What Do You Do When The Guardian Of The Genome Fails?

On one of his visits to the hospital, cancer survivor Bazli Kezi reveals he has not gone for his post-cancer screening for over a year, a fact his doctor is shocked and dismayed to discover.

“You cannot ‘not go’ for follow-up. You must go for follow-up screening, ” admonishes Dr Kavitha Rethanavalan, consultant clinical geneticist at Kuala Lumpur Hospital (HKL). 

Bazli frowns, perplexed. “But they will (CT) scan me,” he says. Dr Kavitha assures him that the screening would be done via radiation-free magnetic resonance imaging (MRI).

While Bazli’s fears may sound odd, he has cause for worry.

He has been skipping his follow-up appointments for a simple but unusual reason. Instead of just detecting cancer in its early stage, he is afraid the computer tomography (CT) scans and the radiation may give him another tumour. Post-cancer surveillance usually involves a CT scan every few months or years.

The 60-year-old father of four has Li-Fraumeni Syndrome, a rare and inherited disorder that predisposes him to various cancers due to a mutation in his TP53 gene, a tumour suppressant gene found in every cell in the body. The disorder can cause more cancers to develop anywhere in the body, making it challenging to monitor and treat.

Li-Fraumeni is estimated to occur in one out 5,000 to 20,000 people. In Southeast Asia, the first case was reported in 2008 in an eight-year-old Malaysian girl, according to a research paper published by Ariffin, H et al. in Cancer Genetics Journal. Three generations of the girl’s family developed cancers at a young age. 

Despite its rarity, health officials say there is a need for more genetic testing in Malaysia to identify Li-Fraumeni cases early and ensure that carriers can take appropriate precautions to stay alive.

“So the TP53, you need to know the gene before you plan for treatment. Because some of these genes are radiation sensitive, sometimes if you (receive radiation) as part of the (treatment for the) primary cancer, it can cause secondary cancers,” explains Dr Kavitha.

GENERATIONAL CANCER

One can find out through their DNA whether they are likely to go bald or prone to developing diseases like diabetes, cardiovascular disease or cancer. In Bazli’s family, the effects are undeniable. In his family tree, several branches of his paternal line developed cancer, such as his aunt and five out of her seven siblings. A few died including his father. 

His generation is not faring well either. His youngest brother passed away three months ago at the age of  43. The latter had kidney cancer and was unaware of his genetic status when he underwent cancer treatment. He then developed colon cancer.

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Bazli too experienced something similar. In 2013, he was diagnosed with soft tissue cancer, or rhabdomyosarcoma, in his left arm. He too was unaware of his TP53 mutation at that time and underwent several bouts of cancer treatment for the rare and aggressive cancer, including radiation therapy. He also had to amputate his arm.

Four years later, he developed cancer in the soft tissue in his torso, which also affected his lungs. Doctors removed a 12-cm tumour from his abdomen and a third of his lungs. 

Bazli never thought his family history of cancer meant tools and therapies to save lives were risking theirs instead.  

His aunt, who is fighting cancer for the third time, was the first person from the family to consult the genetics department at HKL. Once doctors found the mutated TP53 in her genome, three generations of the family were asked to do a genetic test. Some agreed, some refused. 

“My younger siblings didn’t want to come (to do the test). I don’t know if they were scared or couldn’t be bothered,” Bazli said.

The cancer patients in his family tested positive for Li-Fraumeni. A few family members who did not have cancer also tested positive, including his youngest brother’s child. Others were negative.

Li-Fraumeni Syndrome is an autosomal dominant gene, which means carriers have a 50 percent chance of passing it to their children with each pregnancy.

“(The TP53 gene produces) P53, (which) is the protein that is a guardian of the genome. And if anything happens to the DNA, for example, some damage, the P53 will… try to repair this (damage),” explained Professor Dr Thong Meow Keong, clinical geneticist and visiting consultant at Sunway Medical Centre in Subang Jaya.

He said if the protein, dubbed guardian of the genome, was not working properly, then any part of the body containing it would probably develop cancer sooner or later. 

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Cancers associated with Li-Fraumeni Syndrome include cancers of the muscle, soft tissue, outer layer of the adrenal gland, brain, breast and bone. The chances of developing cancer before the age of 40 are 50 percent, going up to 90 percent for women in their lifetime and 70 percent for men.

“So nothing can escape this. So it can be quite devastating in that sense,” added Dr Thong.

For anyone who tests positive, including children, it means a lifetime of full-body MRIs to detect any tumour early. 

As such, doctors say they are careful not to push patients to do the genetic testing until they have been fully counselled and understood the implications of knowing and not knowing. The final decision is up to them.

There are many reasons why possible carriers would not undergo genetic testing. Some feel they may not be able to deal with the stress of knowing how they may die. Others may fear the stigma and financial consequences that come from testing positive for Li-Fraumeni, and any other inherited cancer disorders like Lynch Syndrome and Hunter’s Syndrome.

Nevertheless, Dr Thong, who is also the medical advisor for the Malaysia Rare Disorders Society, said doing the genetic test would be to the patient’s benefit.

“Well, you know, because of the high risk (of cancer), and I would think that (being proactive and undergoing regular screening for early detection) would save lives,” he said.  

KNOW YOURSELF

Doctors and genetic counsellors support the idea of more genetic testing so as to prepare the public to take preventive steps for inherited diseases. As it stands, there is not much data on disease risk in Malaysia, which interferes with planning healthcare strategies.

“We hope to do better with the next generation after we do the genetic test because surveillance is how to monitor for cancer,” said Dr Kavitha.

The government, through the Ministry of Science, Technology and Innovation and the Ministry of Health, is on the same wavelength and launched MyGenom Project last year. The project aims to collect DNA samples from 10,000 healthy Malaysians of all ages and races.

“The main objectives of this project are for local capacity building in genomics and big data and to establish a local genetic reference for precision public health,” the National Institutes of Biotechnology Malaysia, which is involved in the project, said in a statement to Bernama. 

It said the findings would complement Singapore’s genomic study, which found that almost one out of 150 Singaporeans carried the BRCA mutation that carries a high risk of developing breast and ovarian cancer in women, and prostate cancer in men.

The statement did not say whether they would inform their subjects if they tested positive for any genetic disease.

However, knowing oneself at the molecular level is not without its pitfalls. For one thing, there is the fear that people will lose their medical insurance due to the “pre-existing disease” clause. There is also the issue of passing on faulty genes to the next generation. While there are ways to ensure healthy children, the methods are not without controversy.

As for Bazli, he is relieved to know the reason behind his family history of cancer so he can minimise his risks. He constantly reminds his relatives, children and four grandchildren to monitor their health.

Despite losing his limb and part of his lungs, which makes him breathless at times, he tells Bernama he prefers not to dwell on what he has lost.

“(Be) strong, don’t wake up in the morning and immediately think about your illness. Otherwise, without realising it, what was supposed to be just five minutes of thinking will turn into an hour. It’s better to take a shower and do something — do whatever you want, whether it’s meeting friends or anything else. Just avoid being depressed, simple.”