A 67-year-old man comes to the office due to dark urine, pale-appearing stools, and progressive yellowing of his eyes over the last few weeks. He also reports unintentional weight loss, but has had no night sweats, abdominal pain, bloody stools, or vomiting. He has no chronic medical conditions and takes no medication. Vital signs are within normal limits. Scleral icterus is present. The neck is supple. No lymphadenopathy or skin abnormalities are present. There is no hepatosplenomegaly. Laboratory results are as follows: CT scan of the abdomen reveals a pancreatic mass compressing the common bile duct and the pancreatic duct. This patient's disease process is most likely caused by a mutation affecting which of the following genes?

Question

A 67-year-old man comes to the office due to dark urine, pale-appearing stools, and progressive yellowing of his eyes over the last few weeks.  He also reports unintentional weight loss, but has had no night sweats, abdominal pain, bloody stools, or vomiting.  He has no chronic medical conditions and takes no medication.  Vital signs are within normal limits.  Scleral icterus is present.  The neck is supple.  No lymphadenopathy or skin abnormalities are present.  There is no hepatosplenomegaly.  Laboratory results are as follows:  CT scan of the abdomen reveals a pancreatic mass compressing the common bile duct and the pancreatic duct.  This patient's disease process is most likely caused by a mutation affecting which of the following genes?

Quizplus · Accepted Answer

Common bile duct obstructions increase conjugated bilirubin in the bloodstream, leading to jaundice and dark-colored urine; they also prevent bilirubin from entering the digestive tract, which results in clay-colored (acholic) stools. The vast majority (>85%) of obstructing pancreatic masses are due to pancreatic ductal adenocarcinoma. The major genomic abnormality in pancreatic ductal adenocarcinoma is KRAS-activating mutation, which allows tumor cells to grow and divide without input from the cellular milieu due to aberrant activity that relays a continuous growth signal to the nucleus. Because KRAS mutations are one of the earliest oncogenic mutations in pancreatic adenocarcinoma, tests for KRAS abnormalities are being developed to help with early detection. Many colorectal cancers and non-small cell lung cancers also have KRAS-activating mutations. (Choice A) Germline mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are associated with familial adenomatous polyposis (FAP). FAP causes innumerable colon polyps and colon cancer. Patients typically have hematochezia. (Choice B) BCL2 produces a protein that sits on the outer membrane of mitochondria and controls cell survival and apoptosis. BCL2-activating mutation is common in follicular lymphoma. Although patients with follicular lymphoma often have large abdominal masses, almost all cases are marked by significant peripheral lymphadenopathy and B symptoms (eg, night sweats). (Choice C) BRAF is a protooncogene that produces a protein involved in growth signal transduction from the cell membrane to the interior of the cell. BRAF mutations are most strongly associated with malignant melanoma. (Choice D) c-MYC is a protooncogene overexpressed in Burkitt lymphoma, which usually presents with a facial mass (eg, endemic African form) or with ascites and multi-organ involvement (eg, sporadic form). An isolated pancreatic mass with common bile duct obstruction is far more likely to be pancreatic adenocarcinoma. Educational objective: Oncogenesis in pancreatic ductal adenocarcinoma is almost always due to an early activating mutation in the KRAS oncogene, which produces a constitutively active protein that allows for uncontrolled proliferation of tumor cells. __________ References: KRAS: the critical driver and therapeutic target for pancreatic cancer. (http://www.ncbi.nlm.nih.gov/pubmed/29229669)

A 67-Year-Old Man Comes to the Office Due to Dark