Abstract
Mutations in CDH1, which encodes E-cadherin, have been associated with hereditary diffuse gastric cancer (HDGC) in Western populations but have not been shown to play a major role in Asians. Recently, a patient with familial gastric cancer (FGC) was shown to harbor a germline mutation in the TP53 gene, which encodes p53 and has been previously associated with Li-Fraumeni Syndrome (LFS). To determine whether mutations in TP53 are associated with FGC in Asians, we screened the entire coding region of TP53 in probands from 23 Korean FGC families. We identified a nonsense (E287X) TP53 germline mutation in a family whose history is compatible with both HDGC and LFS. Two members of this family (SNU-G2) were afflicted with brain tumors, seven with gastric cancers, two with sarcomas, and one with both gastric cancer and a sarcoma. The E287X TP53 mutation segregated with the cancer phenotype in the family members from whom DNA samples were available. To our knowledge, this is the first report of a large family with both HDGC and LFS. Our results suggest that TP53 mutational screening in FGC families should be interpreted with caution because additional TP53 mutation-carrying HDGC families may also show LFS-related phenotypes.
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References
de Anta JM, Jassem E, Rosell R, Martinez-Roca M, Jassem J, Martinez-Lopez E, Monzo M, Sanchez-Hernandez JJ, Moreno I, Sanchez-Cespedes M (1997) TP53 mutational pattern in Spanish and Polish non-small cell lung cancer patients: null mutations are associated with poor prognosis. Oncogene 15:2951–2958
Bakkar AA, Wallerand H, Radvanyi F, Lahaye JB, Pissard S, Lecerf L, Kouyoumdjian JC, Abbou CC, Pairon JC, Jaurand MC, Thiery JP, Chopin DK, de Medina SG (2003) FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res 63:8108–8112
Birch JM, Alston RD, McNally RJ, Evans DG, Kelsey AM, Harris M, Eden OB, Varley JM (2001) Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20:4621–4628
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, Jackson CE (1999) Familial gastric cancer: overview and guidelines for management. J Med Genet 36:873–880
Chompret A (2002) The Li-Fraumeni syndrome. Biochimie 84:75–82
Fenoglio-Preiser CM, Wang J, Stemmermann GN, Noffsinger A (2003) TP53 and gastric carcinoma: a review. Hum Mutat 21:258–270
Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392:402–405
Huang CL, Taki T, Adachi M, Konishi T, Higashiyama M, Kinoshita M, Hadama T, Miyake M (1998) Mutations of p53 and K-ras genes as prognostic factors for non-small cell lung cancer. Int J Oncol 12:553–563
Iida S, Akiyama Y, Ichikawa W, Yamashita T, Nomizu T, Nihei Z, Sugihara K, Yuasa Y (1999) Infrequent germ-line mutation of the E-cadherin gene in Japanese familial gastric cancer kindreds. Clin Cancer Res 5:1445–1447
Keller G, Vogelsang H, Becker I, Plaschke S, Ott K, Suriano G, Mateus AR, Seruca R, Biedermann K, Huntsman D, Doring C, Holinski-Feder E, Neutzling A, Siewert JR, Hofler H (2004) Germline mutations of the E-cadherin (CDH1) and TP53 genes rather than of RUNX3 and HPP1 contribute to genetic predisposition in german gastric cancer patients. J Med Genet 41:e89
Kim HC, Wheeler JM, Kim JC, Ilyas M, Beck NE, Kim BS, Park KC, Bodmer WF (2000) The E-cadherin gene (CDH1) variants T340A and L599V in gastric and colorectal cancer patients in Korea. Gut 47:262–267
Kim IJ, Park JH, Kang HC, Shin Y, Lim SB, Ku JL, Yang HK, Lee KU, Park JG (2003) A novel germline mutation in the MET extracellular domain in a Korean patient with the diffuse type of familial gastric cancer. J Med Genet 40:e97
Lee JH, Han SU, Cho H, Jennings B, Gerrard B, Dean M, Schmidt L, Zbar B, Vande Woude GF (2000) A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene 19:4947–4953
Li FP, Fraumeni JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW (1988) A cancer family syndrome in twenty-four kindreds. Cancer Res 48:5358–5362
Martin AM, Kanetsky PA, Amirimani B, Colligon TA, Athanasiadis G, Shih HA, Gerrero MR, Calzone K, Rebbeck TR, Weber BL (2003) Germline TP53 mutations in breast cancer families with multiple primary cancers: is TP53 a modifier of BRCA1? J Med Genet 5358–5362:e34
Mitsudomi T, Hamajima N, Ogawa M, Takahashi T (2000) Prognostic significance of p53 alterations in patients with non-small cell lung cancer: a meta-analysis. Clin Cancer Res 6:4055–4063
Oliveira C, Bordin MC, Grehan N, Huntsman D, Suriano G, Machado JC, Kiviluoto T, Aaltonen L, Jackson CE, Seruca R, Caldas C (2002) Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred. Hum Mutat 19:510–517
Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA (2003) Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63:6643–6650
Shin HR, Jung KW, Won YJ, Park JG (2002) Annual report of the Korea central cancer registry: based on registered data from 139 hospitals (2004). Cancer Res Treat 36:103–114
Sugano K, Taniguchi T, Saeki M, Tsunematsu Y, Tomaru U, Shimoda T (1999) Germline p53 mutation in a case of Li-Fraumeni syndrome presenting gastric cancer. Jpn J Clin Oncol 29:513–516
Vega FJ, Iniesta P, Caldes T, Sanchez A, Lopez JA, de Juan C, Diaz-Rubio E, Torres A, Balibrea JL, Benito M (1997) p53 exon 5 mutations as a prognostic indicator of shortened survival in non-small-cell lung cancer. Br J Cancer 76:44–51
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, Yokota J (2002) E-cadherin gene variants in gastric cancer families whose probands are diagnosed with diffuse gastric cancer. Int J Cancer 101:434–441
Yoon KA, Ku JL, Yang HK, Kim WH, Park SY, Park JG (1999) Germline mutations of E-cadherin gene in Korean familial gastric cancer patients. J Hum Genet 44:177–180
Acknowledgements
This work was supported by a research grant from the National Cancer Center, Korea, and the BK21 project for Medicine, Dentistry, and Pharmacy.
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Kim, IJ., Kang, H.C., Shin, Y. et al. A TP53-truncating germline mutation (E287X) in a family with characteristics of both hereditary diffuse gastric cancer and Li-Fraumeni syndrome. J Hum Genet 49, 591–595 (2004). https://doi.org/10.1007/s10038-004-0193-9
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DOI: https://doi.org/10.1007/s10038-004-0193-9
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