Lay Summary: Abnormalities in the PTEN gene are a part of Cowden syndrome. It is rare, but associated with an increased risk of developing several types of cancer, including breast cancer. Under some circumstances it is appropriate to test for PTEN gene mutations.
Cowden syndrome is a complex disorder with malignant and benign (hamartomatous) lesions affecting derivatives of all three germ cell layers. Major organs involved include the breast, thyroid, uterus, brain, and mucocutaneous tissues. It has been estimated to affect about 1 in 200 000 individuals although this is probably an underestimate given the difficulty in diagnosis presented by this highly variable disease and the fact that many component features in and of themselves can occur in the general population. Penetrance is related to age, with most patients presenting by their late twenties with at least the mucocutaneous lesions of this disorder, which are reportedly seen in 99% of affected individuals. The lifetime risk for breast cancer in Cowden syndrome is estimated to be 25–50%, with an average age of diagnosis between 38 and 46 years old.
This mutation testing may be useful to confirm Cowden cases. Recently associations with other disorders, e.e macrocepahly and autism etc, have been reported.On the other hand, recent studies are raising questions about PTEN association with breast cancer syndromes.
If there is a suspicion of this syndrome and NCCN criteria are met, preventive measures might be helpful. NCCN recommends testing if one major and two minor conditions are met.
Follicular thyroid cancer
Multiple gastrointestinal hamartomas or ganglioneuromas
Macular pigmentation of glans penis, meaning a discolored area on the skin
One biopsy proven trichilemmoma
Multiple palmoplantar keratosis, meaning abnormal thickening of the hands and feet
Multifocal or extensive oral mucosal papillomatosis
Multiple cutaneous facial papules that are often verrucous, meaning wartlike projections
Esophageal glycogenic acanthosis (3)
Autism spectrum disorder
Papillary or follicular variant of papillary thyroid cancer
Thyroid structural lesions, such as adenoma, nodule(s), goiter
Renal cell kidney carcinoma
Vascular anomalies, including multiple intracranial developmental venous anomalies
Lipomas, meaning benign soft tissue tumor
Single gastrointestinal hamartoma or ganglioneuroma
There is currently no clear understanding how these other factors can be used in planning therapy or genetic counselling and there are no guidelines to advise physicians.
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http://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf, COWD-1 2012
R Pilarski and C Eng Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome Journal of Medical Genetics 2004;41:323-326
C. A. Haiman, D. O. Stram, I. Cheng, E. E. Giorgi, L. Pooler, K. Penney, L. Le Marchand, B. E. Henderson, and M. L. Freedman
Common Genetic Variation at PTEN and Risk of Sporadic Breast and Prostate Cancer.
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Eng C (November 2000). “Will the real Cowden syndrome please stand up: revised diagnostic criteria”. J. Med. Genet. 37 (11)
S a p n a S y n g a l , et al ,ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes. .Am J Gastroenterol 2015; 110:223262;
Charis Eng, MD, P, hDPTEN Hamartoma Tumor Syndrome (PHTS)
GeneReviews® [Internet]. http://www.ncbi.nlm.nih.gov/books/NBK1488/
Note: Despite a negative (normal) genetic test for mutations in the BRCA1 and BRCA2 genes, about 12 percent of breast cancer patients from high-risk families carried previously undetected cancer-associated mutations. Risks for young women with inherited BRCA1 or BRCA2 mutations are particularly increased. Among white women in the U.S., 5 percent to 10 percent of breast cancer cases are due to inherited mutations in BRCA1 and BRCA2. Inherited mutations in other genes, including CHEK2, TP53 and PTEN, can also influence risk of breast cancer. BART and PTEN mutations are reviewed as separate entries.