Complete genetic testing explains germline variants in Lynch syndrome
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Complete immunohistochemistry diagnostics reduced the need for subsequent gene testing in patients with Lynch syndrome, according to research published in Clinical Gastroenterology and Hepatology.
“Individuals with Lynch syndrome (LS) have an increased risk of developing multiple tumors, particularly colorectal cancer and endometrial cancer. This increased cancer risk is caused by pathogenic germline variants in the DNA mismatch repair (MMR) genes,” Ellis L. Eikenboom, PhD, University Medical Center Rotterdam, Erasmus MC Cancer Institute, and colleagues wrote. “Distinguishing between pathogenic MMR germline variants and sporadic MMR deficiency (MMRd) is relevant for accurate assessment of cancer risks. ... More accurate proportions of LS and unexplained MMRd cases are warranted not only to determine the benefits and costs of universal MMR testing, but also in relation to the quest for more suitable recommendations in clinical guidelines.”
In a systematic review, researchers analyzed 56 studies for the proportion of patients with LS, sporadic MMRd and unexplained MMRd after universal immunohistochemistry analysis and MMR germline analysis. They further performed a meta-analysis to investigate the probability of carrying a germline variant in different circumstances.
Of 58,580 CRCs, researchers identified MMRd in 6.22% (95% CI, 5.08-7.61); they further identified MMR germline pathogenic variants in 2% (95% CI, 1.59-2.5), this ranged from 1.8% to 7.27% based on the completeness of diagnostics. Further analysis of 6,848 CRCs that completed all diagnostic stages yielded germline pathogenic variants in 3.01% of CRCs and biallelic somatic MMR inactivation in 1.75% of CRCs. Only 0.61% of CRCs with full diagnostics remained unexplained MMRd.
“The percentage of germline MMRd cases and unexplained cases is highly dependent on the completeness and type of diagnostics used. ... The relevance of complete diagnostics should therefore be stressed in current guidelines. This can help navigate gastroenterologists, surgeons and clinical geneticists through the genetic workflow in patients with CRC and is relevant for future cost-benefit studies,” Eikenboom and colleagues concluded. “However, more research should be performed to accurately characterize the small and potentially heterogeneous group of unexplained MMRd.”
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