Pancreatic cancer and the FAMMM syndrome

Abstract

Hereditary cancer syndromes provide excellent models for molecular genetic studies that may aid significantly in case detection, surveillance, and management. Ultimately, molecularly based designer pharmaceuticals may emerge from this research, such as the case of trastuzumab (Herceptin) in HER-2/neu positive breast cancer, and imatinib (Gleevec) in chronic myelocytic leukemia and gastrointestinal stromal tumors. Importantly, these molecular findings may fuel significant clues to cancer control. This background is mentioned since surveillance and management of pancreatic cancer, a major concern of this manuscript, has been uniformly unsuccessful as evidenced by the close correspondence between its incidence and its mortality. Yet knowledge about its genetic and molecular pathology will hopefully ameliorate this vexing problem. One molecular genetic clue is the recently identified palladin mutation in two pancreatic cancer prone families. However, caution must be used toward the palladin mutation, as several recent publications have questioned its significance as a pancreatic cancer causing mutation. We provide a concise description of pancreatic cancer in concert with malignant melanoma in the familial atypical multiple mole melanoma (FAMMM) syndrome as a potential preventive model. This knowledge should help clinicians and basic scientists seize on the opportunity to develop more sensitive and specific screening and management programs in this disease; while a relatively small subset of pancreatic cancer may be readily identifiable through its FAMMM phenotype, coupled with its CDKN2A mutation, this hereditary disorder, given a keen knowledge of its natural history and molecular genetics, may prove to be an effective clinical preventive model.

Hereditary Pancreatic Cancer

“…This disorder involves mutations in the p16 gene or CDNK2 gene which also can lead to pancreatic cancer. The risk of pancreatic cancer development by the age of 75 has been reported to be between 17 and 25% [26,27]. In some studies, there has been reported to be a 13-to 22-fold increase of pancreatic cancer [27].…”

“…The risk of pancreatic cancer development by the age of 75 has been reported to be between 17 and 25% [26,27]. In some studies, there has been reported to be a 13-to 22-fold increase of pancreatic cancer [27]. CDKN2A is a tumor suppressor involved in inducing cell cycle arrest in the G1 and G2 phase.…”

Endoscopic ultrasonography for surveillance of individuals at high risk for pancreatic cancer

“…Familial atypical mole-multiple melanoma (FAMMM) is an autosomal dominant disease associated with mutations within CDKN2A gene (p16 Leiden) [45,46] . Its inactivation is associated with PDAC that was found 13 to 38-fold more frequent than expected [46,47] , with a cumulative risk Lami G et al .…”

Cutaneous Manifestations of Internal Malignancy

“…The incidence of melanoma is increased, and a family history of melanoma and pancreatic cancer should be sought. 32 In addition to the increased risk of pancreatic cancer (estimated to be as high as 22-fold) in affected families, reports have linked this family cancer syndrome to an increased risk of breast cancer. 33,34 What's new Melanoma/pancreatic cancer syndrome appears to be related to a mutation of the gene encoding cyclindependent kinase inhibitor-2A (CDKN2A) on chromosome 9p21.…”

“…Endoscopic retrograde cholangiopancreatography and endoscopic ultrasound are sensitive screening tests for pancreatic cancer. 32 Genetic counseling is mandatory for patients with the melanoma/pancreatic cancer syndrome.…”