After losing 25 of its members to stomach cancerin 30 years, a Maori family put aside traditionalsuperstitions and contacted laboratoriesthroughout New Zealand to obtain a scientificexplanation. The study they initiated has identifieda germline mutation in the gene that codes for E-cadherin (E-cad), an epithelial cell adhesionmolecule (Fig. 1). The mutation causes a reductionin the amount of functional E-cadherin producedby stomach epithelial cells and leads toexceptionally high rates of cancer [Guilford, P. etal. (1998) Nature 392, 402–405].

The project is a unique partnership between thefamily and a research team led by Parry Guilford atthe University of Otago in New Zealand. Beforework started, the family spoke at length withGuilford to ensure that their cultural beliefs wouldbe respected. ‘In Maori culture, body parts representthe embodiment of the family tree and so are sacred.The family’s requests were easy to accommodate:we stored all their body samples and DNA in aspecially designated area; we agreed never to sendsamples or DNA oversees; and we promisedcomplete confidentiality’, explains Guilford.

Linkage analysis of DNA from as many familymembers as possible was performed using acandidate gene approach, and several candidateswere identified, including the E-cad gene. Otherresearch groups have identified E-cad as the mainadhesion molecule of epithelia. It has beenimplicated in carcinogenesis because it is frequentlylost in human epithelial cancers. Loss of E-cadfunction is thought to contribute to progression inbreast cancer and other solid tumours by increasing

proliferation, invasion and/or metastasis, andreduced E-cad expression has been associated withtumour growth and metastatic spread to the lymphnodes in many types of cancer. Another paper inNature, published only two weeks before Guilford’sreport, showed that loss of E-cadherin-mediated celladhesion is one rate-limiting step in the progressionfrom adenoma (benign epithelial tumour) tocarcinoma (invasive epithelial cancer) [Perl, A.K. etal. (1998) Nature 392, 190–193)].

Guilford’s team was, therefore, not surprised tofind that many members of the Maori family inquestion did indeed have a mutation in the E-cadgene. What did surprise them were the results fromtwo other Maori families with abnormally high ratesof stomach cancer. Again, a mutation in the E-cadgene seemed to be responsible, but the damageoccurred in two completely different regions of thegene. ‘We had previously assumed that all threefamilies would carry the same mutation and wespent a lot of time tracking down medical recordsand data on family trees to try to show a connection.We now know that the three mutations must havearisen spontaneously and independently,’ saysGuilford.

Now that the genetic cause of their highincidence of cancer has been found, the family facessome tough choices in the years ahead. The time hascome for researchers to start testing samples fromthe surviving members to find out who carries themutation and who does not. Family members haveexpressed their desire to know, and the team isworking with the full back-up of geneticcounsellors. ‘It is an agonising situation,’ comments

Guilford, ‘We know that 7 out of 10 people whocarry the mutation develop stomach cancer.Currently there is no preventative treatment and thetreatment once a cancer is detected – removing thestomach by surgery – is crude to say the least.’

In the short term, family members are beingoffered clinical surveillance every six months. If thecancer is caught early, before it spreads to othertissues, the prognosis is better. The next step is tolook at ways to delay the onset of cancer in mutationcarriers. The three people in ten who carry themutation but show no signs of cancer provide somehope: the team plans to compare them with affectedfamily members for differences in diet, lifestyle,level of Helicobacter pylori infection (a major riskfactor for stomach cancer) and whether they areprone to ulcers. ‘We can eliminate H. pyloriinfection, if it is present, and we can advise on dietsand treatments to avoid ulcers. This is particularlyimportant because the natural healing process thatoccurs at the margin of ulcers involves a reductionin the E-cad expression of stomach epithelial cells.This allows epithelial cells to migrate across thewound but, if small benign tumours happen to be inthat area, this could result in their conversion tomalignant growths.’

There are also a number of compounds thatupgrade the levels of E-cad expressed in cells.Usually, the mutation occurs in only one allele of thegene, leaving one functional allele. If this can beencouraged to express more E-cad to make up forits faulty counterpart, the onset of cancer might bedelayed significantly; even if the cells were tobecome malignant by some other mechanism,increasing the expression of E-cad should act as a‘restraining influence’ that would reduce theirmetastatic potential. One of the most likelycandidates for prophylactic drug therapy istamoxifen.

In the longer term, the team is optimistic thatgene therapy will be developed within five years.They plan to reverse the existing mutation using thecells’ inherent DNA repair machinery. There ismuch work to be done – not least the developmentof an efficient delivery system to ensure that most ofthe stem cells in the crypts can be reached. But howdoes Guilford think gene therapy fits with thecultural beliefs of the Maori family members?

‘Many people from the family started out withquite a high level of suspicion about genetics butthey are equal partners in this project and most arenow very well educated in the science and theethical issues involved. We will continue to takethings carefully and slowly. The bottom linecontinues to be that the individual has the right tochoose.’

Kathryn Senior

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Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00

Maori family initiates successful searchfor stomach cancer gene

Figure 1. E-cadherin and cell–cell adhesion. E-cadherin is a transmembrane molecule that can form homophilic associations with E-cadherin molecules on adjacent cells. Intracellularly, it interacts with theactin cytoskeleton via a, b and g catenin.

Plasma membranes

Intracellularenvironment Intracellular

environment

Extracellularenvironment

E-cadherin Catenins

Actincytoskeleton

βα

γ