NZASE science Gene seekers save lives research

Participants at the 2019 International HDGC guidelines meeting in A discovery made by a Bay of Plenty whānau Wanaka. Maybelle McLeod is in the centre in yellow, with Parry Guilford and University of Otago geneticists has saved to her left. Photo: Han Kwang Yang. the lives of hundreds of people in Aotearoa and around the world, including singer Stan Walker. (lining cells), especially in the Background stomach and breast. Mutations in CDH1, which switch off the Walker, right, is part of the whānau, which was protein, are inherited in an auto- affected by a form of gastric (stomach) cancer somal dominant manner. known as hereditary diffuse gastric cancer Some of the biology and (HDGC) that could develop in those as young genetics of HDGC, and the story as 14. In 1995, the whānau recruited geneticists of the partnership up to the dis- Whanau member Stan from the University of Otago in a partnership covery of the mutated gene, was Walker; see Links panel. research project. At that time, finding cancer told in 2001 in The gene seekers genes was possible only in very large families. by Learning Media, right. The whānau compiled their whakapapa, the largest known familial gastric cancer Later discoveries genealogy at that time, and gathered blood Since then the research part- samples from members. This involvement ners have learnt more about the was unusual at the time, making them co-re- gene, developed tests and treat- searchers rather than research subjects. ments, navigated more ethical The geneticists used this information to issues and saved many lives. search for mutations and in 1997 identified The whānau team is still led by the genetic mutation in the CDH1 gene that Maybelle McLeod, Manager of the Kimihauora caused the cancer in the whānau. This was Health and Research Clinic, next to the whānau the first time this gene had been identified as marae, Tamapahore, on the outskirts of Pa- responsible for gastric cancer. pamoa. Maybelle worked with Whānau Co-or- CDH1 encodes a protein called E-cadherin dinator Pauline Harawira and Aroha Kakau, that helps cells stick to each other in epithelia Whānau Liaison. They wrote two applications for research funding in the 1990s and a later Links to the curriculum one with Dr Parry Guilford, who led the team – Patterns in the inheritance of L6 Living World that identified the gene. He is now a Professor genetically controlled characteristics L7 Living world – DNA and the environment and Director of the University of Otago Centre interact in gene expression for Translational Cancer Research. L4 Nature of Science – Ways in which scientists Once the geneticists identified the CDH1 provide evidence to support their ideas mutation, they developed a diagnostic blood NoS Understanding about science aim - ways test, which sequences the CDH1 gene to find in which the work of scientists interacts with any mutations. society. Every country where the test has been

Representing the needs of science teachers NZASENew Zealand Association of Science Educators tested only for the cancer research, and were “never to leave the country”, says Maybelle. “We went to the lab, they showed us where it was stored and we were happy.” The genet- icists also agreed to report regularly to the whānau. The structure of the E-cadherin protein. All of this was new ground for the genet- used has identified families with HDGC – so icists, but Parry says that such treatment of far 500 families are known worldwide and 20 samples is “pretty standard in New Zealand in Aotearoa. Family members have a one in genetics labs now.” two chance of carrying the mutated gene and The contract also shared any intellectual those with the gene have a 70 percent chance property, such as the patent for the genet- of developing HDGC, and women have a 40 ic test, between the partners. This too was Members percent risk of lobular breast cancer. new. The United Nations said that the project of the research Over 300 Bay of Plenty whānau members provides a model for indigenous families with partnership have been tested for the gene, and more than inherited conditions working with geneticists. in 1999 67 have the mutation. When they are tested, usually at around 20 years old, those found with the mutation have a choice. A few have their stomachs removed (gastrectomy) before cancer symptoms develop, but most choose regular check-ups. These involve endoscopic examina- tions of their stomach lining, looking for subtle Testing protocol changes in texture and colour. However, such In 1998, the whānau formed the Aotearoa monitoring is not guaranteed to find cancer if it Stomach Cancer Susceptibility Project to iden- exists. tify other affected whānau around the coun- Microscopic analysis of removed stomachs try. They also negotiated a protocol for coun- revealed multiple tiny cancer sites underneath selling whānau members when they received an intact surface, which developed without their test result and a monitoring programme symptoms. These small tumours could be with the Tauranga Hospital for those known to missed by endoscopy. have the mutation. Women with the mutated gene also have an- The geneticists had referred the whānau to nual mammograms. Since the first 150 diagnos- the Northern Regional Genetics Service, which tic tests, no whānau member has died of HDGC: used a Pākehā genetic counselling process of “They’re all alive and happy,” says Maybelle. one counsellor telling their test result confi-

Research contract From

Ngā Kupu Paekupu Many aspects of this research have set prece- Irakē - Genetic mutation dents in medical research. The legal contract

Iranga tuku iho - Genetic inheritance and between the whānau and Otago University set Kiripuku - Stomach lining out the ownership and tikanga for the tapu Te Aka Maori Dictionary Mate pukupuku – Cancer blood and tissue samples held by the geneti- Paetara pūtau – Cell membrane cists in Dunedin. Pūtau – Cell The samples and the whakapapa remain Tapu – Sacred the property of the whānau. They had to be Tikanga – Protocol coded for anonymity; kept separate from ani- Urihaumate – Patients mal samples, other human samples and food;

Representing the needs of science teachers NZASENew Zealand Association of Science Educators Stomach cell culture spheres ness, diarrhoea or vomiting. Says Parry: “While in the Dunedin lab with gastrectomy stops people dying, we want to early-stage cancer. Photo: Tanis Godwin and Yasmin replace that operation with a drug and regu- Nouri. lar monitoring.” The genetics team has been searching for such a drug for the last 12 years. dentially to one client. The team investigated the preventive action This was not going to of valproic acid, used to treat epilepsy and work for the whānau. bipolar disorder, against epigenetic affects in “We had to have a kaumatua and family HCG cancer. But they decided that drugs that members there,” says Maybelle; “members could be taken every five years would be more couldn’t do it on their own. The Pākehā coun- sustainable for people with the mutation than sellors were genuinely interested in the ti- drugs that had to be taken every day. kanga, and had to be informed about how we About 200 mutations in the CDH1 gene have wanted it.” Whānau members now have the been identified. The geneticists’ work suggests choice of whether the counsellor or a whānau that these mutations affect receptors on the member gives them the test results, and al- cell surface which send signals into the cell most all choose whānau. that control cell survival. So they are testing As new Māori families with HDGC were drugs that affect the cell surface receptors and identified in Aotearoa and Australia, whānau the signalling pathways into which they feed. representatives travelled with gastroenterolo- “Our goal is to find vulnerabilities in CDH1 gists (medical stomach specialists) and genet- mutant cells that make them sensitive to cer- icists to help those families set up local testing tain drugs,” says Parry. and treatment. “We work as a team,” says Other scientific teams are also studying Maybelle. “For 24 years we’ve all met once a how to enhance the endoscopic examination year at the marae.” to better show potentially cancerous and Previously, most medical research was led hard-to-detect changes. by scientists who laid out the options. Here Says Parry: “We want to be able to offer the whānau was intimately involved in ex- children of the affected whānau an alternative plaining the tikanga, working with new fami- to stomach removal by the time they reach 16. lies to ensure the best outcome and share the We have a photo of young girl from one of the knowledge the partnership had gained. families outside my door. It reminds people in The whānau team also helped write guide- the lab that we need to have a treatment for lines for medical treatment of the condition, her by the time she is old enough to need it.” and helped revise them at the 2019 Heredi- Maybelle expresses a feeling shared by many tary Diffuse Gastric Cancer Consensus Clinical in the partnership: “I feel proud when I look Guidelines Meeting in March 2019 in Wanaka. back. I visited a family member who lost some There, for the first time, Maybelle met mem- of her children to HDGC, but we were able to bers of other families whose lives had been save the grandchildren. If we hadn’t done any- saved as a result of the research project the thing they’d still be panicking, but now there’s whānau started. “They were all coming up, nothing to panic about.” shaking my hand and being so grateful; I felt overwhelmed.” Links Further research • Stan Walker article Stomach removal is a drastic and risky opera- • Stan Walker documentary tion, causing lifelong vitamin B12 deficiency. • Epigenetic chemoprevention of gastric While most people get back to their normal cancer lives, for up to three years they can eat only • Current understanding of the biology small portions of food at a time, can’t tolerate of this gene and its mutation (10-page some foods, and may get regular fatigue, dizzi- academic article)

Representing the needs of science teachers NZASENew Zealand Association of Science Educators