Universal Genetic Testing for Lynch Syndrome Recommended for Colorectal Tumors

Internal organsThe Multi-Society Task Force on Colorectal Cancer (MSTF) now recommends universal genetic testing of newly diagnosed colorectal tumors to identify Lynch syndrome (Gastroenterology 2014;147:502–26). MSTF, a consortium of four medical associations, made the recommendation based on studies of colorectal cancer molecular testing which show that up to 28% of Lynch syndrome cases would be missed based on the most liberal clinical criteria. In addition, patients with Lynch syndrome are at increased risk for many other cancers.

When used appropriately, the guideline states, genetic testing for Lynch syndrome can confirm the diagnosis at the molecular level, justify surveillance of those at-risk, decrease the cost of surveillance by identifying those at highest versus lowest risk, facilitate clinical management of patients with Lynch syndrome, and guide patients and families in their family and career planning. The group cautioned that if used inappropriately, genetic testing can misinform affected patients with false-negative results while also wasting patient and societal resources.

Lynch syndrome is an autosomal dominant disorder that affects about 3% of newly diagnosed colorectal cancer cases. It involves mutations in the DNA mismatch repair (MMR) pathway; cumulative risk for the disease varies depending on the patient’s sex and which MMR gene is mutated, from a low of about 10% in women with MSH6 mutations to a high of approximately 74% in men with MLH1/MSH2 mutations.

The guidelines recommend immunohistochemistry (IHC) testing on all colorectal tumors, followed by BRAF testing if MLH1 is not expressed. Microsatellite instability (MSI) testing is an option before IHC, with high MSI cases only then undergoing IHC testing.

While the authors endorsed universal screening and averred that it likely will become the standard of care, they recognized that getting to this point will require more infrastructure to handle not only genetic testing but also genetic counseling. Therefore, they endorsed testing all patients age 70 or younger, but with thorough family histories for those older than age 70, with IHC and MSI testing performed on those who meet clinical criteria for Lynch syndrome or who have at least 5% risk based on prediction models.

Lyme Disease Testing Practices Baseline: Most Labs Use a Two-Step Methodology

Asurvey of seven large commercial laboratories found that in 2008, approximately 3.4 million Lyme disease tests were performed on 2.4 million specimens at an estimated cost of $492 million (Clin Infect Dis 2014;59:676–81). The data set a baseline for Lyme disease testing practices in the United States, according to the authors.

The investigators, who were associated with the Centers for Disease Control and Prevention (CDC) and other infectious diseases and public health programs and agencies, surveyed seven large commercial labs, including ARUP Laboratories, Focus Diagnostics, LabCorp, Mayo Clinic Laboratories, Quest Diagnostics, and Specialty Laboratories. Together, these labs accounted for more than three-quarters of Lyme disease tests reported in 2008 to health departments in four endemic states, including Connecticut, Maryland, Minnesota, and New York. The authors asked the labs to complete surveys about tests they performed in 2008 for 14 different serologic assays or assay combinations, seven polymerase chain reaction tests, and four culture tests distinguished by specimen type.

The authors found that 62% of tests involved a two-tiered approach, while 38% were stand-alone tests. In cases for which Western blot was performed without a preceding enzyme-linked immunosorbent assay or enzyme immunoassay, 48% were IgM, 49% were IgG, and 3% were combination IgM/IgG.

The authors estimated the percentage of true infections to be 12%, which amounted to 288,000 infected patients, about 10 times higher than the number of cases reported in 2008 to CDC.

Variable Assay Methodologies, Rules Limit SCID Newborn Screening Analysis

An analysis of newborn screening for severe combined immunodeficiency (SCID) in 11 screening programs in the United States revealed that these programs detected 52 cases of SCID out of 3,030,083 newborn samples screened with a T-cell receptor excision circle (TREC) test, giving a population-based incidence of SCID of 1:58,000 births, higher than had been suggested by retrospective clinical diagnoses (JAMA 2014;312:729–38).

SCID was added in 2010 to the Department of Health and Human Services’ Recommended Uniform Screening Panel, and 23 programs currently test for it. The researchers invited all SCID newborn screening programs that were active as of July 31, 2013 to participate in the study. This is the first multi-state report of SCID newborn screening efforts.

SCID incidence was similar in 10 state programs, but as expected was higher (1:3,500) in the Navajo Nation administered by the Navajo Area Indian Health Service and encompassing parts of Arizona, New Mexico, and Utah. The Navajo population is known to have a mutation in DCLRE1C, which encodes a DNA repair protein, leading to SCID.

Of the babies diagnosed with SCID, 81% had typical SCID, whereas 19% had leaky SCID. Referral centers that treat SCID have reported that about 50% of cases are due to mutations in the X chromosome-linked IL2RG gene, but the researchers found this mutation accounted for just 19% of cases across the 11 programs.

The participating newborn screening programs followed similar testing protocols of screening with a TREC test, followed by flow cytometry to enumerate T, B, and NK cells, along with naïve and memory phenotype T cells. However, the programs used different TREC cutoffs for instigating flow cytometry, and they also defined T-cell lymphopenia differently. For example, six programs defined significant T-cell lymphopenia as T-cell count <1,500/µL, whereas four used a cutoff of <2,500/µL, and one left the definition in the hands of individual immunologists. This led to varying false-positive rates, ranging from 0% to 82%.

The researchers called this lack of uniformity in assay methodology and rules a “major limitation” of their study.

Of the babies diagnosed with SCID, 48 received immunity-restoring­ therapies, including hematopoietic cell transplants, gene correction of IL2RG and ADA defects, or adenosine deaminase enzyme injection therapy. Overall, 87% of SCID babies survived, including 92% of those who were treated.

Fasting Not Necessary for Lipid Test Measurements

New research casts doubt on the long-standing practice of collecting fasting blood samples for lipid measurements, according to the authors (Circulation 2014;130:546–53). The investigators used samples collected and survey information taken between 1988–1994 for the National Health Examination and Nutrition Survey (NHANES) III. The researchers analyzed data from 16,161 NHANES-III participants, stratified it on the basis of participants’ fasting status at the time of phlebotomy, and followed the participants for a mean of 14 years.

They matched 4,299 pairs of participants based on fasting status of more or less than 8 hours, and conducted sensitivity analyses at 5, 10, and 15 years of follow-up to assess whether fasting status varied by length of follow-up. The authors also stratified participants by tertiles based on their low-density lipoprotein-cholesterol (LDL-C) levels, with those in the first tertile with LDL-C <100 mg/dL serving as the reference group.

In looking at the primary and secondary outcome measures of all-cause and cardiovascular mortality the authors found similar prognostic value associated with fasting LDL-C as with non-fasting LDL-C (all-cause mortality C-statistic 0.59 versus 0.58, respectively; cardiovascular mortality C-statistic 0.62 versus 0.62, respectively). The researchers saw similar results for triglyceride and total cholesterol measurements.

Based on these findings and in consideration of non-fasting LDL-C measurement being more convenient for patients, the authors called on national and international bodies to reconsider the need for fasting LDL-C sample collection.