A Systematic Review on the Existing Screening Pathways for Lynch Syndrome Identification

Abstract

BackgroundLynch syndrome (LS) is the most common hereditary colon cancer syndrome, accounting for 3–5% of colorectal cancer (CRC) cases, and it is associated with the development of other cancers. Early detection of individuals with LS is relevant, since they can take advantage of life-saving intensive care surveillance. The debate regarding the best screening policy, however, is far from being concluded. This prompted us to conduct a systematic review of the existing screening pathways for LS.MethodsWe performed a systematic search of MEDLINE, ISI Web of Science, and SCOPUS online databases for the existing screening pathways for LS. The eligibility criteria for inclusion in this review required that the studies evaluated a structured and permanent screening pathway for the identification of LS carriers. The effectiveness of the pathways was analyzed in terms of LS detection rate.ResultsWe identified five eligible studies. All the LS screening pathways started from CRC cases, of which three followed a universal screening approach. Concerning the laboratory procedures, the pathways used immunohistochemistry and/or microsatellite instability testing. If the responses of the tests indicated a risk for LS, the genetic counseling, performed by a geneticist or a genetic counselor, was mandatory to undergo DNA genetic testing. The overall LS detection rate ranged from 0 to 5.2%.ConclusionThis systematic review reported different existing pathways for the identification of LS patients. Although current clinical guidelines suggest to test all the CRC cases to identify LS cases, the actual implementation of pathways for LS identification has not been realized. Large-scale screening programs for LS have the potential to reduce morbidity and mortality for CRC, but coordinated efforts in educating all key stakeholders and addressing public needs are still required.

Patient with Lynch syndrome with subsequent development of small bowel adenocarcinoma

“…Although MSI is sensitive for Lynch syndrome cancers, it is not specific, as 15%–20% of sporadic colon cancers have MSI 12 13. Loss of protein expression for any of the MMR proteins indicates a genetic defect, but it does not differentiate among germline, somatic or epigenetic sources 12. Approximately 15% of sporadic MSI CRC is found to be caused by acquired somatic CpG methylation of the MLH1 gene promotor rather than germline mutations in the aforementioned MMR genes, as seen in Lynch syndrome 10 12 13.…”

“…Based on the association of the defective MMR (dMMR) genes and colon cancer in patients with Lynch syndrome, the National Institute for Health and Care Excellence in 2017 confirmed a universal screening approach for patients with newly diagnosed CRC to undergo either MSI DNA-based testing or immunohistochemistry analysis of their tumours to guide further follow-up testing for Lynch syndrome 12 13. Early identification of Lynch syndrome may reduce further cancer risk through intensive screening, follow-up programmes or prophylactic surgery 12. Recent guidelines from the American Society of Clinical Oncology recommend dMMR screening in patients with CRC, as establishing a diagnosis of Lynch syndrome and subsequent active management of cancer risk has been demonstrated to benefit gene mutation carriers; even more so, the diagnosis creates prevention opportunities in all at-risk relatives 13.…”

“…Although our patient was diagnosed with colon cancer 20 years prior to her presentation with SBA, she underwent genetic testing via direct germline testing for MMR genes at the time of her daughter’s CRC diagnosis. Her daughter was screened for Lynch syndrome based on the revised Bethesda Guidelines via immunohistochemical analysis of her CRC and subsequent confirmatory germline testing for MSH2/MLH1 12. Our patient’s positive molecular evaluation supports the previous statement that establishing a diagnosis of Lynch syndrome can confer prevention opportunities in at-risk relatives—in this case, the patient, as she was genetically counselled on her Lynch syndrome test results, provided with current cancer screening guidelines, and given information on testing strategies for her four other living children.…”

Cost-effectiveness analysis of genetic diagnostic strategies for Lynch syndrome in Italy

“…We reported a large heterogeneity of clinical paths to detect LS patients across Europe [17]. In Italy, although international guidelines favour the universal screening approach [15,16], there is no organized screening pathway in place aimed to identifying individuals with LS [18].…”

Universal tumor screening for Lynch syndrome: Perceptions of Canadian pathologists and genetic counselors of barriers and facilitators

“…Nonetheless, LS screening protocols are more likely in research and academic centers, and less likely in community hospitals . A recent systematic review of existing screening pathways for LS revealed only five sites with structured and permanent screening protocols: three in the US, one in Australia, and one in Europe. Of these, three followed a universal screening approach including all patients with CRC.…”