Hereditary pancreatic cancer

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Hereditary pancreatic cancer

Written	2000-12	Ralph H. Hruban, Scott E. Kern
		The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

(Note : for Links provided by Atlas : click)

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:
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."

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

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

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

Bibliography

Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells.

Abbott DW, Freeman ML, Holt JT

Journal of the National Cancer Institute. 1998 ; 90 (13) : 978-985.

PMID 9665145

A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals.

Berman DB, Costalas J, Schultz DC, Grana G, Daly M, Godwin AK

Cancer research. 1996 ; 56 (15) : 3409-3414.

PMID 8758903

Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.

Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE

Nature genetics. 1994 ; 8 (1) : 27-32.

PMID 7726912

Very high risk of cancer in familial Peutz-Jeghers syndrome.

Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV, Cruz-Correa M, Offerhaus JA

Gastroenterology. 2000 ; 119 (6) : 1447-1453.

PMID 11113065

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, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH

The American journal of pathology. 1998 ; 152 (6) : 1501-1507.

PMID 9626054

Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.

Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE

Cancer research. 1996 ; 56 (23) : 5360-5364.

PMID 8968085

Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations.

Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP, Fontaine LS, Organic SM, Dracopoli NC, Clark WH Jr

The New England journal of medicine. 1995 ; 333 (15) : 970-974.

PMID 7666916

A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.

Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Höglund P, Järvinen H, Kristo P, Pelin K, Ridanp M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA

Nature. 1998 ; 391 (6663) : 184-187.

PMID 9428765

Genetics of pancreatic cancer. From genes to families.

Hruban RH, Petersen GM, Ha PK, Kern SE

Surgical oncology clinics of North America. 1998 ; 7 (1) : 1-23.

PMID 9443984

Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits; a syndrome of diagnostic significance.

JEGHERS H, McKUSICK VA, KATZ KH

The New England journal of medicine. 1949 ; 241 (25) : page 993, illust; passim.

PMID 15399020

Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.

Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Müller O, Back W, Zimmer M

Nature genetics. 1998 ; 18 (1) : 38-43.

PMID 9425897

Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations.

Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA, Redston M, Gallinger S

Cancer research. 2000 ; 60 (2) : 409-416.

PMID 10667595

Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group.

Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates LK Jr, Perrault J, Whitcomb DC

Journal of the National Cancer Institute. 1997 ; 89 (6) : 442-446.

PMID 9091646

Genetic counseling and testing for germline p16 mutations in two pancreatic cancer-prone families.

Lynch HT, Brand RE, Lynch JF, Fusaro RM, Smyrk TC, Goggins M, Kern SE

Gastroenterology. 2000 ; 119 (6) : 1756-1760.

PMID 11113097

Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study.

Lynch HT, Voorhees GJ, Lanspa SJ, McGreevy PS, Lynch JF

British journal of cancer. 1985 ; 52 (2) : 271-273.

PMID 4027169

Docetaxel (Taxotere) in the neo-adjuvant setting in non-small-cell lung cancer.

Mattson K

Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 1999 ; 10 Suppl 5 : S69-S72.

PMID 10582143

Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients.

Ozçelik H, Schmocker B, Di Nicola N, Shi XH, Langer B, Moore M, Taylor BR, Narod SA, Darlington G, Andrulis IL, Gallinger S, Redston M

Nature genetics. 1997 ; 16 (1) : 17-18.

PMID 9140390

Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers.

Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, Westerman AM, Entius MM, Goggins M, Yeo CJ, Kern SE

The American journal of pathology. 1999 ; 154 (6) : 1835-1840.

PMID 10362809

Pancreatic cancer--more familial than you thought.

Tascilar M, Tersmette AC, Offerhaus GJ, Hruban RH

Analytical cellular pathology : the journal of the European Society for Analytical Cellular Pathology. 1999 ; 19 (3-4) : 105-110.

PMID 10866272

Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer.

Tersmette AC, Petersen GM, Offerhaus GJ, Falatko FC, Brune KA, Goggins M, Rozenblum E, Wilentz RE, Yeo CJ, Cameron JL, Kern SE, Hruban RH

Clinical cancer research : an official journal of the American Association for Cancer Research. 2001 ; 7 (3) : 738-744.

PMID 11297271

Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.

Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK Jr, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD

Nature genetics. 1996 ; 14 (2) : 141-145.

PMID 8841182

Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity.

Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE

The American journal of pathology. 2000 ; 156 (5) : 1641-1651.

PMID 10793075

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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For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

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: 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."

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 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
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

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

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

OMIM	260350
OMIM	606856
OMIM	613347
OMIM	613348
Orphanet	Familial pancreatic carcinoma
ICD-10	C25
Other database	pancreatic cancer /diseases/4206/familial-pancreatic-cancer (GARD)
Other database	National Familial Pancreas Tumor Registry
Other database	The European Registry Of Hereditary Pancreatitis And Familial Pancreatic Cancer
Genes implicated in	BRCA2 [ Atlas ] [ Entrez ] [ LOVD ] [ GeneReviews ]
Genes implicated in	CDKN2A [ Atlas ] [ Entrez ] [ LOVD ] [ GeneReviews ]
Genes implicated in	MLH1 [ Atlas ] [ Entrez ] [ LOVD ] [ GeneReviews ]
Genes implicated in	PALB2 [ Atlas ] [ Entrez ] [ LOVD ] [ GeneReviews ]
Genes implicated in	PALLD [ Atlas ] [ Entrez ] [ LOVD ] [ GeneReviews ]
Genes implicated in	PHOX2B [ Atlas ] [ Entrez ] [ LOVD ] [ GeneReviews ]
Genes implicated in	PRSS1 [ Atlas ] [ Entrez ] [ LOVD ] [ GeneReviews ]
Genes implicated in	STK11 [ Atlas ] [ Entrez ] [ LOVD ] [ GeneReviews ]
Genes implicated in	TP53 [ Atlas ] [ Entrez ] [ LOVD ] [ GeneReviews ]

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed