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Discovery of Inherited Mutation Sheds Light on Increased Cancer Risk in Brazilians


NEW YORK – A team of researchers at St. Jude Children's Research Hospital and their global partners have identified a variant in the tumor suppressor gene XAF1 that increases cancer risk in Brazilian carriers when coupled with an inherited TP53 founder mutation.

It has been known for more than 20 years that a unique inherited variant in the TP53 gene found in one in 300 people in Southern and Southeast Brazil, TP53-R337H, correlates with an increased risk of developing a variety of cancers, including adrenocortical tumors, breast cancer, sarcoma, and thyroid and lung cancers. However, the extent of this risk varies significantly between mutation carriers, which has made it challenging to establish screening, surveillance, and management programs.

"Of the carriers of this TP53-R337H mutation, you have people that never develop cancer during their lifetime, and then you have individuals that develop a single cancer and individuals that develop two or more tumor types," said Emilia Pinto, a scientist in the department of pathology at St. Jude, who has been researching the cancer risk association in this population. "Everyone [with this mutation] goes through the same protocol of intense imaging and examination, but we don't know which people deserve to have lighter surveillance. Now, we have an explanation."

In a recent publication in Science Advances, Pinto identified a new mutation, XAF1-E134, in Brazilian patients and reported that when individuals have this and the TP53-R337H mutation, their lifetime cancer risk is much greater than that of those with just the TP53-R337H mutation.

Within a worldwide meta-cohort, the TP53-R733H mutation is "rare and virtually absent," wrote Pinto and colleagues in their paper. But within the Brazilian population, the one-in-300 frequency of the mutation puts these new findings on the XAF1 variant in a position to have significant clinical and public health implications.

In a study of more than 40,000 newborns in Brazil, the researchers found that 69 percent of the 147 individuals who harbored the TP53-R337H mutation also had the XAF1-E134 mutation. Also, within a cohort of over 200 patients with cancer who had the TP53-R337H mutation, the researchers found that 79 percent also harbored XAF1-E134. The fact that the frequency of the XAF1-E134 mutation was higher among cancer patients with a TP53-R337H mutation than among infants with the TP53-R337H mutation— not all of whom, presumably, develop cancer — supported the correlation between XAF1-E134 and cancer risk.

Stratified by cancer type, the researchers found that the presence of both mutations was higher in certain kinds of tumors. Specifically, in sarcoma patients with the TP53 mutation, the prevalence of the XAF1 mutation was 93 percent.

"When we found this, I thought, 'Oh my gosh, this is what we were missing.' This is going to be truly important," Pinto said. The discovery, she noted, will be particularly helpful in tailoring surveillance strategies for people with both mutations.

Currently in Brazil, increased cancer screening is recommended for everyone known to harbor the TP53-R337H mutation, Pinto said, and a comprehensive screening protocol coined the "Toronto Protocol" is typically followed. The protocol, which is also recommended for patients with Li-Fraumeni syndrome in numerous other countries, consists of frequent examinations and screening tests, including whole-body MRIs, ultrasounds, and, for adults, earlier and more frequent colonoscopies, endoscopies, and mammograms, among other tests.

"When you live your life always looking for something, it compromises quality of life," Pinto said, explaining that the knowledge of the XAF1-E134 mutation can help focus screening strategies to those at the highest cancer risk and to specific tumor types.  

Elucidating the role of XAF1-E134

The process of identifying the XAF1-E134 mutation and its role in cancer risk began with whole-genome sequencing and whole-exome sequencing of 12 Brazilian patients with adrenocortical tumors carrying a TP53-R337H allele. In five of these patients, the researchers zeroed in on an extended chromosome 17p13 haplotype that contained a mutation of the tumor suppressor gene XAF1.

A series of cell-based and mouse model studies allowed the researchers to clarify the role of XAF1 — and the XAF1-E134 variant — in the development of cancer. Specifically, Pinto explained, XAF1 functions as a tumor suppressor gene in a p53-dependent manner. When researchers irradiated tumor cells with both XAF1 and TP53 mutations, there was no increase in the expression of genes targeted through the p53 pathway, suggesting that the tumor suppression function was hobbled. Then, when the researchers repaired the XAF1 gene using CRISPR editing, expression through the p53 pathway was restored.

"If you have a TP53 that works, XAF1 improves this activity," Pinto explained. "And, if you have a TP53 that is a little bit broken, normal XAF1 can improve the activity of the TP53. But not when the XAF1 is broken, too."

The understanding of how the coupled TP53-R337H and XAF1-E134 mutations work together to increase cancer risk, as well as the prevalence of both mutations in patients with cancer, Pinto said, will have lasting implications for patients, both in terms of cancer risk surveillance in the near term and the development of targeted treatment strategies down the line.

This is only the first paper detailing this finding, acknowledged Pinto. "We need to learn more," she said.

Implications for Brazil and worldwide

Currently in Brazil, the role of TP53-R337H is well known among experts, and larger cancer centers and neonatal divisions within some hospitals have launched programs to screen for the mutation. Although the XAF1 finding is new, screening for this additional mutation is already happening within 10 Brazilian institutions that collaborated with St. Jude on this research, according to Pinto.

The next step will be to integrate the screening for the XAF1 mutation into routine tests for infants across Brazil and manage lifelong surveillance accordingly. For those found to have both mutations, for instance, Pinto said the management might involve screening for specific cancers at appropriate ages, such as for adrenocortical tumors in children and breast cancers in young-adult females. The specific protocol for managing these cases is not yet set in stone, she said, but "this is going to be important for addressing this health problem in Brazil."

The finding also has implications for family members and creating an infrastructure for cascade testing. "Every time we have a patient [with both mutations], we need to call the family members," Pinto said. "We need to educate other institutions and teach them to do [this screening]."

Such screening strategies should also be considered in Portugal and Spain, in Pinto's view, due to historic colonization patterns. Although the TP53-R337H mutation is less frequent in those countries than in Brazil, it still occurs in Portuguese and Spanish patients, and experts believe that this mutation showed up in the people of Brazil when the Portuguese colonized the country centuries ago.

Ultimately, Pinto hopes that this research, specifically the process through which she and her colleagues identified this second mutation and its association with cancer risk, will become a model for different regions seeking to better define cancer risk within their own populations. "We have here a model that probably happens for other genes, not just p53," she said. "Maybe it happens for BRCA1/2 … or for other genes [for which] we don't have the full explanation. That could probably be something that people start looking for."

Finally, Pinto said, one of the biggest takeaways from this paper is that it highlights the importance of global collaboration in genomics research. The research was conducted within the St. Jude Global program, which is a worldwide alliance of institutions that St. Jude's Department of Global Pediatric Medicine established in 2018. The consortium-like program enables worldwide sharing of data, knowledge, technology, and organizational skills to advance research and aims to improve care for children with cancer globally.

"Because of St. Jude Global, we have been able to collaborate with Brazilian and European institutions and group this data together," she said. Pinto, who is Brazilian but works for St. Jude and maintains the International Pediatric Adrenocortical Tumor Registry within her lab, emphasized that international collaboration has been crucial to her research throughout her career.

Indeed, the partnerships forged through the St. Jude Global Alliance established programs in Asia, Central and South America, China, Mediterranean regions, Eurasia, Mexico, and sub-Saharan Africa, and were key to providing the samples needed to conduct this research. These collaborations, Pinto hopes, will likewise lead to additional findings that have critical implications for public health worldwide.