by Karina Ninni, FAPESP

Solar explosion graph depicting spectrum of PGVs and VUSs in pancreatic cancer patients. Inner circle: Number of patients who are PGV carriers, VUS only carriers, neither PGV nor VUS carriers in the panel of genes (wild type); Medium circle: list of PGV affected genes in 37 participants; Outer circle: spectrum of VUS in the panel of genes in PGV carriers and non-carriers. *One patient who was a PGV carrier in CHEK2 and one patient who was a PGV carrier in ATM presented no VUS, but were considered together with the other patients who were PGV carriers in CHEK2 and ATM and were also VUS carriers. Credit: Scientific Reports (2024). DOI: 10.1038/s41598-024-71884-4

Pancreatic cancer has recently been included in the list of diseases about which Brazil's National Cancer Institute (INCA) periodically publishes statistics. Although it is not the most frequent type of cancer, its high lethality makes it one of the leading causes of death from cancer in Brazil, partly owing to late diagnosis.

"It's striking how little data on the disease is available in Brazil and indeed in Latin America as a whole. There are no studies on pancreatic cancer involving Brazilian patients because its incidence is low in this country compared with breast and lung cancer, for example. Yet it's the type of cancer with the highest mortality rate—and it kills very quickly," said Lívia Munhoz Rodrigues, a researcher at the São Paulo State Cancer Institute (ICESP) with a Ph.D. in oncology from the University of São Paulo's Medical School (FM-USP).

Leading a team that included other researchers at ICESP, as well as collaborators at FM-USP's Department of Legal Medicine, Bioethics, Occupational Medicine and Physical Medicine and Rehabilitation, and the D'Or Research and Education Institute (IDOR), Rodrigues conducted a pioneering study of 192 pancreatic ductal adenocarcinoma patients treated at ICESP between 2018 and 2022 at the expense of the SUS (Sistema Único de Saúde), Brazil's public health network. Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer.

The scientists used genomic DNA sequencing to look for alterations to 113 oncogenes—genes that can cause cancer when they undergo mutation or are activated in an abnormal manner—in the shape of pathogenic germline variants (PGVs), which are hereditary mutations.

They found that 6.25% of the study sample (12 patients) had PGVs in genes known to entail a predisposition to pancreatic cancer, while 13% (25 patients) had PGVs in genes associated with pancreatic cancer to a limited extent or not previously associated with the disease.

"We didn't pre-select the sample based on a family history of cancer, and that's one of the strengths of our study. Moreover, the patients included were born in almost every region of Brazil, the only exception being the North: 125 were born in the Southeast, 65 in the Northeast, four in the South, and four in the Center-West," Rodrigues said.

The study is published in the journal Scientific Reports.

"The study was innovative in two ways. First, it involved a representative cross-section of the Brazilian population, which is multiethnic and had never before been the object of pancreatic cancer research. The second innovation was our detection of alterations in genes not previously associated with the disease. There may or may not be an association—we can't say with certainty just yet. More research is needed," said Maria Aparecida Azevedo Koike Folgueira, last author of the article and a professor in FM-USP's Department of Radiology and Oncology.

She is particularly interested in two of the genes associated with the disease to a limited extent. They protect telomeres, the tips of chromosomes that enable cells to divide without losing genes.

"These two genes can be associated with melanoma. We haven't found an association with pancreatic cancer, but we'll be researching this point further," she said.

She also cited several reasons for considering the study highly important. "We're in an era of genetic sequencing and we're discovering the causes of cancer, among which are hereditary genetic mutations that can underlie a predisposition to the disease. Many studies of Europeans, Americans and Asians have been published, but only now do we have a study of a large population as multiethnic and genetically admixed as Brazil's," she said.

Studies of Americans and Europeans have pointed to ethnic differences such as a higher prevalence of PGVs in the genes BRCA1 and BRCA2 among Ashkenazi Jewish patients. Brazil has not compiled statistics on PGVs associated with pancreatic cancer, but data on PGVs associated with breast cancer is available, and the researchers stress the need to fill this gap by finding out more about the Brazilian population.

"At least 20% of previous studies on pancreatic cancer in Caucasians involved patients pre-selected by family history, increasing the likelihood that the scientists detected variations in these genes with higher penetrance. We didn't pre-select our samples based on family history, which is also why we had fewer patients with pathogenic variants in the genes BRCA1 and BRCA2.

"In addition, we had five patients with variants in FANC, a specific gene family. That's unusual and an important finding, but we still have a long way to go to understand its role in pancreatic cancer," Rodrigues said.

According to the researchers, FANC genes produce proteins that repair DNA. "Most of the genes in which we found alterations encode DNA repair proteins, performing a very important function," Folgueira said.

Early diagnosis

The group went further, sequencing the exomes (protein-encoding regions of the genome) in tumors from six patients. They set out to find alterations potentially reflecting the function of the genes in question.

"We sequenced both the blood cells, to see the alterations that were inherited, and the tumor, to investigate the alterations that were already happening and were responsible for its malignancy. In light of the tumor alterations, it wasn't possible to confirm that alterations in the blood were responsible for the disease. We focused on functionality," she said, stressing her concern with the lethality of this type of tumor.

"Most pancreatic cancer patients die from the disease, so early diagnosis is crucial. Discovering these alterations can assist treatment since some are therapeutic targets. Effective medications already exist for alterations to BRCA1 and BRCA2, for example."

In the U.S., she added, anyone with pancreatic cancer is referred to a genetic counselor and submitted to genetic testing, in accordance with guidelines issued by the National Comprehensive Cancer Network (NCCN). In Brazil, genetic tests are not covered by the SUS and have to be approved by private medical plans or insurers.

"Pancreatic cancer exams and tests include magnetic resonance imaging [MRI] or transendoscopic ultrasonography [using an endoscope with an ultrasound device at its tip]. Both cost more than a mammogram, for example. In our view, therefore, studies of cost-effectiveness are needed to find out whether the cost of screening for detection of pancreatic cancer, which is high, is offset by savings due to early diagnosis and treatment of high-risk patients. This is one of our next steps," Folgueira said.

Rodrigues pointed out that only 37 of the 192 patients in the study sample had pathogenic germline variants in some of the 113 genes investigated.

"What about the rest? Well, they didn't have PGVs in the genes we investigated, but half of them were smokers and 60% were overweight or obese. So it's important to stress the significance of a healthy lifestyle and get people to understand that they should quit smoking and keep alcohol consumption to a minimum. These factors may impact the pancreatic cancer statistics," she said.

More information: Lívia Munhoz Rodrigues et al, Prevalence of germline variants in Brazilian pancreatic carcinoma patients, Scientific Reports (2024). DOI: 10.1038/s41598-024-71884-4

Journal information: Scientific Reports 

Provided by FAPESP