PTEN and inherited hamartoma-cancer syndromes (original) (raw)

Nature Genetics volume 19, page 223 (1998)Cite this article

Germline mutations in PTEN, which encodes a dual-specificity phosphatase, have been found in two related autosomal dominant hamartoma syndromes, Cowden syndrome (CS; OMIM158350) and Bannayan-Ruvalcaba-Riley syndrome (BRR; OMIM153480; refs 1, 2, 3, 4, 5, 6). CS is characterized by hamartomas, including gastrointestinal hamartomatous polyps, and risk of neoplasms of the thyroid, breast, uterus and skin7. BRR has early-onset macrocephaly, hamartomatous polyposis, lipomatosis and speckled penis8. Juvenile polyposis syndrome (JPS; OMIM174900) is an autosomal dominant inherited hamartoma syndrome characterized by the presence of gastrointestinal hamartomatous polyps and an increased risk of gastrointestinal malignancy9. The diagnosis of JPS is made only if features classic for other syndromes are not present.

Could PTEN also be the JPS gene? Three groups have found no evidence of germline PTEN mutations in 21 JPS families and 16 sporadic cases10,[11](/articles/ng0798%5F223#ref-CR11 "Riggins, G.J., Hamilton, S.R., Kinzler, K.W. & Vogelstein, B. J. Neg. Obs. Genet. Oncol.(28 July, 1998) http://128.220.85.41:5002/MCGI/SEND1^WEBUTLTY(1378,1)/1674326758

               (1998)."),[12](/articles/ng0798%5F223#ref-CR12 "Howe, J.R. et al. Am. J. Hum. Genet.  62, 1129– 1136 (1998).") and power calculations indicated that if 10% of JPS cases were due to germline   _PTEN_ mutations, there should have been a 0.99 likelihood of detecting at least one mutation among these 37 cases. Power calculations notwithstanding, 'negative studies' always raise an uneasy spectre: were these 37 JPS cases the 37 that happen to not carry germline _PTEN_ mutations? A fourth group strived to answer this question[13](/articles/ng0798%5F223#ref-CR13 "Olschwang, S., Serova-Sinilnikova, O.M., Lenoir, G.M. & Thomas, G. Nature Genet.  18, 12–14 ( 1998).") using a broad operational definition of 'JPS'; all patients who have juvenile polyps were included, irregardless of age or presence of other features. They found three 'JPS' patients with germline _PTEN_ mutations. An adult male (G116) had features highly suggestive of CS, and two children (G796, G710), diagnosed at ages 3 and 14, were reported not to have manifestations of CS or BRR[13](/articles/ng0798%5F223#ref-CR13 "Olschwang, S., Serova-Sinilnikova, O.M., Lenoir, G.M. & Thomas, G. Nature Genet.  18, 12–14 ( 1998)."). The penetrance of CS is well under 10% below 15 years of age[14](/articles/ng0798%5F223#ref-CR14 "Nelen, M.R. et al.  Nature Genet. 13, 114–116 (1996)."), and so while the children have JPS according to diagnostic criteria, they may develop other features of CS as they age. As phenotypic features may be shared by several hamartoma syndromes and the clinical examination is not always straightforward, specific diagnoses could be difficult. It is important to distinguish the various hamartoma syndromes, as predisposition to cancer or types of cancer may be different among them. We would like to propose that the presence of a germline _PTEN_ mutation is a useful molecular diagnostic sign for CS or BRR (ref. [15](/articles/ng0798%5F223#ref-CR15 "Eng, C. & Ji, H. Am. J. Hum. Genet. 62, 1020–1022 (1998).")). If a 'JPS' patient were found to harbour an occult germline _PTEN_ mutation, then it behooves the clinician to consider CS or BRR as the diagnosis, with full implications for surveillance of the skin, thyroid, breast and uterus for cancer development. With regard to the molecular diagnosis of JPS, help is on its way[16](/articles/ng0798%5F223#ref-CR16 "Howe, J.R. et al.  Science 280, 1086–1088 ( 1998)."). Germline mutations in _SMAD4_, on 18q21.1, have been found in a subset of familial and sporadic JPS cases. _SMAD4_ belongs to the _SMAD_ family of genes, which encode cytoplastic mediators in the TGFβ-signalling pathway. Without much extrapolation, one can easily postulate that germline mutations in other _SMAD_ genes could account for the majority of JPS. Only time will tell whether the molecular diagnosis of the inherited hamartoma-cancer syndromes will prove more robust than that based purely on clinical criteria.

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Acknowledgements

We thank J.R. Howe V for sharing prepublication material and O. Gimm for critical review of the manuscript. C.E. is the Lawrence and Susan Marx Investigator in Human Cancer Genetics and a Barr Investigator.

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Authors and Affiliations

  1. Department of Adult Oncology, Translational Research Laboratory, Charles A Dana Human Cancer Genetics Unit, Dana-Farber Cancer Institute, Harvard Medical School, 1 Jimmy Fund Way, SM822, Boston, 02115, Massachusetts, USA
    Charis Eng
  2. Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, Cambridge, CB2 2QQ, UK
    Charis Eng
  3. Departments of Dermatology and Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, VC-1526, 10032, New York, USA
    Monica Peacocke

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  1. Charis Eng
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Eng, C., Peacocke, M. PTEN and inherited hamartoma-cancer syndromes.Nat Genet 19, 223 (1998). https://doi.org/10.1038/897

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