Native American women and children, dressed in traditional clothing, at a market.

Everywhere in the world, liver cancer is caused by cirrhosis or viral hepatitis–everywhere, that is, except in Peru.

© François Canard

Tracking the first indigenous cancer in Peru

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IRD scientists and their partners are fighting on all fronts–decoding the molecular signature, exposing the pathological mechanisms, even identifying possible treatment–to stave off a rare form of liver cancer in Peru.

The mystery surrounding a form of liver cancer that only affects Native American groups in Peru is about to be solved. And findings in this area from specialists from IRD, Institut Pasteur and the Peruvian National Institute of Neoplastic Diseases (INEN)Both members of the Collaborative Consortium for the early detection of Liver Cancer (COCLICAN), a project supported by the European Union’s Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) fund and Research and Innovation Staff Exchange (RISE).1 have radically altered our understanding of this type of disease. “We have identified what may be the first indigenous cancer, affecting a specific group of people sharing a particular mitochondrial genotypeTransmitted by the mother, without modification, the DNA of mitochondria makes it possible to identify individuals belonging to the same population, as well as specific pathophysiological mechanisms,” says Stéphane Bertani, a molecular biologist at PHARMA-DEV. An encouraging prospect has now emerged: after ten years working to understand and tackle this deadly form of the disease, scientists and healthcare professionals have identified promising potential treatment...
 

Very young and elderly patients

Hepatocellular carcinoma, the most common form of liver cancer, is responsible for 745,000 deaths worldwide each year. It is the second leading cause of cancer death.

© Adobestock -SciePro

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Throughout the world, hepatocellular carcinomaMain forms of liver cancer, responsible for 745,000 deaths worldwide each year, they are the second leading cause of cancer death.1, a type of liver cancer, primarily affects older patients. The main risk factor is cirrhosis. When this is not the case, it is caused by viral hepatitis. This is true everywhere–except in Peru. There, cases are divided in two groups: very young patients, around 20-years-old, and older patients, around 60-years old. They develop huge tumors–15 cm in diameter–without any prior warning signs.

X-ray image of a Peruvian patient’s torso showing the liver inside the blue frame, with its characteristic tip towards the bottom and shaded tumor

© Eloy Ruiz

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However, although no causal link could be determined, research had already revealed that all patients had been in contact with an indigenous form of the hepatitis B virus. While Peruvian practitioners work to save patients by breaking away from international treatment protocols, which are ill-suited to this form of the diseaseDue to the size of their tumors, Peruvian patients are not eligible for surgical treatment according to international recommendations on the subject. However, by operating in spite of these recommendations, doctors were able to save 30% of patients.1, scientists continue to explore the specific characteristics of this unusual form of the disease…
 

 

A unique tumor subtype

Molecular biology has shown that all Peruvian patients, both young and old, develop the same type of tumors, and are therefore part of the same clinical event affecting both groups,” the specialist explains. “Thanks to sophisticated tools, using parallel computationsAn approach to analyzing computer data simultaneously, without machine learning and artificial intelligence, we have determined that these tumors share a unique molecular signature that cannot be integrated into the international classification system for hepatocellular carcinoma”.

Although they had not developed perceptible viral hepatitis, the patients affected by the Peruvian form of liver cancer were in contact with an indigenous form of the hepatitis B virus (here, using electronic microscopy).

© Institut Pasteur - Charles Dauguet

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In substance, the Peruvian disease is unlike either of the two major categories described for liver cancerProliferative molecular classes (associated with a lower survival rate among patients and hepatitis B viral etiology), more common in developing and emerging countries, and non-proliferative classes (associated with better patient survival rates, alcohol and hepatitis C viral etiology), more common in developed countries.1, which were based on data from China, Japan, Europe and the United States. It is truly an unprecedented cancer subtype.
Furthermore, analysis of the mitochondrial DNA has established common Native American ancestry among all patients, linked to a core group from the ancient Inca empire in the Cuzco and Ayacucho region. “This is the first description of the development of a cancer subtype preferentially affecting people with indigenous ancestry,” explains Sandro Casavilca, head of the Peruvian tumor biobank developed by the National Institute of Neoplastic Diseases in Peru and IRD to archive and study local cancer tissueFor example, the large American microbial bank, ATCC, which manages a vast collection of cancer cells from around the world, has only one cell line from a Native American patient, a colorectal cancer cell.1.

Operation in progress in an operating room, the surgeons all dressed in blue, are busy around the table.

© IRD - Stéphane Bertani

By operating on patients not eligible for surgical treatment according to international criteria, Peruvian doctors were able to save 30% of patients suffering from life-threatening liver cancer.

An incongruous pathological mechanism

In addition to atypical classification and a unique affinity for Native American ancestry, this cancer subtype is also very unusual in terms of its pathological mechanisms. “We have identified a completely incongruous epigenetic process,” says Pascal Pineau, geneticist at Institut Pasteur.

An atypical liver cancer specifically affecting Native American groups in Peru, with unprecedented pathophysiological mechanisms, marked by the expression of strong methyl-based epigenetic signals.

© François Canard

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Cancerous tumors are usually hypomethylated. In other words, the lack of epigenetic tags–attached to the genes–based on methyl groups (CH3) weakens the structure of the genetic information. This upsets the expression of the genes involved in cell division and the control of tumor proliferation. In this case, the opposite occurs: Peruvian tumors are hypermethylated, which means they receive strong epigenetic signals, causing them to behave as embryonic cells, dividing chaotically to form huge aggressive tumors.
The genomic analysis also revealed interesting leads...

The promising potential of vitamin A

We discovered that the genes in the cancer cells that contribute to retinoid metabolism and retinoic acid activity–vitamin A, which plays a key role in normal cell differentiation–are simply not activated,” says Pascal Pineau. Significant deficiencies observed in patients–75% had levels below the values established by WHO and 60% had clear deficiencies–seems to confirm the role of vitamin A, or rather the lack thereof, in the occurrence or development of the disease.

The atypical Peruvian liver cancer affects very young and older patients, without any detectable history of cirrhosis or viral hepatitis.

© François Canard

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An in vitro experiment on cell cultures comparable to those of the Peruvian tumors confirmed this hypothesis and also opened up a promising possibility for treatment: “The addition of vitamin A inhibits the growth of these cells,” Stéphane Bertani explains. “We can therefore consider the possibility of ending tumor development through suitable supplementation. We are already preparing to initiate a clinical trial in this area,” he says.


 

    Colored reconstruction of a mummy's skull.

    © Wikipedia - Cicero Moraes

    Analysis of genomes from 4,000-year old mummies discovered at the Caral site in Peru could provide insight on co-evolution of Native American and indigenous groups and the hepatitis B virus.

    Mummies, viruses and archeogenomics  

    Native groups have been in contact with the indigenous form of the hepatitis B virus since time immemorial, suggesting a link with the development of the disease... “It was unsettling to discover early cancer in indigenous Yupik patients in Alaska, similar to what had been observed among Native Americans in Peru, also associated with the same type of viral infection,” says molecular biologist Stéphane Bertani. “It suggests that a co-evolution of this hepatitis B virus and Native American groups could be responsible for the early onset of liver cancer among young Native Americans.” In order to explore this interesting hypothesis, the scientists initiated an original study combining modern molecular biology and archeogenomics: in addition to studying the genome of patients with tumors, they will also analyze the genome of 4,000 year-old mummies discovered in Caral, site of the oldest civilization of the Americas, which is listed as a UNESCO World Heritage Site. “This comparison will enable a clearer reconstruction of the evolutionary history connecting Native American groups with the hepatitis B virus,” he says. “In addition to providing scientific knowledge, this could help us develop a profile of vulnerable individuals with a higher risk of developing sudden and early liver cancer, in order to consider targeted preventive measures.”