Interpretation of Germline ATM Variants Identified in Long-Term Survivors of Pancreatic Cancer
J N Burnett Secondary
Floor Location : S 046 F
As the fourth leading cause of cancer death pancreatic cancer remains a notoriously difficult disease to treat despite major advancements in other cancer types. Tumors often go undetected until the later stages of cancer development proving the disease lethal; only 6% of individuals with pancreatic cancer survive. Even for surgically resectable tumors the risk of cancer recurrence and subsequent death remains extremely high. Unless there are breakthroughs in detection or treatment pancreatic adenocarcinoma is predicted to become the second deadliest cancer in North America surpassing colorectal and breast cancer. While standard therapy has displayed only modest effects with substantial toxicity, therapy directed towards genetic mutations have shown promising results in treatment of malignant pancreatic tumors. Due to the low survival rate a particular interest has been taken towards long-term survivors of this devastating disease in order to determine possible genetic variations in normal and tumor cells. 41 long-term survivors of pancreatic adenocarcinoma (>3 years) had their DNA sequenced for known pancreatic cancer susceptibility genes including ATM. ATM (Ataxia Telangiectasia Mutated) is a key player in DNA damage response and has shown promise as a novel pancreatic ductal adenocarcinoma predisposition gene deeming it therapeutically relevant. Being part of the BRCA1 pathway the gene may have responsibility in treatment susceptibility especially with PARP inhibitors. Putative variants that were seen in both the tumor and normal specimens were identified in 2 cases and presumed to be most likely technically valid. Literature and various bioinformatics tools and databases were used to determine the pathogenicity of the specified genes in accordance to ACMG standards. One of the cases showed stronger evidence for pathogenicity while the other one had uncertain significance though leaning towards pathogenicity. Due to the anonymity of the patients the familial information necessary to make a strong decision was not obtainable for the duration of the project.