Real‑world outcome of universal screening for Lynch syndrome in Japanese patients with colorectal cancer highlights the importance of targeting patients with young‑onset disease

Abstract

Despite the recommendations of the latest guidelines, the practical efficacy of universal screening for identifying Lynch syndrome (LS) among patients with colorectal cancer (CRC) may be limited in the real world due to infrequent referrals and the difficulties of genetic testing. Thus, the present study aimed to retrospectively analyze the results of universal screening of patients with CRC at a referral hospital in Japan. Immunohistochemistry was performed for mismatch repair proteins [including DNA mismatch repair protein MSH6 (MSH6), mismatch repair endonuclease PMS2 (PMS2), DNA mismatch repair protein Msh2 (MSH2) and DNA mismatch repair protein Mlh1 (MLH1)] and BRAF V600E mutation. Tumors that showed the following were considered to indicate LS and patients with such tumors were designated as genetic testing candidates (GTCs): i) Loss of MSH6/MSH2; ii) loss of MSH6 alone; iii) loss of PMS2 alone; and iv) loss of PMS2/MLH1 with negative BRAF V600E. MLH1 methylation and BRAF V600E mutation were analyzed in deficient mismatch repair (dMMR) tumors retrospectively. The frequency of dMMR and GTCs in an independent cohort of patients with young-onset CRC were also investigated. Universal screening revealed dMMR tumors, GTCs and LS probands in 7.3, 3.9 and 0.4%, respectively, of 463 patients with CRC. Although dMMR tumors were observed in both younger (<50 years) and older (≥60 years) patients, the GTCs were enriched in younger individuals. Evaluation of mismatch repair status in an independent cohort confirmed the high rate of GTCs in patients with young-onset CRC. The low detection rate of LS demonstrated in this study questions the implementation of routine universal screening in regions with low prevalence of LS. Considering the enrichment of GTCs in young-onset CRCs, age-restricted strategies may be simple and efficient practical alternatives to universal screening in the real world.

Using a multistep approach with multidisciplinary team to increase the diagnosis rate of Lynch syndrome- associated colorectal cancer after universal screening: A single-center study in Japan

“…On the contrary, in Japan, the reported incidence rate of LS among CRC was 0.4-0.7%, which was lower than that of MA group of this study [26,27]. As noted that the detection of LS in clinical practice would be limited in a recent cohort study in Japan, the percentage of genetic testing was 44.4% [27], which was lower than that in our study. It was possible that many LS cases were missed in their study.…”

“…The diagnosis rate of LS in MA group was signi cantly higher than in P-MA group and comparable to previous reports [18,19,24,25]. On the contrary, in Japan, the reported incidence rate of LS among CRC was 0.4-0.7%, which was lower than that of MA group of this study [26,27]. As noted that the detection of LS in clinical practice would be limited in a recent cohort study in Japan, the percentage of genetic testing was 44.4% [27], which was lower than that in our study.…”

Using a multistep approach with multidisciplinary team to increase the diagnosis rate of Lynch syndrome-associated colorectal cancer after universal screening: a single-center study in Japan

“…The diagnosis rate of LS in MA group was significantly higher than in P-MA group and comparable to previous reports [ 23 , 24 ]. On the contrary, in Japan, the reported incidence rate of LS among CRC was 0.4–0.7%, which was lower than that of MA group of this study [ 25 , 26 ]. As noted that the detection of LS in clinical practice would be limited in a recent cohort study in Japan, the percentage of genetic testing was 44.4% [ 26 ], which was lower than that in our study.…”

Prevalence and characteristics of patients with upper urinary tract urothelial carcinoma having potential Lynch syndrome identified by immunohistochemical universal screening and Amsterdam criteria II

“…IHC screening was positive in 2%–11% of UTUC tumors, which was comparable with the results of universal screening in colorectal cancer [ 12 , 14 , 22 , 23 ]. The most common pattern of MMRP loss observed in IHC screening of UTUC tumors was a combination of MSH2 and MSH6 , followed by MSH2 alone, MSH6 alone, and a combination of MLH1 and PMS2 [ 16 ].…”