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An intronic mutation in MLH1 associated with familial colon and breast cancer

An intronic mutation in MLH1 associated with familial colon and breast cancer
An intronic mutation in MLH1 associated with familial colon and breast cancer
Single base substitutions can lead to missense mutations, silent mutations or intronic mutations, whose significance is uncertain. Aberrant splicing can occur due to mutations that disrupt or create canonical splice sites or splicing regulatory sequences. The assessment of their pathogenic role may be difficult, and is further complicated by the phenomenon of alternative splicing. We describe an HNPCC patient, with early-onset colorectal cancer and a strong family history of colorectal and breast tumors, who harbours a germ line MLH1 intronic variant (IVS9 c.790 +4A>T). The proband, together with 2 relatives affected by colorectal-cancer and 1 by breast cancer, have been investigated for microsatellite instability, immunohistochemical MMR protein staining, direct sequencing and Multiplex Ligation-dependent Probe Amplification. The effect of the intronic variant was analyzed both by splicing prediction software and by hybrid minigene splicing assay. In this family, we found a novel MLH1 germline intronic variant (IVS9 c.790 +4A>T) in intron 9, consisting of an A to T transversion, in position +4 of the splice donor site of MLH1. The mutation is associated with the lack of expression of the MLH1 protein and MSI in tumour tissues. Furthermore, our results suggest that this substitution leads to a complete skip of both exon 9 and 10 of the mutant allele. Our findings suggest that this intronic variant plays a pathogenic role
intronic mutation, mlh1, minigene assay, colon cancer, breast cancer
1389-9600
27-35
Bianchi, F.
ab6ec74e-34ec-40be-9f5d-6d377b5eb577
Raponi, M.
f465e77f-b9bf-4c32-80d6-43c0787542b9
Piva, F.
94debc69-4fe3-4b0f-bd0f-91d4681d3548
Viel, A.
20d4d8a2-bbe9-4d69-9ae8-7895082c6fca
Bearzi, I.
585f7a3e-6465-485d-8563-8d9251c148c1
Galizia, E.
b32e6ad2-5585-4f85-a7fd-4939f8f61e55
Bracci, R.
dfff1d2b-0ceb-4b32-b108-e7dd073ad30b
Belvederesi, L.
1777e040-2258-4105-8c94-7c6dd1f797fa
Loretelli, C.
5a808a65-aac9-45b9-8fff-f7a1768eee04
Brugiati, C.
0bc53292-209d-4e41-b6b2-41af29a90db2
Corradini, F.
20b8bdf0-90e3-4591-ab38-bb61cdb5312d
Baralle, D.
faac16e5-7928-4801-9811-8b3a9ea4bb91
Cellerino, R.
de6687fc-df18-443a-8bf4-00ed45935d7d
Bianchi, F.
ab6ec74e-34ec-40be-9f5d-6d377b5eb577
Raponi, M.
f465e77f-b9bf-4c32-80d6-43c0787542b9
Piva, F.
94debc69-4fe3-4b0f-bd0f-91d4681d3548
Viel, A.
20d4d8a2-bbe9-4d69-9ae8-7895082c6fca
Bearzi, I.
585f7a3e-6465-485d-8563-8d9251c148c1
Galizia, E.
b32e6ad2-5585-4f85-a7fd-4939f8f61e55
Bracci, R.
dfff1d2b-0ceb-4b32-b108-e7dd073ad30b
Belvederesi, L.
1777e040-2258-4105-8c94-7c6dd1f797fa
Loretelli, C.
5a808a65-aac9-45b9-8fff-f7a1768eee04
Brugiati, C.
0bc53292-209d-4e41-b6b2-41af29a90db2
Corradini, F.
20b8bdf0-90e3-4591-ab38-bb61cdb5312d
Baralle, D.
faac16e5-7928-4801-9811-8b3a9ea4bb91
Cellerino, R.
de6687fc-df18-443a-8bf4-00ed45935d7d

Bianchi, F., Raponi, M., Piva, F., Viel, A., Bearzi, I., Galizia, E., Bracci, R., Belvederesi, L., Loretelli, C., Brugiati, C., Corradini, F., Baralle, D. and Cellerino, R. (2011) An intronic mutation in MLH1 associated with familial colon and breast cancer. Familial Cancer, 10 (1), 27-35. (doi:10.1007/s10689-010-9371-4). (PMID:20717847)

Record type: Article

Abstract

Single base substitutions can lead to missense mutations, silent mutations or intronic mutations, whose significance is uncertain. Aberrant splicing can occur due to mutations that disrupt or create canonical splice sites or splicing regulatory sequences. The assessment of their pathogenic role may be difficult, and is further complicated by the phenomenon of alternative splicing. We describe an HNPCC patient, with early-onset colorectal cancer and a strong family history of colorectal and breast tumors, who harbours a germ line MLH1 intronic variant (IVS9 c.790 +4A>T). The proband, together with 2 relatives affected by colorectal-cancer and 1 by breast cancer, have been investigated for microsatellite instability, immunohistochemical MMR protein staining, direct sequencing and Multiplex Ligation-dependent Probe Amplification. The effect of the intronic variant was analyzed both by splicing prediction software and by hybrid minigene splicing assay. In this family, we found a novel MLH1 germline intronic variant (IVS9 c.790 +4A>T) in intron 9, consisting of an A to T transversion, in position +4 of the splice donor site of MLH1. The mutation is associated with the lack of expression of the MLH1 protein and MSI in tumour tissues. Furthermore, our results suggest that this substitution leads to a complete skip of both exon 9 and 10 of the mutant allele. Our findings suggest that this intronic variant plays a pathogenic role

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More information

Published date: March 2011
Keywords: intronic mutation, mlh1, minigene assay, colon cancer, breast cancer

Identifiers

Local EPrints ID: 162461
URI: https://eprints.soton.ac.uk/id/eprint/162461
ISSN: 1389-9600
PURE UUID: f08576b0-d082-45a7-b865-961a98306139
ORCID for D. Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 23 Aug 2010 07:35
Last modified: 20 Jul 2019 00:50

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Contributors

Author: F. Bianchi
Author: M. Raponi
Author: F. Piva
Author: A. Viel
Author: I. Bearzi
Author: E. Galizia
Author: R. Bracci
Author: L. Belvederesi
Author: C. Loretelli
Author: C. Brugiati
Author: F. Corradini
Author: D. Baralle ORCID iD
Author: R. Cellerino

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