Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study

Abstract

Summary BACKGROUND Lynch syndrome is caused by germline mutations in mismatch repair genes (MSH2, MLH1, MSH6 or PMS2), which lead to a high risk of predominantly colorectal and endometrial cancer. Recently, we found that also constitutional 3′ end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM expressing tissues. This results in a tissue specific MSH2-deficiency, which may evoke a different cancer risk and spectrum. To optimize the care for EPCAM deletion carriers we studied their cancer risk and spectrum. METHODS Clinical data of 194 carriers from 41 EPCAM families were systematically collected and compared to those of 431 carriers from 91 families with mutations in MLH1, MSH2, or MSH6. FINDINGS EPCAM deletion carriers exhibited a 75% [95%CI 65–85%] cumulative risk of colorectal cancer before the age of 70 years, with a mean age at diagnosis of 43 years, which is comparable to that of carriers of a combined EPCAM-MSH2 deletion (69% [95%CI 47-91%], p=0·8609) or of a mutation in MSH2 (77% [95%CI 64-90%], p=0·5892) or MLH1 (79% [95%CI 68-90%], p=0·5492) and higher than that of MSH6 mutation carriers (50% [95%CI 38-62%], p<0·0001). In contrast, women with EPCAM deletions (n=87) exhibited a 12% [95%CI 0-27%] cumulative risk of endometrial cancer, which is significantly lower than in carriers of a combined EPCAM-MSH2 deletion (55% [95%CI 20-90%], p<0·0001) or of a mutation in MSH2 (51% [95%CI 33-69%], p=0·0006) or MSH6 (34% [95%CI 20-48%], p=0·0309) and lower than in MLH1 (33% [95%CI 15-51%] p=0·1193) mutation carriers. This risk seems to be restricted to large deletions that extend close to the MSH2 gene promoter. Overall, a relatively high incidence of duodenal (n=3) and pancreatic (n=4) cancers was observed. INTERPRETATION EPCAM deletion carriers do have a high risk of colorectal cancer. Only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the impact of mosaic MSH2-deficiency on cancer risk and are indicative for a protocol revision for surveillance and preventive surgery in EPCAM deletion carriers.

Frequency of Rearrangements in Lynch Syndrome Cases Associated with MSH2: Characterization of a New Deletion Involving both EPCAM and the 5′ Part of MSH2

“…The proportion of pathogenic point mutations versus rearrangements in MSH2 versus EPCAM-MSH2 deletions identified in this set of samples is of 50% versus 43.8% versus 6.3%. To the best of our knowledge, the clinical features of families carrying the detected rearrangements were not different from those of families exhibiting other types of mutations, despite results published by other groups such as Kempers and colleagues (13), who showed that endometrial cancer was observed only in carriers with large EPCAM deletions that extended close to or into the MSH2 gene.…”

“…Thus, deletions of the last exon of EPCAM constitute a distinct class mutation associated with Lynch syndrome. Several investigators have reported families with EPCAM deletions (9)(10)(11)(12)(13).…”

Macro lncRNAs

“…Further studies confirmed the 3' end EPCAM deletions as a recurrent cause of Lynch syndrome. 88,89 Similar to the LUC7L-HBA2 fusion transcript, the EPCAM-MSH2 transcripts are likely to consist mainly of co-transcriptionally spliced EPCAM mRNA and 30 kb or 3 kb of RNA transcribed from the intergenic region, depending on the size of the deletion (Fig. 3B).…”

Germline Genetics in Colorectal Cancer Susceptibility and Prognosis

“…EPCAM deletions show a comparable risk of colon cancer to MLH1 and MSH2 mutation carriers, but a decreased risk of endometrial cancer. In families with EPCAM deletions there is a 75% risk of developing cancer by the age of 70 and a 12% risk of endometrial cancer (Kempers et al, 2011). As the risks of colon, endometrial and other cancers are high, regardless of the gene, individuals with LS are recommended to follow more intensive cancer screening guidelines.…”