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Li-Fraumeni syndrome 1(LFS1)

MedGen UID:
322656
Concept ID:
C1835398
Disease or Syndrome
Synonyms: LFS1
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: HPO
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
 
Gene (location): TP53 (17p13.1)
OMIM®: 151623

Disease characteristics

Excerpted from the GeneReview: Li-Fraumeni Syndrome
Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of the following classic tumors: soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias. In addition, a variety of other neoplasms may occur. LFS-related cancers often occur in childhood or young adulthood and survivors have an increased risk for multiple primary cancers. Age-specific cancer risks have been calculated. [from GeneReviews]
Authors:
Katherine Schneider  |  Kristin Zelley  |  Kim E Nichols, et. al.   view full author information

Additional descriptions

From OMIM
Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous inherited cancer syndrome. LFS is characterized by autosomal dominant inheritance and early onset of tumors, multiple tumors within an individual, and multiple affected family members. In contrast to other inherited cancer syndromes, which are predominantly characterized by site-specific cancers, LFS presents with a variety of tumor types. The most common types are soft tissue sarcomas and osteosarcomas, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma. Classic LFS is defined as a proband with a sarcoma before the age of 45 years and a first-degree relative with any cancer before the age of 45 years and 1 additional first- or second-degree relative in the same lineage with any cancer before the age of 45 years or a sarcoma at any age (Li et al., 1988). Li-Fraumeni-like syndrome (LFL) is defined as a proband with any childhood cancer, or a sarcoma, brain tumor, or adrenocortical tumor before the age of 45 years, plus a first- or second-degree relative in the same lineage with a typical LFS tumor at any age, and an additional first- or second-degree relative in the same lineage with any cancer before the age of 60 years (Birch et al., 1994). A less restrictive definition of LFL is 2 different LFS-related tumors in first- or second-degree relatives at any age (Eeles, 1995). Approximately 70% of LFS cases and 40% of LFL cases contain germline mutations in the p53 gene on chromosome 17p13.1 (Bachinski et al., 2005). Genetic Heterogeneity of Li-Fraumeni Syndrome A second form of Li-Fraumeni syndrome (LFS2; 609265) is caused by mutation in the CHEK2 gene (604373), and an LFS locus (LFS3; 609266) has been mapped to chromosome 1q23.  http://www.omim.org/entry/151623
From GHR
Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults.The cancers most often associated with Li-Fraumeni syndrome include breast cancer, a form of bone cancer called osteosarcoma, and cancers of soft tissues (such as muscle) called soft tissue sarcomas. Other cancers commonly seen in this syndrome include brain tumors, cancers of blood-forming tissues (leukemias), and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormone-producing glands on top of each kidney). Several other types of cancer also occur more frequently in people with Li-Fraumeni syndrome.A very similar condition called Li-Fraumeni-like syndrome shares many of the features of classic Li-Fraumeni syndrome. Both conditions significantly increase the chances of developing multiple cancers beginning in childhood; however, the pattern of specific cancers seen in affected family members is different.  http://ghr.nlm.nih.gov/condition/li-fraumeni-syndrome

Clinical features

Colon cancer
MedGen UID:
2839
Concept ID:
C0007102
Neoplastic Process
A primary or metastatic malignant neoplasm that affects the colon. Representative examples include carcinoma, lymphoma, and sarcoma.
Nephroblastoma
MedGen UID:
10221
Concept ID:
C0027708
Neoplastic Process
Wilms' tumor is a rare type of kidney cancer. It causes a tumor on one or both kidneys. It usually affects children, but can happen in adults. Having certain genetic conditions or birth defects can increase the risk of getting it. Children that are at risk should be screened for Wilms' tumor every three months until they turn eight. Symptoms include a lump in the abdomen, blood in the urine, and a fever for no reason. Tests that examine the kidney and blood are used to find the tumor. Doctors usually diagnose and remove the tumor in surgery. Other treatments include chemotherapy and radiation and biologic therapies. Biologic therapy boosts your body's own ability to fight cancer. NIH: National Cancer Institute.
Osteosarcoma
MedGen UID:
10501
Concept ID:
C0029463
Neoplastic Process
A malignant bone tumor that usually develops during adolescence and usually affects the long bones including the tibia, femur, and humerus. The typical symptoms of osteosarcoma comprise bone pain, fracture, limitation of motion, and tenderness or swelling at the site of the tumor.
Acute leukemia
MedGen UID:
43225
Concept ID:
C0085669
Neoplastic Process
A rapidly progressing cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of white blood cells to be produced and enter the blood stream.
Adenocarcinoma of lung
MedGen UID:
57744
Concept ID:
C0152013
Neoplastic Process
A carcinoma that arises from the lung and is characterized by the presence of malignant glandular epithelial cells. There is a male predilection with a male to female ratio of 2:1. Usually lung adenocarcinoma is asymptomatic and is identified through screening studies or as an incidental radiologic finding. If clinical symptoms are present they include shortness of breath, cough, hemoptysis, chest pain, and fever. Tobacco smoke is a known risk factor.
Adrenal Cortex Carcinoma
MedGen UID:
104917
Concept ID:
C0206686
Neoplastic Process
A malignant neoplasm of the ADRENAL CORTEX. Adrenocortical carcinomas are unencapsulated anaplastic (ANAPLASIA) masses sometimes exceeding 20 cm or 200 g. They are more likely to be functional than nonfunctional, and produce ADRENAL CORTEX HORMONES that may result in hypercortisolism (CUSHING SYNDROME); HYPERALDOSTERONISM; and/or VIRILISM.
Neoplasm of the pancreas
MedGen UID:
138068
Concept ID:
C0346647
Neoplastic Process
The pancreas is a gland behind your stomach and in front of your spine. It produces the juices that help break down food and the hormones that help control blood sugar levels. Pancreatic cancer usually begins in the cells that produce the juices. Some risk factors for developing pancreatic cancer include. - Smoking . - Long-term diabetes . - Chronic pancreatitis . - Certain hereditary disorders . Pancreatic cancer is hard to catch early. It doesn't cause symptoms right away. When you do get symptoms, they are often vague or you may not notice them. They include yellowing of the skin and eyes, pain in the abdomen and back, weight loss and fatigue. Also, because the pancreas is hidden behind other organs, health care providers cannot see or feel the tumors during routine exams. Doctors use a physical exam, blood tests, imaging tests, and a biopsy to diagnose it. Because it is often found late and it spreads quickly, pancreatic cancer can be hard to treat. Possible treatments include surgery, radiation, chemotherapy, and targeted therapy. Targeted therapy uses substances that attack cancer cells without harming normal cells. NIH: National Cancer Institute.
Breast Carcinoma
MedGen UID:
146260
Concept ID:
C0678222
Neoplastic Process
The presence of a carcinoma of the breast.
Soft tissue sarcoma
MedGen UID:
834127
Concept ID:
CN231375
Finding
A type of sarcoma (A connective tissue neoplasm formed by proliferation of mesodermal cells) that develops from soft tissues like fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues.
Adrenal Cortex Carcinoma
MedGen UID:
104917
Concept ID:
C0206686
Neoplastic Process
A malignant neoplasm of the ADRENAL CORTEX. Adrenocortical carcinomas are unencapsulated anaplastic (ANAPLASIA) masses sometimes exceeding 20 cm or 200 g. They are more likely to be functional than nonfunctional, and produce ADRENAL CORTEX HORMONES that may result in hypercortisolism (CUSHING SYNDROME); HYPERALDOSTERONISM; and/or VIRILISM.
Acute leukemia
MedGen UID:
43225
Concept ID:
C0085669
Neoplastic Process
A rapidly progressing cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of white blood cells to be produced and enter the blood stream.
Nephroblastoma
MedGen UID:
10221
Concept ID:
C0027708
Neoplastic Process
Wilms' tumor is a rare type of kidney cancer. It causes a tumor on one or both kidneys. It usually affects children, but can happen in adults. Having certain genetic conditions or birth defects can increase the risk of getting it. Children that are at risk should be screened for Wilms' tumor every three months until they turn eight. Symptoms include a lump in the abdomen, blood in the urine, and a fever for no reason. Tests that examine the kidney and blood are used to find the tumor. Doctors usually diagnose and remove the tumor in surgery. Other treatments include chemotherapy and radiation and biologic therapies. Biologic therapy boosts your body's own ability to fight cancer. NIH: National Cancer Institute.
Prostate neoplasm
MedGen UID:
18697
Concept ID:
C0033578
Neoplastic Process
A benign, borderline, or malignant neoplasm that affects the prostate gland. Representative examples include benign prostate phyllodes tumor, prostatic intraepithelial neoplasia, prostate carcinoma, and prostate sarcoma.
Malignant tumor of prostate
MedGen UID:
138169
Concept ID:
C0376358
Neoplastic Process
The prostate is the gland below a man's bladder that produces fluid for semen. Prostate cancer is common among older men. It is rare in men younger than 40. Risk factors for developing prostate cancer include being over 65 years of age, family history, and being African-American. Symptoms of prostate cancer may include. -Problems passing urine, such as pain, difficulty starting or stopping the stream, or dribbling. -Low back pain. -Pain with ejaculation. To diagnose prostate cancer, you doctor may do a digital rectal exam to feel the prostate for lumps or anything unusual. You may also get a blood test for prostate-specific antigen (PSA). These tests are also used in prostate cancer screening, which looks for cancer before you have symptoms. If your results are abnormal, you may need more tests, such as an ultrasound, MRI, or biopsy. Treatment often depends on the stage of the cancer. How fast the cancer grows and how different it is from surrounding tissue helps determine the stage. Men with prostate cancer have many treatment options. The treatment that's best for one man may not be best for another. The options include watchful waiting, surgery, radiation therapy, hormone therapy, and chemotherapy. You may have a combination of treatments. NIH: National Cancer Institute.
Adenocarcinoma of lung
MedGen UID:
57744
Concept ID:
C0152013
Neoplastic Process
A carcinoma that arises from the lung and is characterized by the presence of malignant glandular epithelial cells. There is a male predilection with a male to female ratio of 2:1. Usually lung adenocarcinoma is asymptomatic and is identified through screening studies or as an incidental radiologic finding. If clinical symptoms are present they include shortness of breath, cough, hemoptysis, chest pain, and fever. Tobacco smoke is a known risk factor.
Colon cancer
MedGen UID:
2839
Concept ID:
C0007102
Neoplastic Process
A primary or metastatic malignant neoplasm that affects the colon. Representative examples include carcinoma, lymphoma, and sarcoma.
Neoplasm of the pancreas
MedGen UID:
138068
Concept ID:
C0346647
Neoplastic Process
The pancreas is a gland behind your stomach and in front of your spine. It produces the juices that help break down food and the hormones that help control blood sugar levels. Pancreatic cancer usually begins in the cells that produce the juices. Some risk factors for developing pancreatic cancer include. - Smoking . - Long-term diabetes . - Chronic pancreatitis . - Certain hereditary disorders . Pancreatic cancer is hard to catch early. It doesn't cause symptoms right away. When you do get symptoms, they are often vague or you may not notice them. They include yellowing of the skin and eyes, pain in the abdomen and back, weight loss and fatigue. Also, because the pancreas is hidden behind other organs, health care providers cannot see or feel the tumors during routine exams. Doctors use a physical exam, blood tests, imaging tests, and a biopsy to diagnose it. Because it is often found late and it spreads quickly, pancreatic cancer can be hard to treat. Possible treatments include surgery, radiation, chemotherapy, and targeted therapy. Targeted therapy uses substances that attack cancer cells without harming normal cells. NIH: National Cancer Institute.
Acute leukemia
MedGen UID:
43225
Concept ID:
C0085669
Neoplastic Process
A rapidly progressing cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of white blood cells to be produced and enter the blood stream.
Osteosarcoma
MedGen UID:
10501
Concept ID:
C0029463
Neoplastic Process
A malignant bone tumor that usually develops during adolescence and usually affects the long bones including the tibia, femur, and humerus. The typical symptoms of osteosarcoma comprise bone pain, fracture, limitation of motion, and tenderness or swelling at the site of the tumor.
Breast Carcinoma
MedGen UID:
146260
Concept ID:
C0678222
Neoplastic Process
The presence of a carcinoma of the breast.

Professional guidelines

PubMed

Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee
Genet Med 2015 Jan;17(1):70-87. Epub 2014 Nov 13 doi: 10.1038/gim.2014.147. [Epub ahead of print] PMID: 25394175
ACMG Board of Directors
Genet Med 2015 Jan;17(1):68-9. Epub 2014 Nov 13 doi: 10.1038/gim.2014.151. [Epub ahead of print] PMID: 25356965
Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, Kohlmann W, Lindor NM, Mulvey TM, Robinson L, Rubinstein WS, Stoffel EM, Snyder C, Syngal S, Merrill JK, Wollins DS, Hughes KS; American Society of Clinical Oncology
J Clin Oncol 2014 Mar 10;32(8):833-40. Epub 2014 Feb 3 doi: 10.1200/JCO.2013.50.9257. [Epub ahead of print] PMID: 24493721Free PMC Article
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics
Genet Med 2013 Jul;15(7):565-74. Epub 2013 Jun 20 doi: 10.1038/gim.2013.73. [Epub ahead of print] PMID: 23788249Free PMC Article
Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K; American Society of Clinical Oncology
J Clin Oncol 2010 Feb 10;28(5):893-901. Epub 2010 Jan 11 doi: 10.1200/JCO.2009.27.0660. [Epub ahead of print] PMID: 20065170
Zon RT, Goss E, Vogel VG, Chlebowski RT, Jatoi I, Robson ME, Wollins DS, Garber JE, Brown P, Kramer BS; American Society of Clinical Oncology
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Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, Morris E, Pisano E, Schnall M, Sener S, Smith RA, Warner E, Yaffe M, Andrews KS, Russell CA; American Cancer Society Breast Cancer Advisory Group
CA Cancer J Clin 2007 Mar-Apr;57(2):75-89. PMID: 17392385
Trepanier A, Ahrens M, McKinnon W, Peters J, Stopfer J, Grumet SC, Manley S, Culver JO, Acton R, Larsen-Haidle J, Correia LA, Bennett R, Pettersen B, Ferlita TD, Costalas JW, Hunt K, Donlon S, Skrzynia C, Farrell C, Callif-Daley F, Vockley CW; National Society of Genetic Counselors
J Genet Couns 2004 Apr;13(2):83-114. doi: 10.1023/B:JOGC.0000018821.48330.77. PMID: 15604628
American Society of Clinical Oncology
J Clin Oncol 2003 Jun 15;21(12):2397-406. Epub 2003 Apr 11 doi: 10.1200/JCO.2003.03.189. [Epub ahead of print] PMID: 12692171
Am J Hum Genet 1995 Nov;57(5):1233-41. PMID: 7485175Free PMC Article

Recent clinical studies

Etiology

Giacomazzi CR, Giacomazzi J, Netto CB, Santos-Silva P, Selistre SG, Maia AL, Oliveira VZ, Camey SA, Goldim JR, Ashton-Prolla P
Rev Assoc Med Bras 2015 May-Jun;61(3):282-9. doi: 10.1590/1806-9282.61.03.282. PMID: 26248253
Etzold A, Schröder JC, Bartsch O, Zechner U, Galetzka D
Fam Cancer 2015 Mar;14(1):161-5. doi: 10.1007/s10689-014-9754-z. PMID: 25226867
Xu J, Qian J, Hu Y, Wang J, Zhou X, Chen H, Fang JY
Sci Rep 2014 Feb 27;4:4223. doi: 10.1038/srep04223. PMID: 24573247Free PMC Article
Renaux-Petel M, Sesboüé R, Baert-Desurmont S, Vasseur S, Fourneaux S, Bessenay E, Frébourg T, Bougeard G
Fam Cancer 2014 Mar;13(1):127-30. doi: 10.1007/s10689-013-9667-2. PMID: 23884452
Chadaz T, Hobbs SK, Son H
Clin Nucl Med 2013 Oct;38(10):818-20. doi: 10.1097/RLU.0b013e3182a20033. PMID: 24107814

Diagnosis

Giacomazzi CR, Giacomazzi J, Netto CB, Santos-Silva P, Selistre SG, Maia AL, Oliveira VZ, Camey SA, Goldim JR, Ashton-Prolla P
Rev Assoc Med Bras 2015 May-Jun;61(3):282-9. doi: 10.1590/1806-9282.61.03.282. PMID: 26248253
Ricordel C, Labalette-Tiercin M, Lespagnol A, Kerjouan M, Dugast C, Mosser J, Desrues B, Léna H
Lung Cancer 2015 Jan;87(1):80-4. Epub 2014 Nov 20 doi: 10.1016/j.lungcan.2014.11.005. [Epub ahead of print] PMID: 25433984
Giacomazzi J, Selistre SG, Rossi C, Alemar B, Santos-Silva P, Pereira FS, Netto CB, Cossio SL, Roth DE, Brunetto AL, Zagonel-Oliveira M, Martel-Planche G, Goldim JR, Hainaut P, Camey SA, Ashton-Prolla P
Cancer 2013 Dec 15;119(24):4341-9. Epub 2013 Oct 7 doi: 10.1002/cncr.28346. [Epub ahead of print] PMID: 24122735
Sorrell AD, Espenschied CR, Culver JO, Weitzel JN
Mol Diagn Ther 2013 Feb;17(1):31-47. doi: 10.1007/s40291-013-0020-0. PMID: 23355100Free PMC Article
Fresneau B, Brugières L, Caron O, Moutel G
J Genet Couns 2013 Jun;22(3):315-22. Epub 2012 Dec 12 doi: 10.1007/s10897-012-9556-0. [Epub ahead of print] PMID: 23233110

Therapy

Mosleh O, Tabori U, Bartels U, Huang A, Schechter T, Bouffet E
Pediatr Hematol Oncol 2013 Aug;30(5):386-91. Epub 2013 Jan 9 doi: 10.3109/08880018.2012.756089. [Epub ahead of print] PMID: 23301664
Magnusson S, Gisselsson D, Wiebe T, Kristoffersson U, Borg Å, Olsson H
Pediatr Blood Cancer 2012 Nov;59(5):846-53. Epub 2012 May 31 doi: 10.1002/pbc.24223. [Epub ahead of print] PMID: 22653678
Heymann S, Delaloge S, Rahal A, Caron O, Frebourg T, Barreau L, Pachet C, Mathieu MC, Marsiglia H, Bourgier C
Radiat Oncol 2010 Nov 8;5:104. doi: 10.1186/1748-717X-5-104. [Epub ahead of print] PMID: 21059199Free PMC Article
Dickens DS, Dothage JA, Heideman RL, Ballard ET, Jubinsky PT
J Pediatr Hematol Oncol 2005 Jan;27(1):46-9. PMID: 15654279
Pepper C, Thomas A, Hoy T, Tighe J, Culligan D, Fegan C, Bentley P
Cell Cycle 2003 Jan-Feb;2(1):53-8. PMID: 12695689

Prognosis

Yurgelun MB, Masciari S, Joshi VA, Mercado RC, Lindor NM, Gallinger S, Hopper JL, Jenkins MA, Buchanan DD, Newcomb PA, Potter JD, Haile RW, Kucherlapati R, Syngal S; Colon Cancer Family Registry
JAMA Oncol 2015 May;1(2):214-21. doi: 10.1001/jamaoncol.2015.0197. PMID: 26086041Free PMC Article
Sorrell AD, Espenschied CR, Culver JO, Weitzel JN
Mol Diagn Ther 2013 Feb;17(1):31-47. doi: 10.1007/s40291-013-0020-0. PMID: 23355100Free PMC Article
Magnusson S, Gisselsson D, Wiebe T, Kristoffersson U, Borg Å, Olsson H
Pediatr Blood Cancer 2012 Nov;59(5):846-53. Epub 2012 May 31 doi: 10.1002/pbc.24223. [Epub ahead of print] PMID: 22653678
Heymann S, Delaloge S, Rahal A, Caron O, Frebourg T, Barreau L, Pachet C, Mathieu MC, Marsiglia H, Bourgier C
Radiat Oncol 2010 Nov 8;5:104. doi: 10.1186/1748-717X-5-104. [Epub ahead of print] PMID: 21059199Free PMC Article
Lammens CR, Aaronson NK, Wagner A, Sijmons RH, Ausems MG, Vriends AH, Ruijs MW, van Os TA, Spruijt L, Gómez García EB, Kluijt I, Nagtegaal T, Verhoef S, Bleiker EM
J Clin Oncol 2010 Jun 20;28(18):3008-14. Epub 2010 May 17 doi: 10.1200/JCO.2009.27.2112. [Epub ahead of print] PMID: 20479422

Clinical prediction guides

Yurgelun MB, Masciari S, Joshi VA, Mercado RC, Lindor NM, Gallinger S, Hopper JL, Jenkins MA, Buchanan DD, Newcomb PA, Potter JD, Haile RW, Kucherlapati R, Syngal S; Colon Cancer Family Registry
JAMA Oncol 2015 May;1(2):214-21. doi: 10.1001/jamaoncol.2015.0197. PMID: 26086041Free PMC Article
Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, Gauthier-Villars M, Stoppa-Lyonnet D, Consolino E, Brugières L, Caron O, Benusiglio PR, Bressac-de Paillerets B, Bonadona V, Bonaïti-Pellié C, Tinat J, Baert-Desurmont S, Frebourg T
J Clin Oncol 2015 Jul 20;33(21):2345-52. Epub 2015 May 26 doi: 10.1200/JCO.2014.59.5728. [Epub ahead of print] PMID: 26014290
Ariffin H, Hainaut P, Puzio-Kuter A, Choong SS, Chan AS, Tolkunov D, Rajagopal G, Kang W, Lim LL, Krishnan S, Chen KS, Achatz MI, Karsa M, Shamsani J, Levine AJ, Chan CS
Proc Natl Acad Sci U S A 2014 Oct 28;111(43):15497-501. Epub 2014 Oct 13 doi: 10.1073/pnas.1417322111. [Epub ahead of print] PMID: 25313051Free PMC Article
Renaux-Petel M, Sesboüé R, Baert-Desurmont S, Vasseur S, Fourneaux S, Bessenay E, Frébourg T, Bougeard G
Fam Cancer 2014 Mar;13(1):127-30. doi: 10.1007/s10689-013-9667-2. PMID: 23884452
Magnusson S, Gisselsson D, Wiebe T, Kristoffersson U, Borg Å, Olsson H
Pediatr Blood Cancer 2012 Nov;59(5):846-53. Epub 2012 May 31 doi: 10.1002/pbc.24223. [Epub ahead of print] PMID: 22653678

Recent systematic reviews

Madge SN, Tumuluri K, Strianese D, Bonavolonta P, Wilcsek G, Dodd TJ, Selva D
Ophthalmology 2010 Mar;117(3):606-14. Epub 2009 Dec 22 doi: 10.1016/j.ophtha.2009.08.017. [Epub ahead of print] PMID: 20022639

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