you enjoyed this podcast, you may also like our CGA-IGC Research Collaboration series- or others from the CGA-IGC Podcast Series (Seasons 3, 4, 5, 6 & 7) presented by the CGA-IGC Education Committee. Or, explore our Expert Approach to Hereditary Gastrointestinal Cancers podcast series (Seasons 1 and 2). We're also on Spotify!

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