Genetic testing for a PTEN mutation may be considered medically necessary to confirm the diagnosis when a patient has clinical signs* of a PTEN hamartoma tumor syndrome.
*NOTE: See Description section for clinical signs.
Genetic testing for a PTEN mutation may be considered medically necessary in a first-degree relative of a proband* with a known PTEN mutation. *NOTE: A proband is usually the first affected individual in a family who brings a genetic disorder to the attention of the medical community. A first-degree relative is any relative who is one meiosis away from a particular individual in a family; a relative with whom one-half of an individual's genes are shared, a 50% genetic link to the patient (i.e., parent, sibling, offspring).(6)
Genetic testing for a PTEN mutation is considered experimental, investigational and unproven for all other indications, including, but not limited to, prenatal testing.
The MEDLINE database was searched for literature that describes the analytic validity, clinical validity, and clinical utility of genetic testing for PTEN-related disorders.
Analytic validity (the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)
According to a large reference laboratory, analytical sensitivity and specificity for polymerase chain reaction (PCR) sequencing PTEN-related disorders is 99%, and analytical sensitivity and specificity of testing for deletions/duplications by MLPA (multiplex ligation-dependent probe amplification) is 90% and 98%, respectively. (2)
The order of testing to optimize yield would be 1) sequencing of PTEN exons 1-9 and flanking intron regions. If no mutation is identified, perform 2) deletion/duplication analysis. If no mutation is identified, consider, 3) promoter analysis.
Clinical validity (the diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)
Many reports on the prevalence of the features of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba (BRRS) have been based upon data compiled from case reports and studies of small cohorts. Most of these reports were published before adoption of the International Cowden Consortium diagnostic criteria for CS in 1996, and the true frequencies of the clinical features in CS and BRRS are not known. (1)
According to a large reference laboratory, the clinical sensitivity of PTEN-related disorders sequencing is 80% for CS, 60% for BRRS, 20% for PTEN-related Proteus syndrome (PS) and 50% for Proteus-like syndrome (PSL). For PTEN-related deletion/duplication, it is up to 10% for BRRS and unknown for CS, PS, and PSL. (2)
Germline PTEN mutations have been identified in ~80% of patients meeting diagnostic criteria for CS and in 50-60% of patients with a diagnosis of BRRS, using PCR-based mutation analysis of the coding and flanking intronic regions of the gene. (3, 4) Marsh et al. screened DNA from 37 CS families and PTEN mutations were identified in 30 of 37 CS families (81%), including point mutations, insertions, and deletions. (3)
Whether the remaining patients have undetected PTEN mutations or mutations in other, unidentified genes, is not known. (5)
A 2011 study by Pilarski et al. determined the clinical features most predictive of a mutation in a cohort of patients tested for PTEN mutations. (1) Molecular and clinical data were reviewed for 802 patients referred for PTEN analysis by a single laboratory. All of the patients were classified as to whether they met revised International Cowden Consortium Diagnostic criteria. Two hundred and thirty of the 802 patients met diagnostic criteria for a diagnosis of CS. Of these, 79 had a PTEN mutation, for a detection rate of 34%. The authors commented that this mutation frequency was significantly lower than previously reported, possibly suggesting that the clinical diagnostic criteria for CS are not as robust at identifying patients with germline PTEN mutations as previously thought. In contrast, in their study, of the patients meeting diagnostic criteria for BRRS, 23 of 42 (55%) had a mutation, and 7 of 9 patients (78%) with diagnostic criteria for both CS and BRRS had a mutation, consistent with the literature.
Conclusions: Evidence from several small studies indicates that the clinical sensitivity of genetic testing for PTEN mutations may be highly variable. This may be a reflection of the phenotypic heterogeneity of the syndromes and an inherent referral bias as patients with more clinical features of CS/BRRS are more likely to get tested. The true clinical specificity is uncertain because the syndrome is defined by the mutation.
Clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)
The clinical utility of genetic testing can be considered in the following clinical situations: 1) individuals with suspected PTEN hamartoma tumor syndrome (PHTS), 2) family members of individuals with PHTS, and 3) prenatal testing. These situations will be discussed separately below.
- Individuals with suspected PHTS. The clinical utility for these patients depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes. There is no direct evidence for the clinical utility of genetic testing in these patients as no studies were identified that described how a molecular diagnosis of PHTS changed patient management.
However, for patients who are diagnosed with PHTS by identifying a PTEN mutation, the medical management focuses on increased cancer surveillance to detect tumors at the earliest, most treatable stages.
- Family members. When a PTEN mutation has been identified in a proband, testing of at-risk relatives can identify those who also have the mutation and have PTEN hamartoma tumor syndrome (PHTS). These individuals need initial evaluation and ongoing surveillance.
- Prenatal screening. Prenatal diagnosis is possible for pregnancies at increased risk, by amniocentesis or chorionic villus sampling; the disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
Conclusions: Direct evidence of the clinical utility of PTEN testing is lacking. However, the clinical utility of genetic testing for PTEN mutations is that genetic testing can confirm the diagnosis in patients with clinical signs and symptoms of PHTS. Management changes include increased surveillance for the cancers that are associated with these syndromes.
A PTEN mutation can be identified in up to 85% of patients who meet the clinical criteria for a diagnosis of Cowden Syndrome and 65% of patients with a clinical diagnosis of Bannayan-Riley-Ruvalcaba Syndrome. Most of these mutations can be identified by sequence analysis of the coding and flanking intronic regions of genomic DNA. A smaller number of mutations are detected by deletion/duplication or promoter region analysis.
However, the published clinical validity of testing for PTEN mutations is variable, and the true clinical validity is difficult to ascertain, as the syndrome is defined by the presence of a PTEN mutation.
The clinical utility of genetic testing for a PTEN mutation is high, in that confirming a diagnosis in a patient with clinical signs of a PTEN hamartoma tumor syndrome (PHTS) will lead to changes in clinical management by increasing surveillance to detect cancers known to be associated with PHTS at an early and treatable stage. Although most cases of a PHTS occur in individuals with no known family history of PHTS, testing of at-risk relatives will identify those who should also undergo increased cancer surveillance. Therefore, genetic testing for a PTEN mutation may be considered medically necessary when a presumptive diagnosis of a PTEN hamartoma tumor syndrome (PHTS) has been made, based on clinical signs and also in first-degree relatives of a probands with a known PTEN mutation.
Guidelines and Position Statements
2012 National Comprehensive Cancer Network (NCCN) guidelines recommend the following for CS management:
- Breast self-exam training and education starting at age 18 years.
- Clinical breast exam every 6-12 months, starting at age 25 years or 5-10 years before the earliest known breast cancer in the family.
- For endometrial cancer screening, encourage patient education and prompt response to symptoms and participation in a clinical trial to determine the effectiveness and necessity of screening modalities.
- Discuss option of risk-reducing mastectomy and hysterectomy on case-by-case basis and counsel regarding degree of protection, extent of cancer risk, and reconstructive options.
For men and women:
- Annual comprehensive physical exam starting at age 18 years or 5 years before the youngest age of diagnosis of a component cancer in the family, with particular attention to breast and thyroid exam.
- Baseline thyroid ultrasound at age 18 years, and consider annual thereafter.
- Consider colonoscopy, starting at age 35 years, then every 5-10 years or more frequently if patient is symptomatic or polyps found.
- Consider annual dermatologic exam.
- Education regarding the signs and symptoms of cancer.
- Advise about possible inherited cancer risk to relatives, options for risk assessment, and management.
- Recommend genetic counseling and consideration of genetic testing for at-risk relatives.
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