TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes

Abstract

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. germline mutations may also occur in less obvious phenotypes. As a result, different criteria are in use to decide which patients qualify for TP53 mutation analysis, including the LFS, LieFraumeni-like (LFL) and Chompret criteria. We investigated which criteria for TP53 mutation analysis resulted in the highest mutation detection rate and sensitivity in Dutch families. We describe the tumour spectrum in TP53-positive families and calculated tumour type specific relative risks. Method A total of 180 Dutch families referred for TP53 mutation analysis were evaluated. Tumour phenotypes were verified by pathology reports or clinical records.Results A TP53 germline mutation was identified in 24 families. When the Chompret criteria were used 22/24 mutations were detected (sensitivity 92%, mutation detection rate 21%). In LFS and LFL families 18/24 mutations were found (sensitivity 75%). The two mutations detected outside the 'Chompret group' were found in a child with rhabdomyosarcoma and a young woman with breast cancer. In the mutation carriers, in addition to the classical LFS tumour types, colon and pancreatic cancer were also found significantly more often than in the general population. Conclusion We suggest TP53 mutation testing for all families fulfilling the Chompret criteria. In addition, TP53 mutation testing can be considered in the event of childhood sarcoma and breast cancer before 30 years. In addition to the risk for established LFS tumour types, TP53-positive individuals may also have an elevated risk for pancreatic and colon cancer.

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

“…116 For these guidelines, we are adopting a combination of the Eeles and revised Chompret criteria. 117 In two large studies, 29% 118 and 35% 112 of individuals who met the original, slightly more restrictive, Chompret criteria 119 had a TP53 mutation. However, 14% of individuals who met the looser Eeles criteria also had a TP53 mutation.…”

Síndrome de Li-Fraumeni

“…Los tumores filoides malignos de mama pueden estar asociados al síndrome de Li-Fraumeni, como en el caso de esta paciente; sin embargo, estos no son tan frecuentes como los tumores de estirpe epitelial (18)(19)(20). Hasta el momento, son pocos los casos reportados de cáncer de mama masculino asociados al síndrome de Li-Fraumeni.…”

Germline Genetics in Colorectal Cancer Susceptibility and Prognosis

“…Li-Fraumeni syndrome (LFS) is a rare autosomal dominant inherited condition caused by germline mutations in TP53. The classical types of cancer seen in individuals with LFS include breast cancer, sarcomas, brain tumors, leukemia and adrenal cortical tumours; however, there is also an increased risk of colon cancer of 2.8-fold over the general population (Ruijs et al, 2010).…”