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Spectrum and frequency of germline mutations in cancer predisposing genes in patients with pancreatic carcinoma


Pancreatic carcinoma is a very aggressive disease with a very low 5-year relative survival rate of only 8%. The survival rate may be higher when the disease is localized, however, only about 9% of the cases are diagnosed in an early stage. There are no effective therapies or well established early detection methods. Therefore, early detection of the disease is the best chance of treatment success, which is mainly based on surgical resection. There are estimates indicating that the number of new cases and deaths due to pancreatic cancer is rising over the years. In fact, Globocan estimates indicate an increase of about 31% and 24% in the number of deaths from pancreatic cancer, in Brazil and in the world respectively, by 2020 as compared to the year 2012. In addition, it is estimated that by the year 2030, pancreatic cancer will become the second leading cause of cancer deaths in the United States of America. There is some evidence that high-risk individuals may benefit from screening tests for detection of early pancreatic cancer. About 90% of the pancreatic cancer cases are considered sporadic, while 10% demonstrate a familial aggregation, including 3% attributed to mutations in genes involved in hereditary cancer syndromes. Therefore, one of the strategies to identify high risk individuals is through the detection of pathogenic mutations in cancer susceptibility genes. In order to identify cancer predisposing genes, a few studies were conducted, involving mainly Caucasian patients from the North America and Europe, who reported a family history of pancreatic cancer and were included from pancreatic cancer registries. There are indications that even patients without a family history of cancer may present with pathogenic germline mutations, which would go unnoticed if only family history criteria were used to indicate genetic tests. Therefore, the number of patients tested to the present date is less than what is desired and there is a chance that a certain bias of inclusion of patients might have occurred. Hence, the spectrum and frequency of germline mutations in pancreatic cancer was not totally clarified. Therefore, our aim is to evaluate the family history, spectrum and frequency of mutations in cancer susceptibility genes in pancreatic carcinoma patients in Brazil. Pancreatic cancer is an aggressive disease, little understood and largely neglected, that deserves better attention, in an attempt to reduce the dramatic impact of the estimated increase in mortality rates for the coming years. This is a prospective study that intends to include 200 consecutive patients, unselected for cancer family history. A panel of 94 genes associated with cancer will be sequenced. The panel includes, among others, genes involved in hereditary predisposition cancer syndromes related with pancreatic cancer. The results will be deposited in a public database and a cost-effectiveness study will be conducted to evaluate the introduction of early detection tests in family members who are mutation carriers. This study presents as original aspects: inclusion of a population outside the North Hemisphere, sequencing of a broad panel of genes that may be associated with cancer, prospective character with inclusion of patients who were not selected by family history, application of a questionnaire to define predictive factors for indication of the genetic test (family history and habits), evaluation of cost effectiveness of screening tests in high risk individuals (relatives who are also mutation carriers). (AU)

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