乌鸦传媒

Lynch syndrome (LS), also called hereditary nonpolyposis colorectal cancer, causes about 4200 colorectal cancer cases and 1800 endometrial cancer (EC) cases per year.¹ This autosomal dominant syndrome is caused by a mutation in one of the genes involved in DNA mismatch repair (MMR).¹

According to the American Gastroenterological Association, healthcare practitioners are strongly recommended to test all patients with colorectal cancer for LS, either with immunohistochemistry (IHC) or microsatellite instability (MSI) testing.² Furthermore, the National Comprehensive Cancer Network states that screening for genetic mutations such as LS should be considered in all patients with EC, especially those under the age of 50 years.³

Because performing IHC, MSI testing, and MMR genetic testing in every patient can be cost-prohibitive, there鈥檚 a clear need to develop screening methods to narrow down which patients require the full panel. Identifying women with LS and EC allows for the use of preventive medical care for subsequent cancers, and also opens up opportunities for hereditary evaluation in the patient鈥檚 relatives. From the perspective of health economics and social welfare, better screening methods can be expected to have far-reaching benefits.⁴

Taking the first step: IHC testing in EC patients

A prospective observational study was recently carried out to establish both practical and efficient screening methods for identifying LS in patients with EC.⁴ The 100 individuals included in the study, who ranged in age from 21 to 89 years (median 58 years), were enrolled from the National Hospital Organization, Hokkaido Cancer Center, Department of Gynecology, Sapporo, Japan. All participants underwent surgical treatment, and the surgical specimens were tested by IHC for 4 MMR-related proteins: MLH1, MSH2, MSH6, and PMS2. For those patients found to be missing one or more of the MMR proteins, further screening was done using MSI testing, MLH1 promoter DNA methylation testing, and MMR genetic testing.

In this study, histological subtypes included endometrioid carcinoma grades 1 through 3 (92%), serous carcinoma (4%), clear cell carcinoma (3%), and mucinous carcinoma (1%). Out of 19 patients with missing MMR proteins, 16 (84.2%) were found to have MSI-high frequency, 11 (57.9%) were positive for MLH1 promoter DNA methylation, and two (10.5%) were found to have pathogenic variants of the MSH2 and MSH6 genes (one in each patient), confirming LS in these two patients.

A promising outlook on LS detection

As the first report in Japan focused on the use of universal screening techniques to diagnose LS in a prospective study of EC, this study makes an important stride toward higher detection rates and better treatment options for EC patients with LS. Importantly, the prevalence of patients with missing MMR proteins by IHC and those with germline pathological variants were comparable to previous estimates.

鈥淪creening programs centered on IHC are more cost-effective than universal screening,鈥� the authors wrote. 鈥淭he significance of this is that since it would be very costly to perform universal screening (IHC, MSI testing, and MMR genetic testing) in all cases, it is possible to efficiently and cost-effectively confirm LS if only IHC-lost cases are followed by MSI testing and MMR genetic testing.鈥�⁴

Although conducting a family history interview is standard for patients with EC, these interviews are likely to miss some cases of LS. However, the number of missed cases can be considerably reduced by conducting IHC to identify patients with a higher likelihood of an LS diagnosis. As the authors concluded, 鈥淔or the future, we recommend the establishment of universal screening, focusing on DNA and molecular analysis, for gynecological cancers, especially EC.鈥�⁴

Published: June 28, 2022