Identification and surveillance of 19 Lynch syndrome families in southern Italy: report of six novel germline mutations and a common founder mutation

Abstract

Lynch syndrome (LS), or hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant condition responsible for early onset cancer mostly in the colonrectum and endometrium as well as in other organ sites. Lynch syndrome is caused by germline mutations in mismatch repair genes, prevalently in hMSH2, hMLH1, and less frequently in hMSH6 and hPMS2. Twenty-nine non-related index cases with colorectal cancer (CRC) were collected from a region in southeast Italy (Apulia). Among this set of patients, fifteen fulfilled the Amsterdam criteria II. The presence of tumor microsatellite instability (MSI) was assessed in all index cases and 19 (15 AC+/4 AC-) were classified as MSI-H. Mutation analysis performed on all patients, identified 15 pathogenic mutations in hMLH1 and 4 in hMSH2. 4/15 mutations in hMLH1 and 2/4 hMSH2 mutations have not been previously reported. Three previously reported mutations were further investigated for the possibility of a common founder effect. Genetic counseling was offered to all probands and extended to 183 relatives after molecular testing and 85 (46%) mutation carriers were identified. Eighty mutation carriers underwent an accurate clinical and instrumental surveillance protocol. Our results confirm that the identification of LS patients based exclusively on family history may miss patients carrying germline mutations in the MMR genes. Moreover, our results demonstrated that molecular screening and subsequent instrumental surveillance are very effective in identifying CRCs at earlier stages and reducing the number of deaths from secondary cancers in HNPCC patients.

Analysis of telomere dynamics in peripheral blood cells from patients with Lynch syndrome

“…We cannot rule out the possibility that the G244D mutation, which was present in nearly 50% of our MLH1 carriers,40 may influence telomere dynamics differently from the other classic truncating mutations present in MSH2 carriers and in the remaining MLH1 mutation carriers. Nevertheless, all of our patients who harbored the G244D mutation belonged to classic HNPCC‐AC‐I–positive families, with complete loss of MLH1 protein in the tumors and high‐level MSI.…”

A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns

“…In Italy, a founder MLH1 mutation was found in six Lynch families originating from a relatively small geographic area of Northern Italy [42,43] and three other have been described in Southern Italy [44].…”

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

“…In a study of Italian LS families, c.643_648 dupA, c.2156_2157 dupT, c.684_685 dupC and c.1701_1704 delT frameshift mutations andc.2206 G < T, that cause a truncating protein were first time determined in MLH1 gene. Other truncating protein causing mutations, c.1089 G < T andc.2634-2 A < G, that results with a splice defect was originally reported in MSH2 gene [24] . In Malaysia population, two novel mutations, c.3341_3342insC and c.3885_3891delTAAAAGC were characterized in MSH6 and c.2395C > T mutation was defined in PMS2 gene [25] .…”