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Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification

Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification
Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification
Multiplex ligation-dependent probe amplification (MLPA) is a recently described method for detecting gross deletions or duplications of DNA sequences, aberrations which are commonly overlooked by standard diagnostic analysis. To determine the incidence of copy number variants in cancer predisposition genes from families in the Wessex region, we have analysed the hMLH1 and hMSH2 genes in patients with hereditary nonpolyposis colorectal cancer (HNPCC), BRCA1 and BRCA2 in families with hereditary breast/ovarian cancer (BRCA) and APC in patients with familial adenomatous polyposis coli (FAP). Hereditary nonpolyposis colorectal cancer (n=162) and FAP (n=74) probands were fully screened for small mutations, and cases for which no causative abnormality were found (HNPCC, n=122; FAP, n=24) were screened by MLPA. Complete or partial gene deletions were identified in seven cases for hMSH2 (5.7% of mutation-negative HNPCC; 4.3% of all HNPCC), no cases for hMLH1 and six cases for APC (25% of mutation negative FAP; 8% of all FAP). For BRCA1 and BRCA2, a partial mutation screen was performed and 136 mutation-negative cases were selected for MLPA. Five deletions and one duplication were found for BRCA1 (4.4% of mutation-negative BRCA cases) and one deletion for BRCA2 (0.7% of mutation-negative BRCA cases). Cost analysis indicates it is marginally more cost effective to perform MLPA prior to point mutation screening, but the main advantage gained by prescreening is a greatly reduced reporting time for the patients who are positive. These data demonstrate that dosage analysis is an essential component of genetic screening for cancer predisposition genes.
hmlh1, hmsh2, brca1, brca2, apc, mlpa
0007-0920
1155-1159
Bunyan, D.J.
41347b93-e79b-4026-93f9-dd1004cfa05e
Eccles, D.M.
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Sillibourne, J.
59c2d8c9-fc79-4eb3-815f-c934c5849f14
Wilkins, E.
3fbd36c6-5f40-44d2-bc0a-a9929edadf48
Thomas, N. Simon
1a601957-288d-4f12-a9f7-4f4279b7f9b3
Shea-Simonds, J.
481842a4-cf00-44ba-8065-3e2e9e66e9f1
Duncan, P.J.
4575f549-3a20-4895-b6c9-78e833f3f7b4
Curtis, C.E.
a3e6ee40-bc80-4d94-9ef6-048868ea5a94
Robinson, D.O.
6b7e8cdc-b9c4-4ecf-a344-1bf0ae990f8a
Harvey, J.F.
587c3d67-fe7c-4601-b5b8-60600ca39a63
Cross, N.C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Bunyan, D.J.
41347b93-e79b-4026-93f9-dd1004cfa05e
Eccles, D.M.
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Sillibourne, J.
59c2d8c9-fc79-4eb3-815f-c934c5849f14
Wilkins, E.
3fbd36c6-5f40-44d2-bc0a-a9929edadf48
Thomas, N. Simon
1a601957-288d-4f12-a9f7-4f4279b7f9b3
Shea-Simonds, J.
481842a4-cf00-44ba-8065-3e2e9e66e9f1
Duncan, P.J.
4575f549-3a20-4895-b6c9-78e833f3f7b4
Curtis, C.E.
a3e6ee40-bc80-4d94-9ef6-048868ea5a94
Robinson, D.O.
6b7e8cdc-b9c4-4ecf-a344-1bf0ae990f8a
Harvey, J.F.
587c3d67-fe7c-4601-b5b8-60600ca39a63
Cross, N.C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4

Bunyan, D.J., Eccles, D.M., Sillibourne, J., Wilkins, E., Thomas, N. Simon, Shea-Simonds, J., Duncan, P.J., Curtis, C.E., Robinson, D.O., Harvey, J.F. and Cross, N.C.P. (2004) Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification. British Journal of Cancer, 91 (6), 1155-1159. (doi:10.1038/sj.bjc.6602121).

Record type: Article

Abstract

Multiplex ligation-dependent probe amplification (MLPA) is a recently described method for detecting gross deletions or duplications of DNA sequences, aberrations which are commonly overlooked by standard diagnostic analysis. To determine the incidence of copy number variants in cancer predisposition genes from families in the Wessex region, we have analysed the hMLH1 and hMSH2 genes in patients with hereditary nonpolyposis colorectal cancer (HNPCC), BRCA1 and BRCA2 in families with hereditary breast/ovarian cancer (BRCA) and APC in patients with familial adenomatous polyposis coli (FAP). Hereditary nonpolyposis colorectal cancer (n=162) and FAP (n=74) probands were fully screened for small mutations, and cases for which no causative abnormality were found (HNPCC, n=122; FAP, n=24) were screened by MLPA. Complete or partial gene deletions were identified in seven cases for hMSH2 (5.7% of mutation-negative HNPCC; 4.3% of all HNPCC), no cases for hMLH1 and six cases for APC (25% of mutation negative FAP; 8% of all FAP). For BRCA1 and BRCA2, a partial mutation screen was performed and 136 mutation-negative cases were selected for MLPA. Five deletions and one duplication were found for BRCA1 (4.4% of mutation-negative BRCA cases) and one deletion for BRCA2 (0.7% of mutation-negative BRCA cases). Cost analysis indicates it is marginally more cost effective to perform MLPA prior to point mutation screening, but the main advantage gained by prescreening is a greatly reduced reporting time for the patients who are positive. These data demonstrate that dosage analysis is an essential component of genetic screening for cancer predisposition genes.

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More information

Published date: 2004
Keywords: hmlh1, hmsh2, brca1, brca2, apc, mlpa

Identifiers

Local EPrints ID: 24643
URI: https://eprints.soton.ac.uk/id/eprint/24643
ISSN: 0007-0920
PURE UUID: 3e2aa113-60ba-45c6-b6e6-bf28422edc7e
ORCID for N.C.P. Cross: ORCID iD orcid.org/0000-0001-5481-2555

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Date deposited: 03 Apr 2006
Last modified: 06 Jun 2018 12:49

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Contributors

Author: D.J. Bunyan
Author: D.M. Eccles
Author: J. Sillibourne
Author: E. Wilkins
Author: N. Simon Thomas
Author: J. Shea-Simonds
Author: P.J. Duncan
Author: C.E. Curtis
Author: D.O. Robinson
Author: J.F. Harvey
Author: N.C.P. Cross ORCID iD

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