PTEN hamartoma tumor syndromes.
The PTEN hamartoma tumor syndromes (PHTS) are a collection of rare clinical syndromes characterized by germline mutations of the tumor suppressor PTEN. These syndromes are driven by cellular overgrowth, leading to benign hamartomas in virtually any organ. Cowden syndrome (CS), the prototypic PHTS syndrome, is associated with increased susceptibility to breast, thyroid, and endometrial cancer. PTEN is located on chromosome 10q22-23 and negatively regulates the prosurvival PI3K/Akt/mTOR pathway through its lipid phosphatase activity. Loss of PTEN activates this pathway and leads to increased cellular growth, migration, proliferation, and survival. Clinical management of patients with PHTS, particularly those with CS, should include early and frequent screening, surveillance, and preventive care for associated malignancies. Concomitant with improved understanding of the biology of PTEN and the PI3K/Akt/mTOR pathway, inhibitors of this pathway are being developed as anticancer agents. These medications could have applications for patients with PHTS, for whom no medical options currently exist.
Blumenthal
Gideon M
GM
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Dennis
Phillip A
PA
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006223:Hamartoma Syndrome, Multiple / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human
JAMA. 2006 Jun 21;295(23):2727-41
16754727
Cell. 2007 Jan 12;128(1):157-70
17218262
Cancer Res. 2007 Sep 1;67(17):7960-5
17804702
Cell. 1998 Oct 2;95(1):29-39
9778245
Physiol Res. 2005;54(1):1-16
15717836
J Pediatr Surg. 1992 Jun;27(6):722-3
1501032
AJNR Am J Neuroradiol. 1992 Jan-Feb;13(1):287-90
1595461
J Med Genet. 2000 Nov;37(11):828-30
11073535
PLoS Med. 2008 Jan 22;5(1):e8
18215105
Cancer Res. 2008 Jan 15;68(2):425-33
18199536
J Med Genet. 2001 Mar;38(3):159-64
11238682
J Med Genet. 2002 Dec;39(12):937-40
12471211
Breast Dis. 2006-2007;27:21-50
17917139
J Med Genet. 2001 Dec;38(12):820-3
11748304
Eur J Dermatol. 2007 Mar-Apr;17(2):133-6
17337396
Am J Gastroenterol. 2003 Jun;98(6):1429-34
12818292
Oncogene. 2001 Jul 27;20(33):4457-65
11494141
Arch Pathol. 1971 Jul;92(1):1-5
5091590
Am J Med Genet. 1989 Dec;34(4):548-51
2624267
Lancet. 2001 Jul 21;358(9277):210-1
11476841
Circulation. 2000 Feb 15;101(6):660-7
10673259
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10320-5
11504907
Am J Med Genet. 1984 Oct;19(2):225-34
6507473
J Med Genet. 2004 May;41(5):323-6
15121767
Cell. 2007 Jan 12;128(1):141-56
17218261
Am J Hum Genet. 2006 Jul;79(1):23-30
16773562
J Neuropathol Exp Neurol. 2005 Apr;64(4):341-9
15835270
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10314-9
11504908
Cancer Res. 2005 Aug 15;65(16):7052-8
16103051
Nat Genet. 1997 May;16(1):64-7
9140396
Ann Intern Med. 1963 Jan;58:136-42
13931122
J Natl Cancer Inst. 2005 Nov 16;97(22):1652-62
16288118
Oncogene. 2007 Mar 22;26(13):1932-40
17001314
Lancet. 2001 Dec 15;358(9298):2079-80
11755638
J Med Genet. 2007 Sep;44(9):594-602
17526801
Eur J Hum Genet. 2007 Jul;15(7):767-73
17392703
Hum Mol Genet. 1999 Aug;8(8):1461-72
10400993
Nat Rev Cancer. 2007 Jan;7(1):35-45
17167516
Semin Oncol. 2007 Oct;34(5):428-34
17920899
Clin Cancer Res. 2002 Jun;8(6):1904-14
12060635
Exp Cell Res. 2001 Mar 10;264(1):29-41
11237521
Br J Dermatol. 2007 May;156(5):1089-90
17388921
Nat Genet. 1998 Aug;19(4):348-55
9697695
Endocr Relat Cancer. 2001 Sep;8(3):249-58
11566616
Ann Genet. 1996;39(1):35-42
9297442
Cell. 2007 Jan 12;128(1):129-39
17218260
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12479-84
9356475
Am J Med Genet C Semin Med Genet. 2005 Aug 15;137C(1):38-52
16010681
Am J Med Genet A. 2004 Oct 1;130A(2):123-7
15372512
N Engl J Med. 2001 Jul 19;345(3):159-64
11463009
Am J Med Genet B Neuropsychiatr Genet. 2007 Jun 5;144B(4):484-91
17427195
Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1563-8
9990064
Hum Mol Genet. 2006 Mar 1;15(5):777-87
16436456
Hum Mol Genet. 2001 Mar 15;10(6):605-16
11230180
Cancer Res. 2006 Feb 1;66(3):1500-8
16452206
J Natl Cancer Inst. 2001 Nov 7;93(21):1633-7
11698567
J Med Genet. 2007 Sep;44(9):579-85
17526800
J Med Genet. 2001 Jan;38(1):52-8
11332402
Nat Clin Pract Oncol. 2008 Jun;5(6):357-61
18431376
Science. 1998 Jun 5;280(5369):1614-7
9616126
Hum Pathol. 1998 Jan;29(1):47-53
9445133
Am J Med Genet A. 2003 Nov 1;122A(4):323-4
14518070
Cancer Res. 2002 Sep 1;62(17):5027-34
12208757
Cancer Res. 2006 Jul 1;66(13):6546-52
16818626
Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5703-8
15824318
Am J Hum Genet. 2003 Aug;73(2):404-11
12844284
Hum Mol Genet. 1998 Mar;7(3):507-15
9467011
Eur J Pediatr. 1983 Mar;140(1):5-12
6873112
Clin Genet. 1986 Mar;29(3):222-33
3698331
N Engl J Med. 2008 Jan 10;358(2):140-51
18184959
Ann Diagn Pathol. 1999 Dec;3(6):331-40
10594284
Hum Mutat. 2003 Sep;22(3):183-98
12938083
Am J Hum Genet. 2003 Nov;73(5):1191-8
14566704
Gut. 2008 May;57(5):623-7
18178612
Curr Biol. 1998 Oct 22;8(21):1169-78
9799734
JAMA. 2005 Nov 16;294(19):2465-73
16287957