The most important tumor database in Latin America

The A.C. Camargo Cancer Center biorepository maintains tumor samples from more than 30,000 people. Each sample is correlated to patient data and individual disease history.

By José Tadeu Arantes

Agência FAPESP – When FAPESP and the Ludwig Cancer Institute launched the Human Genome Cancer Project in 1999, the A.C. Camargo Hospital – to which the institute belonged – began to store samples of tumor tissues from cancer patients. This material resulted in the first, largest and most important biorepository in Latin America, which contains tumor samples from more than 30,000 people.

This tumor database became a valuable research and development tool for the diagnosis, prognosis and treatment of cancer. Each sample is associated with patient data and disease history. Thus, in addition to the tumor database, which contains the pathological data, there is a clinical database of patient information, and the two are integrated.

As an example, this allows the characteristics of each tumor tissue to be studied in relation to the development of the disease in its carrier and the response to treatment. At the same time, it also enables the data to be analyzed and compared with the tissue data and clinical responses of other patients in an effort to find mechanisms that allow early detection or predict the development of the disease.

“Thanks to this tumor database, we were able to request funding from FAPESP to participate in the Research, Innovation and Dissemination Centers (RIDC) Program, which allowed the project to be carried out and expanded,” explained pathologist Fernando Soares, director of the hospital’s Pathology Department – recently renamed the A.C. Camargo Cancer Center.

Soares led the Antonio Prudente Cancer Research Center, which was approved during the first round of the RIDC Program in 2000 and funded by FAPESP for a period of 11 years. The research conducted by this RIDC has continued at the Ricardo Brentani International Center for Research (CIPE), and its laboratory infrastructure has been absorbed by the Center for Research Pathology (CPI), both located at the A.C. Camargo Cancer Center.

Samples deposited in the tumor database are collected from patients who are undergoing surgery. The removed tumor is then analyzed by pathologists to determine the proper treatment, and the excess material is processed under “highly controlled conditions” before being frozen in liquid nitrogen or embedded in paraffin, among other procedures.

“Immunohistochemical tests or genomic analysis techniques allow us not only to make the diagnosis but also to obtain a variety of additional information about the tumors, such as their resistance to particular treatments and measurement of the prognostic biomarkers,” explained Vilma Martins, director of the Ricardo Brentani International Center for Research.

She reports that with the structure now available at the Antonio Prudente Cancer Research Center, cell lines can be generated from these tumors and utilized in animal models to understand the mechanisms associated with the tumor process. “Today, we have a structure that allows us to study these tumors at the molecular, cellular and system levels, using a variety of experimental approaches,” said Martins.

Sample collection and storage occur only with authorization from the patient or her legal guardian, signed in a document known as an “Informed Consent Form.” The stored material is encoded to ensure the privacy of the patient and all associated information. Studies that use material from this tumor database are evaluated and approved by the Research Ethics Committee and, in some cases, by the National Commission for Ethics in Research.

The patients who visit the A.C. Camargo Cancer Center every day directly benefit from these studies. “Today, there is a set of routine procedures in the hospital that have been the direct result of the research – knowledge acquired in research that has been incorporated into patient care,” Fernando Soares noted.

Prevention and diagnosis

One of the principal uses of the samples of the A.C. Camargo Center Tumor Database in the cancer study is to search for genetic variants that lead to an increased risk of developing cancer. The carriers of these variants benefit from the adoption of preventive measures or early treatment. A DNA variant, for example, may allow the identification of risks for the disease in patients who do not yet have clinical symptoms and trigger prevention actions.

“One practical case is the detection of mutations associated with family cancer syndromes that allow us to identify asymptomatic individuals who are at risk for developing the disease. In this case, the patients can be monitored, diagnosed and treated early,” said Vilma Martins. “The patients and their families are then sent for genetic counseling at the Oncogenetics Department, which was established and expanded during the RIDC project at the A.C. Camargo Cancer Center,” she explains further.

One line of research into this topic was to analyze mutations in the BRCA1 and BRCA2 genes in women who develop breast cancer at an early age. Mutations in these genes, which have a tumor suppression function, predispose patients to breast and ovarian cancer.

The study, developed jointly with researchers from the School of Medicine of the University of São Paulo, was conducted on women who had breast cancer between the ages of 20 and 35. Both BRCA1 and BRCA2 were analyzed, beginning with sequencing DNA obtained from the patients’ blood. The greatest benefit of this study was the possibility of identifying not only those patients at risk but also high-risk families. On the basis of the study, the hospital began to make the test available to detect mutations in those genes as a method of early diagnosis.

“The mutations in the BRCA1 and BRCA2 genes that are associated with a history of breast or ovarian cancer in a family indicate a higher probability that the disease will manifest itself. Therefore, the sequencing of these genes can be offered to patients who have this kind of family history,” explained Vilma Martins.

Li-Fraumeni syndrome

A potential family cancer that has been widely studied and characterized is Li-Fraumeni syndrome, which increases susceptibility to the development of tumors in children (brain, kidney and adrenal glands), adolescents (sarcoma) and young adults (breast). In Brazil, the presence of a specific mutation in the TP53 gene, known as R337H, was identified in patients with this syndrome or related syndromes, and it is estimated that this mutation is present in 0.3% of the Southern region’s population, increasing the risk of developing cancer over one’s lifetime.

“The studies conducted at A.C. Camargo have led to implementation of a genetic test to identify the mutation and diagnose tumors in patients who have a family history associated with the syndrome. Furthermore, the test is offered to the family members of these patients, and carriers of the genetic variant are monitored regularly for early detection of these tumors,” said Martins.

Studies that have used the tumor database have allowed the establishment of protocols for notifying individuals at high risk of hereditary tumors. If a condition of actual risk is identified, the patients go on to receive stricter medical monitoring, which increases the probability of success.

Another breast cancer study identified markers that may predispose individuals to the progression of a tumor still in its very early stages. This type of tumor, termed in situ, demonstrates only a slight capacity for becoming a significant disease, but a small percentage of the cases may develop into one. In seeking a cure for female carriers, the standard treatment usually ends up being aggressive.

The great challenges were to identify which tumors were at risk of becoming invasive diseases while still in the very early stages and to properly treat their carriers, saving others from more aggressive treatments. The research has identified a group of genes with such potential, and these are now being validated in a greater number of cases. A study, also aimed at the possibility of early diagnosis, analyzed tissue samples from patients with gastritis, intestinal metaplasia (gastric epithelial cell differentiation in intestinal cells) and stomach cancer.

Some patients with gastritis develop intestinal metaplasia. The research has shown that carriers of metaplasia and stomach cancer have very similar gene expression profiles. By analyzing the gene expression profile and comparing these two groups with each other and normal tissues, researchers were able to identify classifiers that enabled distinctions to be made between tumor and non-tumor samples.

“Two functional modules, one related to lipid metabolism (active in samples of metaplasia and inactive in adenocarcinoma) and another related to cytokines (inactive in normal gastric tissue samples) allowed us to identify patients who had a higher risk of developing stomach cancer and to remove the lesion early, before it became cancerous,” explained Martins.

One line of research is geared toward studies related to the prognosis of the disease. Among the insights incorporated into the hospital procedures, for example, is the result of a study on the claudin 7 protein, whose presence may indicate a higher probability for breast tumor recurrence. The protein began to be utilized as a marker, and it is currently being measured in patients.

Many other studies are aimed at making cancer treatments more effective. One study, which is currently underway, is trying to identify a blood marker that can indicate the most appropriate therapy for metastatic cancers of the lungs, ovaries, colon and pancreas. It is known as circulating tumor cell (CTC) therapy.

By collecting just 8 ml of blood, circulating tumor cells can be identified and quantified and then correlated with treatment response and disease progression. To date, 150 patients have been included in the study, and as soon as the test is validated, it will be conducted on all patients who receive care at A.C. Camargo Hospital as a way to monitor the development of the disease and determine the best treatment.

To learn more: Developing a translational center and New drugs increase the accuracy of treatment.