Lynch syndrome is an inherited autosomal-dominant cancer-predisposition condition that results from germline defects in the DNA mismatch-repair (MMR) pathway or inactivation of the EPCAM gene. Variants involving EPCAM are detected in roughly 1–3 % of Lynch syndrome cases, whereas combined EPCAM–MSH2 deletions remain very uncommon. We investigated two Iranian families from the same village, each with multiple members affected by colorectal cancer (CRC), to identify the underlying genetic causes. In Family A, colon tumor immunohistochemistry showed loss of MSH2 and MSH6 expression in formalin-fixed paraffin-embedded tissue. Despite negative Sanger sequencing results for MSH2 , whole-exome sequencing (WES) followed by copy number variant (CNV) analysis using CNVkit and ExomeDepth identified a large CNV across EPCAM and MSH2 . Breakpoints were confirmed by MLPA and SYBR Green qPCR. A second family from the same village showed multi-generational CRC; Family B was therefore tested by MLPA/qPCR for the same CNV. We identified a heterozygous ∼76.7 kb deletion spanning EPCAM exons 1–9 and MSH2 exons 1–8. In Family A, 15/23 tested relatives were carriers; six carriers had CRC at 35–53 years, and no extracolonic tumors were observed. The CRC affected proband of Family B harbored the identical deletion. Cascade testing achieved remarkable uptake, with >20 relatives tested in family A—over tenfold higher than typical reports—facilitated by direct clinician contact and streamlined logistics such as convenient blood collection. This is the first documented EPCAM–MSH2 deletion reported from the Middle East and North Africa region (MENA).
First Middle East and North Africa report of an EPCAM–MSH2 deletion in two Iranian Lynch syndrome families: a case report
Sina M.;Ferraro R. M.;Mazzoldi E. L.;Giliani S. C.
2025-01-01
Abstract
Lynch syndrome is an inherited autosomal-dominant cancer-predisposition condition that results from germline defects in the DNA mismatch-repair (MMR) pathway or inactivation of the EPCAM gene. Variants involving EPCAM are detected in roughly 1–3 % of Lynch syndrome cases, whereas combined EPCAM–MSH2 deletions remain very uncommon. We investigated two Iranian families from the same village, each with multiple members affected by colorectal cancer (CRC), to identify the underlying genetic causes. In Family A, colon tumor immunohistochemistry showed loss of MSH2 and MSH6 expression in formalin-fixed paraffin-embedded tissue. Despite negative Sanger sequencing results for MSH2 , whole-exome sequencing (WES) followed by copy number variant (CNV) analysis using CNVkit and ExomeDepth identified a large CNV across EPCAM and MSH2 . Breakpoints were confirmed by MLPA and SYBR Green qPCR. A second family from the same village showed multi-generational CRC; Family B was therefore tested by MLPA/qPCR for the same CNV. We identified a heterozygous ∼76.7 kb deletion spanning EPCAM exons 1–9 and MSH2 exons 1–8. In Family A, 15/23 tested relatives were carriers; six carriers had CRC at 35–53 years, and no extracolonic tumors were observed. The CRC affected proband of Family B harbored the identical deletion. Cascade testing achieved remarkable uptake, with >20 relatives tested in family A—over tenfold higher than typical reports—facilitated by direct clinician contact and streamlined logistics such as convenient blood collection. This is the first documented EPCAM–MSH2 deletion reported from the Middle East and North Africa region (MENA).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
