Gene Screening Tops in Finding Lynch Syndrome

Gene Screening Tops in Finding Lynch Syndrome

By Michael Smith, North American Correspondent, MedPage Today

Published: October 16, 2012

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

• Lynch syndrome is a form of hereditary colorectal cancer and is caused by germline mutations in DNA mismatch repair genes.
• This study suggests that universal tumor mismatch repair gene testing among colorectal cancer patients had a modestly greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies.

Universal genetic screening of colorectal cancer patients for Lynch syndrome did better at identifying the hereditary condition than several other strategies, researchers reported.
Testing colorectal tumors for defects in the DNA mismatch repair genes -- the cause of the syndrome -- was completely accurate in finding Lynch syndrome, according to Antoni Castells, MD, PhD, of the Hospital Clínic in Barcelona, Spain, and colleagues.
Other screening strategies -- involving patient and family characteristics instead of genetic testing -- missed up to 15% of cases, Castells and colleagues reported in the Oct. 17 issue of the Journal of the American Medical Association.
Lynch syndrome, or hereditary nonpolyposis colorectal cancer, accounts for between 1% and 3% of all colorectal tumors. It's caused by germline mutations in the DNA mismatch repair genes MSH2, MLH1, MSH6, and PMS2, the researchers noted.
Identification of the syndrome is important, they added, because it allows for highly effective preventive measures to be implemented. "The more patients who are diagnosed, the more at-risk relatives can undergo genetic evaluation and receive appropriate cancer surveillance and other preventive interventions."
Several sets of criteria for picking up Lynch syndrome exist -- most involving patient and family characteristics -- but they are limited in clinical practice, either because of low sensitivity or because they are difficult to apply, Castells and colleagues wrote.
Testing the tumor for defective mismatch repair genes is "the cornerstone for identification of Lynch syndrome," they wrote. "However, it is still under debate which ... patients should undergo these analyses."
To help clarify the issue, they compared screening strategies in a pooled analysis of 10,206 newly diagnosed colorectal cancer patients from four large cohorts.
Of the patients, 312, or 3.1%, had defects in one or more of the mismatch repair genes, Castells and colleagues found.
Tumor screening, they reported, was 100% sensitive in the population-based cohorts, while other strategies had sensitivity ranging from 95.1% to 85.4%. On the other hand, gene testing was only 93% specific, but other strategies had specificities ranging from 95.5% to 97.5%, they found.
The so-called diagnostic yield -- the likelihood that a test will give enough information to make a diagnosis -- was 2.2% for universal screening, higher than the other strategies, the researchers noted, but not markedly so.
Nonetheless, they concluded, the results show that unless universal genetic screening is done, "a clinically meaningful proportion of (mismatch repair) gene mutation carriers will remain undiagnosed."
Specifically, they reported, the other strategies -- such as the so-called Bethesda guidelines or the Jerusalem recommendations -- would miss between 5% and 15% of all cases.
The rationale for any screening program is "the potential for individualized preventive medicine," argued Uri Ladabaum, MD, and James Ford, MD, of Stanford University School of Medicine in Stanford, Calif.
In an accompanying editorial, they noted that most patients with colorectal cancer do not have Lynch syndrome but those who do are not impossible to uncover.
"A systematic search can find them," they argued, and would yield reduced cancer incidence and mortality, both among patients and "their unsuspecting relatives."
Castells and colleagues cautioned that the findings have not been replicated in an independent set of patients, because of the low prevalence of Lynch syndrome.

The study had support from the Spanish Ministerio de Economía y Competividad, the Agència de Gestió d'Ajuts Universitaris i de Recerca, the Asociación Española contra el Cáncer, the Hospital Clínic of Barcelona, the Instituto de Salud Carlos III, the National Cancer Institute, the National Institutes of Health, the National Colon Cancer Research Alliance, and the Hansen Foundation. The journal said the researchers made no disclosures of potential conflicts.
Editorial author Ladabaum reported financial links with Given Imaging, GE Healthcare, Abbott Molecular, Quest Diagnostics, RA Capital, Roche, Vaxart, Endosphere, Epigenomics and Abbott Molecular.
Editorial author Ford reported financial links with Bristol-Myers Squibb.

Primary source: Journal of the American Medical Association
Source reference:
Moreira L, et al "Identification of Lynch Syndrome among patients with colorectal cancer" JAMA 2012; 308(15): 1555-1565.
Additional source: Journal of the American Medical Association
Source reference:
Ladabaum U, Ford JM "Lynch Syndrome in patients with colorectal cancer: Finding the needle in the haystack" JAMA 2012; 308(15): 1581-1583.