Cancer prone diseases
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Hereditary pancreatic cancer
Ralph H. Hruban
Scott E. Kern
The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Hereditary pancreatic cancer
Familial pancreatic cancer
it has been estimated that as many as 10% of pancreatic cancers have a hereditary basis; five genetic syndromes have been identified that are associated with the familial aggregation of pancreatic cancer; these include: ,
the second breast cancer syndrome (BRCA2), ,
the familial atypical multiple mole melanoma (FAMMM), ,
the Peutz-Jeghers Syndrome, ,
the hereditary pancreatitis and ,
the hereditary non-polyposis colorectal cancer (HNPCC) syndrome ,
most kindreds with familial pancreatic cancer, however, do not fall into one of these well-defined syndromes and these are referred to simply as \"family pancreatic cancer.\"
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1333 Familial pancreatic carcinoma
a generally accepted definition of familial pancreatic cancer is a kindred in which at least a pair of first-degree relatives (sibling-sibling or parent-child) have been diagnosed with pancreatic cancer; several large registries have been established to define the patterns of inheritance and genetic basis for the familial aggregation of pancreatic cancer in these kindreds;
the National Pancreas Tumor Registry (NFPTR) is the largest such registry; over 260 familial pancreatic cancer kindreds have enrolled in this registry and studies of these kindreds has revealed that when followed prospectively, apparently healthy, first-degree relatives of patients with familial pancreatic cancer have an 18-fold increased risk of developing pancreatic cancer; when there are three or more family members with pancreatic cancer in a kindred, the first-degree relatives of the index patient with pancreatic cancer have a 56-fold increased risk of developing pancreatic cancer
each of the five clinically recognized syndromes associated with the familial aggregation of pancreatic cancer has its own unique clinical findings
second breast cancer syndrome: the BRCA2 tumor suppressor gene is located on chromosome 13q and carriers of germline BRCA2 mutations have a significant lifetime risk of developing breast cancer (30-85%) at a young age; they are also at risk for bilateral breast cancer; BRCA2 is also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer; the lifetime risk of pancreatic cancer in carriers of germline BRCA2 mutations is approximately 10%; germline BRCA2 mutations are particularly common amongst individuals of Ashkenazi Jewish heritage because of a founder effect
familial atypical multiple mole melanoma (FAMMM) syndrome has an autosomal dominant mode of transmission; most cases are caused by germline mutations in the p16 tumor suppressor gene on chromosome 9p; individuals affected with FAMMM develop multiple melanocytic nevi, some of which can be atypical; they also are at increased risk of developing melanoma and pancreatic cancer; the lifetime risk of pancreatic cancer in individuals with germline p16 mutations is about 20%
the Peutz-Jeghers Syndrome is inhertied in an autosomal dominant mode; it has recently been shown to be caused by germline mutaitons in the STK11\/LKB1 gene on chromosome 19p; individuals with this syndrome typically develop multiple mucocutaneus melanin macules, harmartomatous gastrointestinal polyps and they have an increased risk of developing cancers of the gastrointestinal tract; it has been estimated that the lifetime risk of pancreatic cancer in patient with the Peutz-Jeghers Syndrome is approximately 30%
hereditary pancreatitis has an autosomal dominant mode of transmission; it is caused by germline mutations in the cationic trypsinogen gene (called PRSS1) on chromosome 7q35; affected individuals develop recurrent episodes of pancreatitis at a young age and they have an elevated lifetime risk of developing pancreatic cancers that approaches 40%
the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is caused by germiline mutations in one of the DNA mismatch repair genes (such as hMLH1 on chromosome 3 p and hMSH2 on chromosome 2p); in addition to colorectal neoplasia, affected family members have an increased risk of developing pancreatic cancer; the pancreatic cancers that arise in patients with HNPCC often have a distinct histologic appearance referred to as \"medullary\" histology
the ataxia-telangectasia and familial adenomatous polyposis syndromes have also been associated with an increased risk of developing pancreatic cancer, however, these associations are not well-established
currently, there are no effective methods to screen individuals at-risk for early pancreatic cancer; several studies are underway to examine the effectiveness of endoscopic ultrasound (EUS) in the early detection of pancreatic cancer
prognosis will depend on the stage of the disease at diagnosis more than it does on hereditary sysceptibility
Genes involved and Proteins
gene spanning more than 70kb of genomic DNA; the coding sequence comprises 27 exons (11 395 nucleotides)
the Brca2 protein binds to Rad51 and serves as an important co-factor in the
-dependent DNA repair of double strand breaks; the Brca2 protein may also have transcription activation potential
more than 300 unique germ-line mutations have been reported; the 6174 delT mutation is particularly common in Jewish subjects
acquired mutations in BRCA2 rare in pancreatic cancer
MTS1, CDKN2A, p16 (INK4)
the coding sequence comprises 3 exons: this locus gives rise to 2 distinct transcripts from different promoters (p16 and p16(ARF))
cyclin-dependent kinase inhibitor 2A binds to CDK4 and inhibits the ability of CDK4 to interact with cyclinA thereby inducing a G1 cell cycle arrest
germline mutations are associated with the FAMMM Syndrome
virtually all invasive pancreatic carcinomas show inactivation of the p16 gene; forty percent by homozygous deletion, 40% by an intragenic mutation coupled with loss of heterozygocity (LOH) and 15% by hypermethylation of the p16 promoter
gene Spanning 23kb of genomic DNA, the coding sequence comprises 9 exons (1446bp)
serine throeonine protein kinase 11
almost all germline mutations are predicted to disrupt the function of the kinase domain
approximately 4% of sporadic pancreatic cancers have somatic inactivation of STK11
cationic trypsinogen, trypsin 1, trypsinogen 1
the coding sequence comprise 5 exons (800bp)
the arg117-to-his mutation (R117H) is the most common mutation identified to date
human homolog of MUTL
the coding sequence comprises 2484b
one of at least 5 known human mismatch repair genes associated with the hereditary non-polyposis colorectal cancer syndrome: the neoplasms that develop in these patients typically show microsatellite instability
human homolog of MULT S
the MSH2 locus covers approximately 73kb and contains 16 exons
one of at least 5 known human mismatch repair genes associated with the hereditary non-polyposis colorectal cancer syndrome; the neoplasms that develop in these patients typically show microsatellite instability
To be noted
http:\/\/pathology.jhu.edu\/pancreas_nfptr National Familial Pancreas Tumor Registryhttp:\/\/www.europac-org.eu\/index.html The European Registry Of Hereditary Pancreatitis And Familial Pancreatic Cancer
Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells.
Abbott DW et al
A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals.
Berman DB et al
Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.
Caldas C et al
Very high risk of cancer in familial Peutz-Jeghers syndrome.
Giardiello FM et al
Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+.
Goggins M et al
Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.
Goggins M et al
Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations.
Goldstein AM et al
A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.
Hemminki A et al
Genetics of pancreatic cancer. From genes to families.
Hruban RH et al
Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits; a syndrome of diagnostic significance.
JEGHERS H et al
Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.
Jenne DE et al
Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations.
Lal G et al
Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group.
Lowenfels AB et al
Genetic counseling and testing for germline p16 mutations in two pancreatic cancer-prone families.
Lynch HT et al
Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study.
Lynch HT et al
Docetaxel (Taxotere) in the neo-adjuvant setting in non-small-cell lung cancer.
Mattson K et al
Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients.
Ozçelik H et al
Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers.
Su GH et al
Pancreatic cancer--more familial than you thought.
Tascilar M et al
Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer.
Tersmette AC et al
Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.
Whitcomb DC et al
Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.
Wilentz RE et al
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