Utilization of Genetic Testing for RET Mutations in Patients with Medullary Thyroid Carcinoma: a Single‐Center Experience

Abstract

Medullary thyroid carcinoma (MTC) is often due to the hereditary condition multiple endocrine neoplasia type 2 (MEN2) and it is standard of care to offer genetic testing to all diagnosed patients. This study used the Kaiser Permanente integrated medical record system to identify patients at risk for MEN2, assess adherence to clinical practice guidelines, and offer genetic counseling and testing. A query of the electronic medical records system identified patients with MTC. All patients with MTC who had not had RET gene testing, as well as patients who had positive RET gene testing, but had not yet had genetic counseling, were contacted and offered a genetics consultation. The query identified 142 patients with MTC. Fifty-six (40%) of those patients had not had the RET testing that all endocrine professional groups recommend. Forty-nine patients were eligible for the outreach, and, from this, 14 patients were scheduled for genetic counseling. Of the 94 individuals at our institution who had RET genetic testing, 25 (27%) were positive for a mutation. Of the 82 apparently sporadic cases, 13 (16%) carried a RET mutation. A family history of endocrine cancer and younger age at diagnosis significantly increased the risk carrying a RET mutation. However, approximately half of RET-positive patients did not have a significant family history of cancer and one-third were over age 50 at diagnosis. This study concludes that a significant proportion of patients with MTC are not receiving standard of care genetic testing and reinforces previous research that sporadic-appearing cases of MTC are often, in fact, hereditary.

Cascading After Peridiagnostic Cancer Genetic Testing: An Alternative to Population-Based Screening

“…[35][36][37][38][39][40][41] Even if universally accessible, it is now evident that 26%-56% of individuals with inherited pathogenic variants in cancer susceptibility genes will not be detected by clinical guidelines based on family history; this has been shown for "panel" genetic testing, 20 as well as family history-targeted testing for BRCA1/2, RET, FH, BAP1, VHL, MET, SDHA, and SDHB germline mutations. 17,18,[42][43][44][45][46][47][48][49] Despite calls for population screening for common cancer predisposition genes such as BRCA1/2, 6 and other high penetrance genes, 7 there remain concerns about accessibility to diverse populations, including needs for intensive counseling and evaluation after detection of variants of unknown significance (VUS) 15,16 and adverse Tornado plot depicting univariate sensitivity analysis performed using baseline model: 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, 15% of incident patients with cancer undergoing germline testing, and 25% first-degree relatives, 25% second-degree relatives, and 25% thirddegree relatives cascading, the time to detect 3.9 million individuals with a germline cancer susceptibility mutation was 22.2 years. The plot shows the effect on the output (number of years) of varying each input variable at a time, keeping all the other input variables at their baseline value.…”

Completeness of<em> RET</em> testing in patients with medullary thyroid carcinoma in Denmark 1997&ndash;2013: a nationwide study

“…3,5,6 The first study aiming to determine the completeness of RET testing in MTC patients recently reported a completeness of 60% (86/142) in a single center. 7 This completeness is remarkably discordant with both past and current recommendations. 3,5,6 However, it is unknown if such low completeness is also the standard when examining a population-based cohort.…”

“…The study was based on the Southern California Kaiser Permanente health care network and reported a completeness of 60% (86/142). 7 Often such differences between Danish and US cohorts may be explained by a different access to health care systems. However, all patients from the Californian study obtained medical insurance from the Kaiser Permanente health care network and all patients in Denmark are provided with free public health care.…”

Medullary thyroid cancer: molecular factors, management and treatment

“…RET mutations can be found in more than 95% of cases of hereditary MTC and up to 65% of cases of sporadic MTC. The main difference between these two types of MTC is that in familial cases RET mutation is genetically transmitted and, thus, all body cells harbor the mutation, while in cases of sporadic MTC the mutation is somatic and, thus, limited to the thyroid cells only [ 28 ]. The RET gene is located on chromosome 10q11.21.…”