{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T19:25:45Z","timestamp":1791141945900,"version":"4.1.0"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2005,6,7]],"date-time":"2005-06-07T00:00:00Z","timestamp":1118102400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes Chromosomes &amp; Cancer"],"published-print":{"date-parts":[[2005,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A systematic search by Southern blot analysis in a cohort of 439 hereditary nonpolyposis colorectal cancer (HNPCC) families for genomic rearrangements in the main mismatch repair (MMR) genes, namely, <jats:italic>MSH2<\/jats:italic>, <jats:italic>MLH1<\/jats:italic>, <jats:italic>MSH6<\/jats:italic>, and <jats:italic>PMS2<\/jats:italic>, identified 48 genomic rearrangements causative of this inherited predisposition to colorectal cancer in 68 unrelated kindreds. Twenty\u2010nine of the 48 rearrangements were found in <jats:italic>MSH2<\/jats:italic>, 13 in <jats:italic>MLH1<\/jats:italic>, 2 in <jats:italic>MSH6<\/jats:italic>, and 4 in PMS2. The vast majority were deletions, although one previously described large inversion, an intronic insertion, and a more complex rearrangement also were found. Twenty\u2010four deletion breakpoints have been identified and sequenced in order to determine the underlying recombination mechanisms. Most fall within repetitive sequences, mainly <jats:italic>Alu<\/jats:italic> repeats, in agreement with the differential distribution of deletions between the <jats:italic>MSH2<\/jats:italic> and <jats:italic>MLH1<\/jats:italic> genes: the higher number and density of <jats:italic>Alu<\/jats:italic> repeats in <jats:italic>MSH2<\/jats:italic> corresponded with a higher incidence of genomic rearrangement at this disease locus when compared with other MMR genes. Long interspersed nuclear element (LINE) repeats, relatively abundant in, for example, <jats:italic>MLH1<\/jats:italic>, did not seem to contribute to the genesis of the deletions, presumably because of their older evolutionary age and divergence among individual repeat units when compared with short interspersed nuclear element (SINE) repeats, including <jats:italic>Alu<\/jats:italic> repeats. Moreover, Southern blot analysis of the introns and the genomic regions flanking the MMR genes allowed us to detect 6 novel genomic rearrangements that left the coding region of the disease\u2010causing gene intact. These rearrangements comprised 4 deletions upstream of the coding region of <jats:italic>MSH2<\/jats:italic> (3 cases) and <jats:italic>MSH6<\/jats:italic> (1 case), a 2\u2010kb insertion in intron 7 of <jats:italic>PMS2<\/jats:italic>, and a small (459\u2010bp) deletion in intron 13 of <jats:italic>MLH1<\/jats:italic>. The characterization of these genomic rearrangements underlines the importance of genomic deletions in the etiology of HNPCC and will facilitate the development of PCR\u2010based tests for their detection in diagnostic laboratories. \u00a9 2005 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/gcc.20219","type":"journal-article","created":{"date-parts":[[2005,6,7]],"date-time":"2005-06-07T20:16:38Z","timestamp":1118175398000},"page":"123-138","source":"Crossref","is-referenced-by-count":110,"title":["Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes <i>MSH2<\/i>, <i>MLH1<\/i>, <i>MSH6,<\/i> and <i>PMS2<\/i> responsible for hereditary nonpolyposis colorectal cancer (HNPCC)"],"prefix":"10.1002","volume":"44","author":[{"given":"Heleen","family":"van der 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