{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:04:13Z","timestamp":1785888253133,"version":"3.56.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2012,4,16]],"date-time":"2012-04-16T00:00:00Z","timestamp":1334534400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2012,4,16]],"date-time":"2012-04-16T00:00:00Z","timestamp":1334534400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Breast Cancer Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>Germline <jats:italic>TP53<\/jats:italic> mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or Li-Fraumeni-like (LFL) features. However, in Asia and in many low resource settings, it is challenging to obtain accurate family history and we, therefore, sought to determine whether the presence of early-onset breast cancer is an appropriate selection criteria for germline <jats:italic>TP53<\/jats:italic> testing.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>A total of 100 patients with early-onset breast cancer (\u2264 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in <jats:italic>BRCA1, BRCA2<\/jats:italic> and <jats:italic>TP53<\/jats:italic> by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>We identified 11 <jats:italic>BRCA1<\/jats:italic> (11%) and 6 <jats:italic>BRCA2<\/jats:italic> (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in <jats:italic>TP53<\/jats:italic>. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant <jats:italic>TP53<\/jats:italic> germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (&lt; 2%) with no family history of breast or LFS-linked cancers.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>Our study reports germline <jats:italic>BRCA1, BRCA2<\/jats:italic> and <jats:italic>TP53<\/jats:italic> mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that <jats:italic>TP53<\/jats:italic> mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline <jats:italic>TP53<\/jats:italic> mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/bcr3172","type":"journal-article","created":{"date-parts":[[2012,5,9]],"date-time":"2012-05-09T12:15:45Z","timestamp":1336565745000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1\/2 screening to early-onset breast cancer patients"],"prefix":"10.1186","volume":"14","author":[{"given":"Daphne SC","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sook-Yee","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai Meng","family":"Looi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In Nee","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavitta","family":"Sivanandan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hany","family":"Ariffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meow Keong","family":"Thong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kin Fah","family":"Chin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nur Aishah","family":"Mohd Taib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Har","family":"Yip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo-Hwang","family":"Teo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,4,16]]},"reference":[{"key":"2969_CR1","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1001\/jama.295.12.1379","volume":"295","author":"T Walsh","year":"2006","unstructured":"Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S, Foretova L, Soucek P, King MC: Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. 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