PTEN Germline Mutations in Patients Initially Tested for Other Hereditary Cancer Syndromes: Would Use of Risk Assessment Tools Reduce Genetic Testing?

Abstract

Purpose. PTEN Hamartoma Tumor syndrome (PHTS) includes patients with Cowden syndrome or other syndromes with germline mutation of the PTEN tumor suppressor gene. The risk for breast, colorectal, and endometrial cancer and polyposis is increased, creating clinical overlap with hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS), and adenomatous polyposis syndromes (APS). We reviewed our series of patients with PHTS to determine how often testing criteria for these syndromes were met and how often othergene testing was ordered before testing PTEN. Patients and Methods. Patients were prospectively recruited by relaxed International Cowden Consortium criteria or presence of known germline PTEN mutation. Mutations were identified by mutation scanning/multiplex ligation-dependent probe amplification analysis and confirmed by sequencing/quantitative polymerase chain reaction. Patients were excluded if they were adopted, were Ͻ18 years of age, or if they were diagnosed with Cowden syndrome before 1998.Standard risk-assessment models were applied to determine whether patients met HBOC testing criteria, LS-relevant Amsterdam II/Bethesda 2004 criteria, or had adenomatous polyps. Prior probability of PTEN mutation was estimated with the Cleveland Clinic PTEN risk calculator. Results. Of 137 PTEN mutation-positive adult probands, 59 (43.1%) met testing criteria for HBOC or LS. Of these, 45 (32.8%) were first offered HBOC, LS, or APS testing. Of those who underwent APS testing, none of the six patients met criteria. Initial risk assessment by a genetics specialist was significantly associated with immediate PTEN testing in patients also meeting HBOC testing criteria. Using this PTEN risk assessment tool could have spared gene testing for 22 unlikely syndromes, at a total cost of $66,080. Conclusion. PHTS is an important differential diagnosis for patients referred for HBOC, LS, or APS. Risk assessment tools may help focus genetic analysis and aid in the interpretation of multiplex testing. The Oncologist 2013;18:1083-1090 Implications for Practice: Whereas hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial adenomatous polyposis are some of the most common causes of hereditary cancer predisposition, other conditions with overlapping clinical spectra exist. Timely identification of the right syndrome is critical for patient management and testing at-risk relatives. When multiple conditions are possible, risk assessment tools help clinicians judge which condition is most likely, allowing genetic testing to proceed in a stepwise and cost-effective manner. Here we present a series of patients with germline mutations of PTEN, a gene causing predisposition to breast, uterine, colorectal, and other cancers as well as to gastrointestinal polyposis. Many patients were tested for another syndrome prior to PTEN testing. Had now-existent risk assessment tools been used, elevated PTEN mutation risk in these patients might have been recognized immediately, leading to health care savings and shor...

Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability

“…The 13 remaining subjects with negative LS diagnosis were excluded from these experiments; however, given the selection criteria for enrolment in the present study, these cases are not to be considered sporadic CRC cases, as they were likely to have genetic causes. Recently, it has been described that other Mendelian syndromes with autosomal-dominant inheritance patterns, including the phosphatase and tensin homolog (PTEN) Hamartoma Tumor Syndrome (PHTS), show an overlapping clinical presentation with LS, but tumors do not show any MSI (17). In line with this, in previous studies by our group, one patient with MSS status of tumorous tissue, who underwent germ-line testing for the PTEN gene, showed a germ-line mutation in this gene (18), which was associated with the disease in the family (19).…”

PTEN: Multiple Functions in Human Malignant Tumors

“…Germline mutations of PTEN are the underlying genetic causes of related disorders clinically referred to as PTEN hamartoma syndromes (PHTS) including: Cowden syndrome, Bannayan–Zonana syndrome, Lhermitte–Duclos syndrome, Proteus syndrome, and Proteus-like syndrome. Mutations responsible for these syndromes result in a non-functional or absent protein, which causes uncontrolled cell growth, leading to tumor (either benign or malignant) growth ( 34 , 155 – 157 ). Cowden syndrome is the best-described syndrome within PHTS, with approximately 80% of patients having germline PTEN mutations.…”

“…Cowden syndrome is the best-described syndrome within PHTS, with approximately 80% of patients having germline PTEN mutations. Patients with Cowden syndrome have a high risk for benign and malignant tumors of the breast (lifetime risk – LR-85%), thyroid (LR 35%), kidney (renal cell carcinoma – RCC-, LR 33%), and endometrium (LR 28%), which correspond to sporadic tumor types that commonly exhibit somatic PTEN inactivation ( 155 , 157 , 158 ) (Table 2 ). In addition, increased risk for colorectal cancer (9%) and melanoma (6%), previously not believed to be part of PHTS, have also been described ( 35 ).…”

“…Germline PTEN mutation in Cowden syndrome has a predisposition to breast cancer, where female CS patients have up to 85% LR of developing breast cancer ( 155 , 157 , 158 ). In sporadic breast carcinomas, the frequency of PTEN loss is 30–40% ( 36 ).…”

Lynch syndrome: five unanswered questions

“…Given the increased perception that the broad spectrum of LS cancers can overlap with other hereditary cancer syndromes (21)(22)(23), the use of multiple gene panels can help to elucidate the genetic cause in patients that would have not been diagnosed by using a gene-by-gene limited screening. Somatic NGS panels (15) as well as MSI/IHC testing should also be taken into account in a NGS-based LS-predisposition model (Fig.…”