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  • Review Article
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Cancer phenomics: RET and PTEN as illustrative models

Nature Reviews Cancer volume 7, pages 35–45 (2007)Cite this article

Key Points

  • Cancer phenomics refers to the systematic and meticulous collection, objective documentation and cataloguing of phenotypic data at many levels, including clinical, molecular and cellular phenotype. Compared with other genes that predispose to the development of cancer, robust phenomic data exists for rearranged during transfection (RET) and phosphatase and tensin homologue (PTEN).

  • Germline PTEN and RET mutations predispose to the cancer-associated syndromes Cowden syndrome (CS) and multiple endocrine neoplasia type 2 (MEN 2), respectively. Both genes also predispose to developmental disorders with seemingly disparate phenotypes.

  • CS predisposes to breast, thyroid and endometrial cancer, whereas MEN 2 predisposes to medullary thyroid cancer (MTC), phaeochromocytoma and hyperparathyroidism.

  • Phenomics has shown that germline RET and PTEN mutations are present in a subset of patients with apparently sporadic cancer involving neoplasias that are components of MEN 2 and CS, respectively. Identifying these mutations will have important implications for personalized genetic health care.

  • Meticulous characterization of RET phenomics at the clinical and biochemical levels has resulted in individualized patient management with respect to cancer surveillance and prophylactic surgery in MEN 2. In addition, phenomics offers valuable insight into the aetiology of the variable expression of features seen in MEN 2.

  • Through phenomic-based research, the spectrum of phenotypes associated with germline PTEN mutations is continually evolving, and these are collectively termed the PTEN hamartoma tumour syndromes (PHTS). Such research has also led to the continual refinement of the diagnostic criteria for CS.

  • The current opinion is that all patients with PHTS, irrespective of phenotype, follow the cancer surveillance guidelines recommended for CS. These guidelines are updated annually by the US National Comprehensive Cancer Network.

  • Molecular phenomic research has explored new mechanisms of PTEN dysfunction, including splice-site variation and the localization of PTEN to different cellular compartments.

  • Through an understanding of the PTEN–AKT pathway, and its cross-talk with other pathways important in tumorigenesis, the use of targeted therapies seems promising for the treatment of PHTS. However, these agents must be used with caution, as their effects on the development and homeostasis of normal tissue deserves careful consideration.

Abstract

Cancer phenomics, the systematic acquisition and objective documentation of host and/or somatic cancer phenotypic data at many levels, is a young field compared with other molecular-based 'omics'. Two relatively advanced phenomic paradigms are associated with phosphatase and tensin homologue (PTEN) and rearranged during transfection (RET), genes that are associated with cancer predisposition syndromes in addition to developmental disorders. The phenomic characterization of PTEN and RET underscores the importance of incorporating robust phenomics into the host 'omic' profile, and shows that the evolution of phenomics will be crucial to the advancement of personalized medicine.

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Figure 1: PTEN and RET signalling pathways.
Figure 2: Schematic representation of RET and codons affected by mutations in MEN 2.
Figure 3: Schematic representation of reported germline PTEN mutations in PHTS.

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Acknowledgements

C.E. is a recipient of the Doris Duke Distinguished Clinical Scientist Award and is supported by grants from the US National Institutes of Health, US National Cancer Institute and American Cancer Society. K.Z. is a Crile Fellow of the Cleveland Clinic, United States.

Author information

Authors and Affiliations

  1. Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Kevin M. Zbuk & Charis Eng

  2. Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Kevin M. Zbuk & Charis Eng

  3. Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA

    Charis Eng

  4. Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

    Charis Eng

  5. Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

    Charis Eng

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  1. Kevin M. Zbuk
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Correspondence to Charis Eng.

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Related links

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DATABASES

National Cancer Institute

MTC

pheochromocytoma

OMIM

CS

FA

HNPCC

HSCR

MEN2

FURTHER INFORMATION

Genomic Medicine Institute

National Comprehensive Cancer Network

PROPHECY

PhenomicDB

Glossary

Personalized medicine

The individualized tailoring of diagnostic, prognostic and therapeutic decisions on the basis of an individual, genomic, epigenomic, proteomic and phenomic profile.

Germline mutation

A mutation that is present in every cell of the body; the mutation can be transmitted through the sperm or ova.

Medullary thyroid cancer

A malignancy that develops from the neural-crest-derived C cells of the thyroid. C cells secrete calcitonin, a hormone important in normal calcium homeostasis.

Phaeochromocytoma

A neoplasm of the adrenal gland that often secretes catecholamines, leading to symptoms such as sweating, palpitations and hypertension.

Hyperparathyroidism

Excessive production of the parathyroid hormone, often leading to symptoms related to elevated serum calcium.

Hamartoma

A non-malignant tumour characterized by the proliferation of normal cellular elements, but with disordered architecture.

Compound heterozygous

Refers to the presence of two different minor (disease causing) alleles in a single individual.

Multifocal

Several discrete tumour foci in different locations within the same organ.

Penetrance

The degree to which a genotype is expressed phenotypically. For example, the penetrance of breast cancer in CS patients with PTEN mutations might be as high as 50%.

Prophylactic

An intervention, often surgical, performed to prevent a disease from occurring.

Thyroidectomy

The surgical removal of the thyroid gland.

Haemangioblastomas

The abnormal, but non-malignant, proliferation of blood vessels, usually capillaries, in the CNS.

Pathognomonic

Absolutely diagnostic of, or specific to, a disorder. For example trichilemmomas are pathognomic of CS and their presence, in adequate numbers, enables the clinician to make a definitive diagnosis.

Hyperplastic polyps

Colonic polyps composed of a proliferation of normal cellular elements.

Loss of heterozygosity

Refers to the loss of one allele in a tumour from a locus for which normal tissue is heterozygous.

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Zbuk, K., Eng, C. Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer 7, 35–45 (2007). https://doi.org/10.1038/nrc2037

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