Written | 2000-12 | Ralph H. Hruban, Scott E. Kern |
The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA |
Identity |
Other names | Familial pancreatic cancer |
Atlas_Id | 10068 |
Genes implicated in | BRCA2 CDKN2A MLH1 PALB2 PALLD PHOX2B PRSS1 STK11 TP53 |
Inheritance | 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: |
Clinics |
Note | 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
|
Treatment | 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 | prognosis will depend on the stage of the disease at diagnosis more than it does on hereditary sysceptibility |
Genes involved and Proteins |
Gene Name | BRCA2 (breast cancer 2, early onset) |
Location | 13q13.1 |
DNA/RNA | |
Description | gene spanning more than 70kb of genomic DNA; the coding sequence comprises 27 exons (11 395 nucleotides) |
Protein | |
Description | the corresponding protein has 3 418 amino acid residues (384 kDa) |
Function | the Brca2 protein binds to Rad51 and serves as an important co-factor in the Rad51 -dependent DNA repair of double strand breaks; the Brca2 protein may also have transcription activation potential |
Mutations | |
Germinal | more than 300 unique germ-line mutations have been reported; the 6174 delT mutation is particularly common in Jewish subjects |
Somatic | acquired mutations in BRCA2 rare in pancreatic cancer |
Gene Name | CDKN2A (cyclin dependent kinase 2a / p16) |
Alias | MTS1, CDKN2A, p16 (INK4) |
Location | 9p21.3 |
DNA/RNA | |
Description | the coding sequence comprises 3 exons: this locus gives rise to 2 distinct transcripts from different promoters (p16 and p16(ARF)) |
Protein | |
Description | the corresponding protein, called cyclin-dependent kinase inhibitor-2A, has 156 amino acid residues |
Function | 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 |
Mutations | |
Germinal | germline mutations are associated with the FAMMM Syndrome |
Somatic | 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 Name | STK11 (serine/threonine kinase 11) |
Alias | LKB1 |
Location | 19p13.3 |
DNA/RNA | |
Description | gene Spanning 23kb of genomic DNA, the coding sequence comprises 9 exons (1446bp) |
Protein | |
Description | the corresponding protein has 433 amino acid residues |
Function | serine throeonine protein kinase 11 |
Mutations | |
Germinal | almost all germline mutations are predicted to disrupt the function of the kinase domain |
Somatic | approximately 4% of sporadic pancreatic cancers have somatic inactivation of STK11 |
Gene Name | PRSS1 (protease, serine 1) |
Alias | cationic trypsinogen, trypsin 1, trypsinogen 1 |
Location | 7q34 |
DNA/RNA | |
Description | the coding sequence comprise 5 exons (800bp) |
Protein | |
Description | trypsin, which is active in the pacreas, in inactivated by cleavage; mutations which abrogate this cleavage site can result in autodigestion and pancreatitis |
Mutations | |
Germinal | the arg117-to-his mutation (R117H) is the most common mutation identified to date |
Gene Name | MLH1 (human mutL homolog 1) |
Alias | human homolog of MUTL |
Location | 3p22.2 |
DNA/RNA | |
Description | the coding sequence comprises 2484b |
Protein | |
Description | MLH1 forms a complex with other DNA mismatch repair gene; functions in DNA mismatch repairs |
Mutations | |
Germinal | 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 |
Gene Name | MSH2 (human mutS homolog 2) |
Alias | human homolog of MULT S |
Location | 2p21 |
DNA/RNA | |
Description | the MSH2 locus covers approximately 73kb and contains 16 exons |
Protein | |
Description | MSH2 functions in DNA mismatch repair |
Mutations | |
Germinal | 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 |
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Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. |
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Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. |
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Pancreatic cancer--more familial than you thought. |
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Citation |
This paper should be referenced as such : |
Hruban, RH ; Kern, SE |
Hereditary pancreatic cancer |
Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):72-75. |
Free journal version : [ pdf ] [ DOI ] |
On line version : http://AtlasGeneticsOncology.org/Tumors/HeredPancrCanID10068.html |
Other genes implicated (Data extracted from papers in the Atlas) [ 2 ] |
Genes | BRCA2 | PALB2 |
External links |
REVIEW articles | automatic search in PubMed |
Last year articles | automatic search in PubMed |
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