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From developmental disorder to heritable cancer: it's all in the BMP/TGF-β family

Nature Reviews Genetics volume 4, pages 763–773 (2003)Cite this article

Key Points

  • Germline mutations in the genes that encode the BMP/TGF-β superfamily are associated with heritable vascular disorders and cancer syndromes.

  • The TGF-β pathway involves the heterodimerization of type II and type I receptors after ligand binding, which leads to heterodimerization of R-SMAD and Co-SMAD. The SMAD complex translocates to the nucleus, where it regulates transcription.

  • Germline mutations in BMPR2, which result in haploinsufficiency, cause primary pulmonary hypertension (PPH). BMPR2 encodes BMPR-II, which is a type II receptor in the TGF-β pathway. Most of these mutations occur in the ligand- or kinase-binding domains and disrupt the signal-transducing abilities of the receptor.

  • Germline mutations in ENG, which encodes endoglin (a co-receptor for type II receptors), are associated with hereditary haemorrhagic telangiectasia 1 (HHT1). Germline mutations cause haploinsufficiency or dominant-negative protein expression.

  • Germline mutations in ALK1, which encodes the type I receptor ALK1, are associated with HHT2. Mutations in ALK1 are predicted to cause truncated proteins and haploinsufficiency.

  • Germline mutations in either MADH4, which encodes SMAD4, or BMPR1A, which encodes the type IA receptor for BMP2, are involved in juvenile polyposis syndrome. Mutations in MADH4 prevent the heterodimerization of SMAD4 with R-SMADs, whereas mutations in BMPR1A result in the loss of ligand binding or kinase activity.

  • BMPR1A is a minor susceptibility gene for Cowden syndrome, which is a hamartoma-cancer syndrome.

  • The BMP and PTEN pathways might crosstalk.

Abstract

Transforming growth factor-β (TGF-β) regulates many cellular processes through complex signal-transduction pathways that have crucial roles in normal development. Disruption of these pathways can lead to a range of diseases, including cancer. Mutations in the genes that encode members of the TGF-β pathway are involved in vascular diseases as well as gastrointestinal neoplasia. More recently, they have been implicated in Cowden syndrome, which is normally associated with mutations in the phosphatase and tensin homologue gene PTEN. Molecular studies of TGF-β signalling are now showing why mutations in genes that encode components of this pathway result in inherited cancer and developmental diseases.

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Figure 1: Complexity of TGF-β signal transduction.
Figure 2: Model for TGF-β signalling in the cell.
Figure 3: Germline BMPR2 mutational spectrum in primary pulmonary hypertension.
Figure 4: Germline mutations in ENG in hereditary haemorrhagic telangiectasia.
Figure 5: Germline mutations in ACVRL1 in hereditary haemorrhagic telangiectasia.
Figure 6: Germline mutations in MADH4 in juvenile polyposis syndrome.
Figure 7: Spectrum of germline mutations in BMPR1A in juvenile polyposis syndrome.

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Acknowledgements

We are grateful to J. Howe for sharing pre-publication data, and to L. Aaltonen, W. Friedl and R. Trembath for helpful discussions. C.E. is the recipient of a Doris Duke Distinguished Clinical Scientist Award and is partially funded by the American Cancer Society, the Department of Defense United States Army Breast and Prostate Cancer Research Programs, the Susan G. Komen Breast Cancer Research Foundation, the National Cancer Institute, the National Institutes of Health, the State of Ohio Biomedical Research and Technology Transfer Fund and the V Foundation Jimmy V Golf Classic Translational Cancer Research Award.

Author information

Authors and Affiliations

  1. Division of Human Cancer Genetics, Department of Molecular Virology, Human Cancer Genetics and Clinical Cancer Genetics Programs, Comprehensive Cancer Center, Immunology and Medical Genetics, The Ohio State University, Columbus, 43210, Ohio, USA

    Kristin A. Waite & Charis Eng

  2. Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, 43210, Ohio, USA

    Charis Eng

  3. Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, Cambridge, CB2 2XZ, UK

    Charis Eng

Authors
  1. Kristin A. Waite
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Correspondence to Charis Eng.

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DATABASES

Entrez

BMP2

BMP7

SMAD1

SMAD2

SMAD3

SMAD4

SMAD5

TGF-β1

TGF-β3

LocusLink

ACVRL1

BMPR1A

BMPR2

ENG

MADH4

PTEN

RET

STK11

OMIM

Bannayan–Riley–Ruvalcaba syndrome

Cowden syndrome

hereditary haemorrhagic telangiectasia

hereditary mixed polyposis syndrome

juvenile polyposis syndrome

Lynch syndrome

multiple endocrine neoplasia type 2

Peutz–Jeghers syndrome

primary pulmonary hypertension

PTEN hamartoma tumour syndrome

FURTHER INFORMATION

Genomic Disorders Research Centre

Human Genome Variation Society Nomenclature for the Description of Sequence Variations

Medical Genetics Information Resource

Mutation Nomenclature Committee

Glossary

HAEMATOPOIESIS

The development of blood cells.

ARTERIOLES

Small arteries. Blood flows from arteries to arterioles to capillaries, and returns to the heart through venules (small veins) and then veins.

RIGHT HEART FAILURE

Heart failure that is limited to the right-sided chambers of the heart, which is usually caused by lung problems.

LOCUS HETEROGENEITY

Refers to an inherited disorder with more than one susceptibility gene.

HAPLOINSUFFICIENCY

The half dosage of a gene product, which leads to an adverse phenotype.

SDS-PAGE

Sodium dodecyl sulphate-polyacrimide gel electrophoresis. A rapid and inexpensive method for resolving a protein into its subunits and determining their relative molecular masses.

MULTI-SYSTEM VASCULAR DYSPLASIA

The atypical growth of vessels in many organs.

TELANGIECTASIAS

Dilated capillaries and arterioles.

FOUNDER EFFECT

A mutation that originated in a single individual, which has been passed on through the generations and spread through the population.

MESENCHYMAL

(Stromal). Cells that do not form gap junctions with one another.

MODIFIER GENES

Variants in these genes themselves do not produce a phenotype, but when they are present with other variants of germline mutations they produce a phenotypic effect.

INTERSUSSCEPTION

The telescoping of the bowel on itself.

HAMARTOMATOUS POLYPS

Hamartomas are benign developmentally incorrect overgrowths of any tissue that comprise at least two elements of the tissue. Hamartomatous polyps are outgrowths in the gastrointestinal tract, which comprise at least two components of the normal intestine but in developmentally incorrect apposition. They are not considered to be pre-neoplastic.

PROBANDS

The first known affected individual in any given family.

ENDOMETRIAL CARCINOMAS

Cancer of the inner-lining of the uterus.

LIPOMATOSIS

Multiple fatty tumours.

POLYPECTOMIES

The removal of polyps.

PATHOGNOMONIC

Absolutely diagnostic.

HAEMODYNAMICS

The physics of all aspects of blood flow in large and small arteries.

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Waite, K., Eng, C. From developmental disorder to heritable cancer: it's all in the BMP/TGF-β family. Nat Rev Genet 4, 763–773 (2003). https://doi.org/10.1038/nrg1178

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