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Journal of Clinical Oncology, Vol 26, No 13 (May 1), 2008: pp. 2234 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.8949
Germline PTEN Mutations As a Cause of Early-Onset Endometrial CancerMedical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD To the Editor: In the article by Lu et al,1 the investigators conducted a prospective assessment of the prevalence of Lynch syndrome in women diagnosed with endometrial cancer before age 50 years. Although they identified germline Lynch syndrome–associated mutations in 9% of their patient population, their data also suggest that for 91% of patients with early-onset endometrial cancer, the genetic basis is unclear. One genetic condition that could contribute is Cowden syndrome (CS), which is another inherited cancer susceptibility syndrome in which early endometrial cancer can occur. CS is characterized by germline mutations in the tumor suppressor PTEN that is located on chromosome 10q23.3. Loss of PTEN increases activation of the Akt/mTOR pathway, increases tumorigenesis in many organs in preclinical studies (including the uterus), and is a poor prognostic factor for many types of cancer. Germline mutations in PTEN are associated with a number of hamartomatous syndromes, of which CS is the prototype. CS patients develop thyroid, breast, and endometrial cancers at an earlier age than the general population, and have an overall increased incidence of these cancers compared with the general population. In a young woman diagnosed with endometrial cancer, a thorough history and physical examination evaluating signs of CS such as macrocephaly, mucocutaneous lesions (ie, facial trichilemmomas, acral keratoses, papillomatous lesions, or mucosal lesions) should be performed. If a patient meets established clinical criteria for CS,2 or has a family member diagnosed with CS, referral for genetic testing and sequencing for germline mutation of PTEN should be considered. Although Lynch syndrome and CS can independently contribute to early-onset endometrial cancer, defects in mismatch repair (MMR), microsatellite instability (MSI), and PTEN mutations might be etiologically related. For example, in a population-based study of patients with sporadic endometrial cancer,3 tumors with MSI had a higher frequency of PTEN mutations. Patients whose tumors harbored MSI and PTEN mutations were more likely to be diagnosed at an advanced stage and exhibited a worse prognosis. Zhou et al4 demonstrated that a high frequency of somatic PTEN mutations, especially frameshift mutations, are found in endometrial carcinomas arising in individuals with Lynch syndrome. This suggests that PTEN mutations in Lynch syndrome–associated endometrial cancers are a consequence of deficiencies in MMR. Similarly, in mutational analysis of colorectal cancer,5 somatic PTEN mutations were found only in individuals with Lynch syndrome and sporadic colorectal cancers with MSI. All somatic PTEN mutations were frameshift mutations, occurring in the two 6(A) coding mononucleotide tracts in PTEN, again suggesting that defects in MMR lead to PTEN mutations. Although it is unclear if germline PTEN mutations occur in individuals with Lynch syndrome, we believe that women with early-onset endometrial cancer should be evaluated for CS and/or somatic PTEN mutations. Such an analysis could have therapeutic implications, given that inhibitors of the Akt/mTOR pathway are being studied in patients with advanced endometrial cancer,6 and may be preferentially active in tumors harboring PTEN mutations. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Lu KH, Schorge JO, Rodabaugh KJ, et al: Prospective determination of prevalence of lynch syndrome in young women with endometrial cancer. J Clin Oncol 25:5158-5164, 2007 2. Eng C: Will the real Cowden syndrome please stand up: Revised diagnostic criteria. J Med Genet 37:828-830, 2000 3. Bilbao C, Rodriguez G, Ramirez R, et al: The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer. Int J Cancer 119:563-570, 2006[CrossRef][Medline] 4. Zhou XP, Kuismanen S, Nystrom-Lahti M, et al: Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors. Hum Mol Genet 11:445-450, 2002 5. Zhou XP, Loukola A, Salovaara R, et al: PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. Am J Pathol 161:439-447, 2002 6. Colombo NMS, Schwartz P, et al: A phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer. J Clin Oncol, 25:278s, 2007 (suppl; abstr 5516) Related Reply
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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