Familial GIST with Inherited Mutations in the Genes for KIT or PDGFRA

Occasionally GIST may run in families due to an inherited germline mutation of the gene for KIT or for PDGFRA. A germline mutation means that the mutation was present in the egg or sperm cell at the conception of the individual, and therefore all the cells of the individual’s body carry the mutation.  There are fewer than 20 reports of familial GIST in the medical literature.  Because the initial mutation is already present in all the body’s cells, the first step toward developing GIST has occurred before birth. Therefore, there is a high probability that multiple GISTs will develop, and at a younger adult age than in sporadic GIST.  Most affected individuals have been diagnosed with GIST between age 25 and 45.


The pattern of inheritance in many of these families has been an autosomal dominant pattern, implying that each child of an affected parent has a 50% chance of inheriting the mutant gene.  The figure above illustrates that the affected father passes on the trait to half of his offspring.  The affected offspring then have a 50% chance of passing it on to each of their children.  Unaffected offspring cannot pass on the trait, as ilustrated in the following figure.  Note, however, that in the case of familial GIST, people who inherit the mutant gene do not necessarily develop GIST, or may not do so until middle age or later.


Individuals with familial GIST often show excess growth called hyperplasia of interstitial cells of Cajal in the intestinal nerve centers called the myenteric plexus. This hyperplasia is apparently a precursor condition to the development of multiple tumors.

Familial Mutations of the KIT Gene

Mutations of the gene encoding the KIT receptor have been identified in most of the kindreds with familial GIST.  It is important to note that different families display different KIT gene mutations and may show different symptoms, which may or may not include:

  • skin hyperpigmentation: patterns of dark skin on the face, neck, hands, feet, groin, or other areas
  • nevi: skin moles
  • urticaria pigmentosa: a mastocytosis disorder in which excess mast cells occur in brown or salmon-colored itchy patches on the skin
  • swallowing difficulty, sometimes referred to as dysphagia or as achalasia

Familial Mutations of the PDGFRA Gene

Mutation in the gene encoding PDGFRA has been reported in one family (Chompret et al, 2004).  No skin problems or swallowing difficulties were associated with this family.

Related Pages

Please also see these contributions to our Ask the Professional series:

Case History of A Family with GIST by Jonathan C. Trent, MD PhD.  This poster includes illustrations of hyperplasia of interstitial cells of Cajal, as well as describing the affected proportion of one family.

Genetic Factors in GIST by genetics counselors Kelly Branda and Irene Rainville, PhD.

Genetics of Carney-Stratakis Syndrome by Constantine Stratakis, MD.  This tutorial covers a genetic form of GIST caused by mutations in a different gene, causing GIST plus paragangliomas.


To access the PubMed abstracts of all the papers cited below, click here.

Antonescu CR.
Gastrointestinal stromal tumor (GIST) pathogenesis, familial GIST, and animal models.
Semin Diagn Pathol. 2006 May;23(2):63-9. Review.
PMID: 17193819

Antonescu CR, Viale A, Sarran L, Tschernyavsky SJ, Gonen M, Segal NH, Maki RG, Socci ND, DeMatteo RP, Besmer P.
Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site.
Clin Cancer Res. 2004 May 15;10(10):3282-90.
PMID: 15161681

Beghini A, Tibiletti MG, Roversi G, Chiaravalli AM, Serio G, Capella C, Larizza L.
Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa.
Cancer. 2001 Aug 1;92(3):657-62.
PMID: 11505412

Carballo M, Roig I, Aguilar F, Pol MA, Gamundi MJ, Hernan I, Martinez-Gimeno M.
Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation.
Am J Med Genet A. 2005 Feb 1;132(4):361-4.
PMID: 15742474

Chen H, Hirota S, Isozaki K, Sun H, Ohashi A, Kinoshita K, O’Brien P, Kapusta L, Dardick I, Obayashi T, Okazaki T, Shinomura Y, Matsuzawa Y, Kitamura Y.
Polyclonal nature of diffuse proliferation of interstitial cells of Cajal in patients with familial and multiple gastrointestinal stromal tumours.
Gut. 2002 Dec;51(6):793-6.
PMID: 12427778

Chompret A, Kannengiesser C, Barrois M, Terrier P, Dahan P, Tursz T, Lenoir GM, Bressac-De Paillerets B.
PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor.
Gastroenterology. 2004 Jan;126(1):318-21.
PMID: 14699510

Corless CL, Fletcher JA, Heinrich MC.
Biology of gastrointestinal stromal tumors.
J Clin Oncol. 2004 Sep 15;22(18):3813-25. Review.
PMID: 15365079

de Raedt T, Cools J, Debiec-Rychter M, Brems H, Mentens N, Sciot R, Himpens J, de Wever I, Schöffski P, Marynen P, Legius E.
Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA.
Gastroenterology. 2006 Dec;131(6):1907-12.
PMID: 17087943

Graham J, Debiec-Rychter M, Corless CL, Reid R, Davidson R, White JD.
Imatinib in the management of multiple gastrointestinal stromal tumors associated with a germline KIT K642E mutation.
Arch Pathol Lab Med. 2007 Sep;131(9):1393-6.
PMID: 17824795

Hartmann K, Wardelmann E, Ma Y, Merkelbach-Bruse S, Preussner LM, Woolery C, Baldus SE, Heinicke T, Thiele J, Buettner R, Longley BJ.
Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis.
Gastroenterology. 2005 Sep;129(3):1042-6.
PMID: 16143141

Hirota S, Nishida T, Isozaki K, Taniguchi M, Nishikawa K, Ohashi A, Takabayashi A, Obayashi T, Okuno T, Kinoshita K, Chen H, Shinomura Y, Kitamura Y.
Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene.
Gastroenterology. 2002 May;122(5):1493-9.
PMID: 11984533

Hirota S, Okazaki T, Kitamura Y, O’Brien P, Kapusta L, Dardick I.
Cause of familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germline mutation of the c-kit gene.
Am J Surg Pathol. 2000 Feb;24(2):326-7.
PMID: 10680913

Isozaki K, Terris B, Belghiti J, Schiffmann S, Hirota S, Vanderwinden JM.
Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors.
Am J Pathol. 2000 Nov;157(5):1581-5.
PMID: 11073817

Kang DY, Park CK, Choi JS, Jin SY, Kim HJ, Joo M, Kang MS, Moon WS, Yun KJ, Yu ES, Kang H, Kim KM.
Multiple gastrointestinal stromal tumors: Clinicopathologic and genetic analysis of 12 patients.
Am J Surg Pathol. 2007 Feb;31(2):224-32.
PMID: 17255767

Kim HJ, Lim SJ, Park K, Yuh YJ, Jang SJ, Choi J.
Multiple gastrointestinal stromal tumors with a germline c-kit mutation.
Pathol Int. 2005 Oct;55(10):655-9.
PMID: 16185297

Kleinbaum EP, Lazar AJ, Tamborini E, Mcauliffe JC, Sylvestre PB, Sunnenberg TD, Strong L, Chen LL, Choi H, Benjamin RS, Zhang W, Trent JC.
Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor.
Int J Cancer. 2008 Feb 1;122(3):711-8.
PMID: 17943734

Lasota J, Miettinen M.
A new familial GIST identified.
Am J Surg Pathol. 2006 Oct;30(10):1342. No abstract available. Erratum in: Am J Surg Pathol. 2007 May;31(5):816.
PMID: 17001171

Li FP, Fletcher JA, Heinrich MC, Garber JE, Sallan SE, Curiel-Lewandrowski C, Duensing A, van de Rijn M, Schnipper LE, Demetri GD.
Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred.
J Clin Oncol. 2005 Apr 20;23(12):2735-43.
PMID: 15837988

Maeyama H, Hidaka E, Ota H, Minami S, Kajiyama M, Kuraishi A, Mori H, Matsuda Y, Wada S, Sodeyama H, Nakata S, Kawamura N, Hata S, Watanabe M, Iijima Y,

Katsuyama T.
Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene.
Gastroenterology. 2001 Jan;120(1):210-5.
PMID: 11208730

Nishida T, Hirota S, Taniguchi M, Hashimoto K, Isozaki K, Nakamura H, Kanakura Y, Tanaka T, Takabayashi A, Matsuda H, Kitamura Y.
Familial gastrointestinal stromal tumours with germline mutation of the KIT gene.
Nat Genet. 1998 Aug;19(4):323-4.
PMID: 9697690

O’Brien P, Kapusta L, Dardick I, Axler J, Gnidec A.
Multiple familial gastrointestinal autonomic nerve tumors and small intestinal neuronal dysplasia.
Am J Surg Pathol. 1999 Feb;23(2):198-204.
PMID: 9989847

O’Riain C, Corless CL, Heinrich MC, Keegan D, Vioreanu M, Maguire D, Sheahan K.
Gastrointestinal stromal tumors: insights from a new familial GIST kindred with unusual genetic and pathologic features.
Am J Surg Pathol. 2005 Dec;29(12):1680-3.
PMID: 16327443

Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S, Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin E, Chompret A, Ellison JW, Briere
JJ, Rustin P, Gimenez-Roqueplo AP, Eng C, Carney JA, Stratakis CA.
Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits

Eur J Hum Genet. 2008 Jan;16(1):79-88.
PMID: 17667967

Robson ME, Glogowski E, Sommer G, Antonescu CR, Nafa K, Maki RG, Ellis N, Besmer P, Brennan M, Offit K.
Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia.
Clin Cancer Res. 2004 Feb 15;10(4):1250-4.
PMID: 14977822

Sihto H, Franssila K, Tanner M, Vasama-Nolvi C, Sarlomo-Rikala M, Nupponen NN, Joensuu H, Isola J.
Platelet-derived growth factor receptor family mutations in gastrointestinal stromal tumours.
Scand J Gastroenterol. 2006 Jul;41(7):805-11.
PMID: 16785193

Tarn C, Merkel E, Canutescu AA, Shen W, Skorobogatko Y, Heslin MJ, Eisenberg B, Birbe R, Patchefsky A, Dunbrack R, Arnoletti JP, von Mehren M, Godwin AK.
Analysis of KIT mutations in sporadic and familial gastrointestinal stromal tumors: therapeutic implications through protein modeling.
Clin Cancer Res. 2005 May 15;11(10):3668-77.
PMID: 15897563

Thalheimer A, Schlemmer M, Bueter M, Merkelbach-Bruse S, Schildhaus HU,
Buettner R, Hartung E, Thiede A, Meyer D, Fein M, Maroske J, Wardelmann E.
Familial gastrointestinal stromal tumors caused by the novel KIT exon 17 germline mutation N822Y.
Am J Surg Pathol. 2008 Oct;32(10):1560-5.
PMID: 18724244

Woźniak A, Rutkowski P, Sciot R, Ruka W, Michej W, Debiec-Rychter M.
Rectal gastrointestinal stromal tumors associated with a novel germline KIT mutation.
Int J Cancer. 2008 May 1;122(9):2160-4.
PMID: 18183595