Intragenic deletion of cdh1 as the inactivating mechanism of the wild-type allele in an hdgc tumour

ABSTRACT Mutations in _CDH1_, encoding E-cadherin, are the underlying genetic defect in approximately one-third of the hereditary diffuse gastric cancer (HDGC) families described so far.

Tumours arising in these families show abnormal or absence of E-cadherin expression, following the model of tumour suppressor gene inactivation. A single study has been reported showing

inactivation of the _CDH1_ wild-type allele in tumour cells from HDGC families either by promoter methylation or by somatic mutation. In order to find the genetic alteration responsible for

the presence of diffuse gastric cancers in four members of a Caucasian family, we have screened the coding sequence of _CDH1_ for germline mutations and searched for the second inactivating

hit in the tumour samples. In this family, we have found a germline splice-site mutation in all members affected by gastric cancer and, in one tumour, a somatic deletion affecting at least

exon 8 of _CDH1._ Our results show that a _CDH1_ intragenic deletion is the second hit inactivating the wild-type allele, in one of the tumours in this family. Access through your

institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 50 print

issues and online access $259.00 per year only $5.18 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to

local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT

BEING VIEWED BY OTHERS A MOSAIC _PIK3CA_ VARIANT IN A YOUNG ADULT WITH DIFFUSE GASTRIC CANCER: CASE REPORT Article Open access 01 June 2021 MULTIPLE NEOPLASIA IN A PATIENT WITH GITELMAN

SYNDROME HARBORING GERMLINE MONOALLELIC _MUTYH_ MUTATION Article Open access 18 September 2020 FAMILIAL WILD-TYPE GASTROINTESTINAL STROMAL TUMOUR IN ASSOCIATION WITH GERMLINE TRUNCATING

VARIANTS IN BOTH _SDHA_ AND _PALB2_ Article Open access 15 April 2021 REFERENCES * Avizienyte E, Launonen V, Salovaara R, Kiviluoto T and Aaltonen L . (2001). _J. Med. Genet._, 38, 49–52. *

Caldas C, Carneiro F, Lynch HT, Yokota J, Wiesner GL, Powell SM, Lewis FR, Huntsman DG, Pharoah PD, Jankowski JA, MacLeod P, Vogelsang H, Keller G, Park KG, Richards FM, Maher ER, Gayther

SA, Oliveira C, Grehan N, Wight D, Seruca R, Roviello F, Ponder BA and Jackson CE . (1999). _J. Med. Genet._, 36, 873–880. * Chen YT, Stewart DB and Nelson WJ . 1999. _J. Cell Biol._, 144,

687–699. * Dussaulx-Garin L, Blayau M, Pagenault M, Le Berre-Heresbach N, Raoul JL, Campion JP, David V and Bretagne JF . (2001). _Eur. J. Gastroenterol. Hepatol._, 13, 711–715. * Gayther

SA, Gorringe KL, Ramus SJ, Huntsman D, Roviello F, Grehan N, Machado JC, Pinto E, Seruca R, Halling K, MacLeod P, Powell SM, Jackson CE, Ponder BAJ and Caldas C . (1998). _Cancer Res._, 58,

4086–4089. * Grady WM, Willis J, Guilford PJ, Dunbier AK, Toro TT, Lynch H, Wiesner G, Ferguson K, Eng C, Park JG, Kim SJ and Markowitz S . (2000). _Nat. Genet._, 26, 16–17. * Graff JR,

Herman JG, Myohanen S, Baylin SB and Vertino PM . (1997). _J. Biol. Chem._, 272, 22322–22329. * Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller

A and Reeve AE . (1998). _Nature_, 392, 402–405. * Guilford PJ, Hopkins JB, Grady WM, Markowitz SD, Willis J, Lynch H, Rajput A, Wiesner GL, Lindor NM, Burgart LJ, Toro TT, Lee D, Limacher

JM, Shaw DW, Findlay MP and Reeve AE . (1999). _Hum. Mutat._, 14, 249–255. * Handschuh G, Candidus S, Luber B, Reich U, Schott C, Oswald S, Becke H, Hutzler P, Birchmeier W, Hofler H and

Becker KF . 1999. _Oncogene_, 18, 4301–4312. * Huber AH, Stewart DB, Laurents DV, Nelson WJ and Weis WI . 2001. _J. Biol. Chem._, 276, 12301–12309. * Humar B, Toro T, Graziano F, Muller H,

Dobbie Z, Kwang-Yang H, Eng C, Hampel H, Gilbert D, Winship I, Parry S, Ward R, Findlay M, Christian A, Tucker M, Tucker K, Merriman T and Guilford P . (2002). _Hum. Mutat._, 19, 518–525. *

Iida S, Akiyama Y, Ichikawa W, Yamashita T, Nomizu T, Nihei Z, Sugihara K and Yuasa Y . (1999). _Clin. Cancer Res._, 5, 1445–1447. * Jonsson BA, Bergh A, Stattin P, Emmanuelsson M and

Gronberg H . (2002). _Int. J. Cancer_, 98, 838–843. * Keller G, Vogelsang H, Becker I, Hutter J, Ott K, Candidus S, Grundei T, Becker KF, Mueller J, Siewert JR and Hofler H . (1999). _Am. J.

Pathol._, 155, 337–342. * Machado JC, Carneiro F, Beck S, Rossi S, Lopes J, Taveira-Gomes A and Cardoso-Oliveira M . (1998). _Int. J. Surg. Pathol._, 6, 135–144. * Machado JC, Nogueira AM,

Carneiro F, Reis CA and Sobrinho-Simoes M . 2000. _J. Pathol._, 190, 437–443. * Nabais S, Machado JC, Lopes C, Seruca R, Carneiro F and Sobrinho-Simoes M . (2003). _Int. J. Surg. Pathol._,

11, 1–9. * Oliveira C, Bordin MC, Grehan N, Huntsman D, Suriano G, Machado JC, Kiviluoto T, Aaltonen L, Jackson CE, Seruca R and Caldas C . (2002). _Hum. Mutat._, 19, 510–517. * Oliveira C,

Seruca R and Caldas C. . 2003. _Expert Ver. Mol. Diagn._, 3, 201–215. * Richards FM, McKee SA, Rajpar MH, Cole TR, Evans DG, Jankowski JA, McKeown C, Sanders DS and Maher ER . (1999). _Hum.

Mol. Genet._, 8, 607–610. * Shinmura K, Kohno T, Takahashi M, Sasaki A, Ochiai A, Guilford P, Hunter A, Reeve AE, Sugimura H, Yamaguchi N and Yokota J . (1999). _Carcinogenesis_, 20,

1127–1131. * Wang Y, Song JP, Ikeda M, Shinmura K, Yokota J and Sugimura H. . 2003. _Jpn. J. Clin. Oncol._, 33, 17–20. * Yabuta T, Shinmura K, Tani M, Yamaguchi S, Yoshimura K, Katai H,

Nakajima T, Mochiki E, Tsujinaka T, Takami M, Hirose K, Yamaguchi A, Takenoshita S and Yokota J . (2002). _Int. J. Cancer_, 101, 434–441. * Yoon KA, Ku JL, Yang HK, Kim WH, Park SY and Park

JG . (1999). _J. Hum. Genet._, 44, 177–180. Download references ACKNOWLEDGEMENTS This study was funded by grants from Fundação para a Ciência e a Tecnologia, Portugal (Project:

POCTI/35374/CBO/2000 and POCTI/CBO/40820/2001). AUTHOR INFORMATION Author notes * Carla Oliveira and Joyce de Bruin: We wish it to be known that, in our opinion, the first two authors should

be regarded as joint first authors AUTHORS AND AFFILIATIONS * Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, 4200-465, Portugal Carla

Oliveira, Sérgio Nabais, Cátia Moutinho, Raquel Seruca & Fátima Carneiro * Department of Pathology, University Medical Centre Nijmegen, Nijmegen, 6500 HB, The Netherlands Joyce de Bruin,

 Marjolijn Ligtenberg & Han van Krieken * Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, 6500 HB, The Netherlands Marjolijn Ligtenberg * Department of

Gastroenterology, University Medical Centre Nijmegen, Nijmegen, 6500 HB, The Netherlands Fokko M Nagengast * Medical Faculty of the University of Porto, Porto, 4200-465, Portugal Raquel

Seruca & Fátima Carneiro Authors * Carla Oliveira View author publications You can also search for this author inPubMed Google Scholar * Joyce de Bruin View author publications You can

also search for this author inPubMed Google Scholar * Sérgio Nabais View author publications You can also search for this author inPubMed Google Scholar * Marjolijn Ligtenberg View author

publications You can also search for this author inPubMed Google Scholar * Cátia Moutinho View author publications You can also search for this author inPubMed Google Scholar * Fokko M

Nagengast View author publications You can also search for this author inPubMed Google Scholar * Raquel Seruca View author publications You can also search for this author inPubMed Google

Scholar * Han van Krieken View author publications You can also search for this author inPubMed Google Scholar * Fátima Carneiro View author publications You can also search for this author

inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Carla Oliveira. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Oliveira, C., de Bruin,

J., Nabais, S. _et al._ Intragenic deletion of _CDH1_ as the inactivating mechanism of the wild-type allele in an HDGC tumour. _Oncogene_ 23, 2236–2240 (2004).

https://doi.org/10.1038/sj.onc.1207335 Download citation * Received: 30 July 2003 * Revised: 03 November 2003 * Accepted: 11 November 2003 * Published: 08 December 2003 * Issue Date: 18

March 2004 * DOI: https://doi.org/10.1038/sj.onc.1207335 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable

link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * E-cadherin * hereditary diffuse gastric

cancer * HDGC * mutation * intragenic deletion * second hit