Hereditary diffuse gastric cancer: an overview for primary care

Stomach cancer disproportionately affects Māori

Stomach cancer is the 11th most common cancer in New Zealand, and the eighth most common cause of cancer deaths.¹ One in 110 people will be diagnosed with stomach cancer during their lifetime.² The vast majority of these cases are sporadic. However, in about 1% of cases, there is a genetic predisposition to hereditary diffuse gastric cancer, an autosomal dominant cancer syndrome caused by germline mutation of the CDH1 gene.² CDH1 is a tumour suppressor gene that codes for the cell adhesion protein, E-cadherin. Carrying an abnormal CDH1 gene confers a lifetime risk of up to 70% for developing stomach cancer.^{2, 3} Female carriers also have an approximately 40% lifetime risk of developing lobular breast cancer.²

Several Māori families in New Zealand have had a long history of developing and dying from stomach cancer at an early age. However, it was only in the 1990s that scientists from the University of Otago identified the gene that caused the stomach cancer within these families.^{3, 4} It is now estimated that approximately 13% of all advanced diffuse gastric cancer cases in Māori can be attributed to germline CDH1 mutations.² The incidence and mortality of stomach cancer is three times greater in Māori compared with non-Māori in New Zealand.⁵

Identifying the genetic cause

Hereditary diffuse gastric cancer is caused predominantly by mutations in the CDH1 gene, with a small number of additional families outside New Zealand having CTNNA1 mutations.⁶ It is thought that an abnormal E-cadherin protein results in some cells in the stomach and breast being displaced from the epithelial plane, causing poorly regulated cell growth.

Inheritance of the CDH1 gene is autosomal dominant, meaning that a biological child of a carrier has a 50% chance of getting the gene, and consequently a 70% risk of developing stomach cancer.² There are about 18 different CDH1 mutations in the New Zealand population affecting several hundred people, the majority of whom are Māori.²

To watch a video on how the CDH1 gene mutation was identified, see: www.youtube.com/watch?v=iqLPdcvHBvE

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Figure 1: Algorithm for managing patients with a personal or family history of diffuse gastric cancer, adapted from van der Post et al, 2015.⁹
GC = gastric cancer, DGC = diffuse gastric cancer, LBC = lobular breast cancer, MLPA = multiplex-ligation probe amplification.

Managing patients with a family history of diffuse gastric cancer

Hereditary diffuse gastric cancer is initially asymptomatic, and there are no reliable surveillance methods, therefore prophylactic total gastrectomy is the key management intervention for patients who have tested positive for the CDH1 gene mutation.⁹ By the time symptoms develop, it is often too late for a cure.

Pathological examination after a prophylactic gastrectomy often finds patients to have multiple (≥ 100) small spots (foci) of signet ring cell carcinoma within the stomach, that are under a millimeter in diameter.

Gastric endoscopic surveillance is undertaken while patients are awaiting surgery (or have deferred the decision). This can provide some reassurance to patients and larger foci may be detected, but it is not a reliable long-term surveillance method.

For full clinical guidelines on managing patients with hereditary diffuse gastric cancer, see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453626

Gastrectomy surgery and recovery

The surgery that is performed is a total gastrectomy with a Roux-en-Y reconstruction. Proximal resection must be within the distal oesophagus to ensure that no stomach mucosa is left behind. There is generally no need for a radical lymph node dissection as most tumours are T1a N0. If the stomach looks abnormal on gastric endoscopy or biopsies are positive for cancer, a more radical operation may be needed.

There is significant morbidity associated with the operation. Short-term morbidity revolves around the surgery itself, anastomotic leaks and learning to eat again. Long-term morbidity is related to nutrition and quality of life. As there is no storage capacity from the stomach, patients initially need to eat little and often (e.g. six to eight small meals per day and snacks) and usually require support from a dietitian. Over time, the oesophagus/intestine junction grows into a pouch which can accommodate larger meals.

Eating too much or too quickly can cause abdominal pain. Dumping syndrome can occur; this is where rapid emptying of food, particularly sugars, into the gastrointestinal tract causes symptoms such as abdominal pain, diarrhoea and sweating. Patients can also experience lactose intolerance, fat malabsorption and steatorrhoea. Recovery is individual, however in most cases symptoms resolve (or become manageable) within six months to one year following the surgery.

There is limited information about vitamin and mineral requirements following a gastrectomy. Although gastric bypass surgery for managing obesity has some differences to a total gastrectomy in that a portion of the stomach remains, nutritional deficiencies may share some similarities:¹¹

Fat is the most difficult nutrient to absorb. Following a gastrectomy there is reduced time that food is mixed with bile and pancreatic juice. This may lead to reduced digestion of fat, resulting in bacteria breaking down the fats and releasing gas/flatus and steatorrhoea. The diagnosis is based on history of a layer of oil in the toilet pan, diarrhoea, post-prandial loose bowel motions and cramping abdominal pain, and may be confirmed with a faecal elastase test. This may lead to overall nutritional and vitamin deficiencies. Treatment is with pancreatin 300 mg (Creon 25,000), two to three capsules with each meal, taken at the beginning and during the meal.

Fat soluble vitamins – vitamin A, D, E, K are generally easily absorbed, however if the patient has steatorrhoea deficiencies of these vitamins can arise. This may manifest with night blindness (vitamin A) and bruising (vitamin K). Oral multivitamins may be useful.

Protein and sugar malabsorption are less frequent as these nutrients are more easily absorbed. Hair loss, skin and nail changes are early signs of protein deficiencies.

Calcium, vitamin and protein absorption occurs mostly in the duodenum. As this is bypassed during the gastrectomy operation, absorption may be reduced. Therefore, long-term multivitamins are required morning and evening. Calcium deficiencies only become apparent in later life. However, replacing oral calcium is not considered beneficial as it appears to deposit in the arteries. Therefore, patients are recommended to undertake regular weight bearing activity and take multivitamins containing vitamin D; a walk in the sun each day would contribute to both requirements.

Vitamin B12 cannot be absorbed without a stomach as intrinsic factor is not secreted. Regular vitamin B12 injections are required (hydroxocobalamin 1000 micrograms, intramuscular injection, administered every one to three months).

Iron in food is poorly absorbed without a stomach as iron needs to be converted to a useable form by stomach acid. Oral iron supplements are easily absorbable but are often not well tolerated. Iron infusion every six months to yearly may be an alternative.

For further information on dietary advice, recipes and patient experiences post-gastrectomy, see: www.nostomachforcancer.org

Future directions in gastric cancer management

Extensive research is being undertaken at the University of Otago to develop a chemo-preventative treatment for people with the CDH1 mutation. A “synthetic lethal” approach is being used to exploit cellular vulnerabilities that arise with the loss of the tumour suppressor gene, CDH1. These vulnerabilities are likely caused by the cell membrane disorganisation observed in mutant CDH1-deficient cells. A successful pharmacological agent will render CDH1-deficient cells unviable and induce cell death, while having minimal effect on normal CDH1-expressing cells. As a result, these medicines could be used to reduce or eliminate the risk of gastric cancer in families who carry the gene.

There are two primary aims for current research:

1. Develop new models of hereditary diffuse gastric cancer with improved representation of in vivo disease. Three new models of increasing complexity are currently in use or being developed:
   • Gastric cancer isogenic cell lines with and without CDH1 mutations
   • Gastric organoids (miniature 3D stomach structures), cultured from murine stem cells
   • A transgenic mouse model for in vivo experiments
2. Use these models to screen drug libraries for potentially therapeutic compounds, with the eventual goal of developing a chemo-preventative treatment.

So far, this research has yielded promising results, with thousands of compounds already screened in the isogenic cell lines and many hits identified. Organoid development and optimisation is largely complete, and drug screening on this more complex model is set to begin shortly. With these novel pre-clinical models and robust screening systems, there is much confidence and optimism among researchers around future results and their potential impact. With the current progress, it is envisaged the first human trials could start within five years.