Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark

Ulrik Stoltze, Anne-Bine Skytte, Henriette Roed, Henrik Hasle, Bent Ejlertsen, Thomas van Overeem Hansen, Kjeld Schmiegelow, Anne-Marie Gerdes, Karin Wadt

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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Resumé

INTRODUCTION: TP53 mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration.

METHODS: We performed a nation-wide exploration of TP53 mutation carrier families identified through all clinical genetics departments in Denmark. Pedigrees were expanded and verified using unique national person identification, cancer, cause of death, pathology, and church registries.

RESULTS: We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three de novo germline mutations. All but two (96%) developed cancer by age 54 years [mean debut age; 29.1 y., median 33.0 y., n = 26 (17F, 9M), range 1-54 y]]. Cancer was the primary cause of all deaths [average age at death; 34.5 years]. Two tumors were identified through registry data alone. Two independent families harbored novel c.80delC mutations shown to be related through an ancestor born in 1907. This exhaustive national collection yielded markedly fewer TP53 mutation carriers than the 300-1,100 expected based on estimated background population frequencies.

CONCLUSION: Germline TP53 mutations in Denmark are likely to be drastically underdiagnosed despite their severe phenotype. Following recent advances in surveillance options of LFS patients, lack of pre-symptomatic testing may lead to the mismanagement of some individuals.

OriginalsprogEngelsk
Artikelnummere0190050
TidsskriftPLOS ONE
Vol/bind13
Udgave nummer1
Antal sider11
ISSN1932-6203
DOI
StatusUdgivet - 1. jan. 2018

Fingeraftryk

Religious buildings
Germ-Line Mutation
Pathology
Denmark
Pedigree
pedigree
Registries
Tumors
germ cells
mutation
Mutation
Li-Fraumeni Syndrome
Testing
neoplasms
Cause of Death
Neoplasms
death
Cohort Studies
Genetics
cohort studies

Citer dette

Stoltze, U., Skytte, A-B., Roed, H., Hasle, H., Ejlertsen, B., Overeem Hansen, T. V., ... Wadt, K. (2018). Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark. PLOS ONE, 13(1), [e0190050]. https://doi.org/10.1371/journal.pone.0190050
Stoltze, Ulrik ; Skytte, Anne-Bine ; Roed, Henriette ; Hasle, Henrik ; Ejlertsen, Bent ; Overeem Hansen, Thomas van ; Schmiegelow, Kjeld ; Gerdes, Anne-Marie ; Wadt, Karin. / Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark. I: PLOS ONE. 2018 ; Bind 13, Nr. 1.
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abstract = "INTRODUCTION: TP53 mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration.METHODS: We performed a nation-wide exploration of TP53 mutation carrier families identified through all clinical genetics departments in Denmark. Pedigrees were expanded and verified using unique national person identification, cancer, cause of death, pathology, and church registries.RESULTS: We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three de novo germline mutations. All but two (96{\%}) developed cancer by age 54 years [mean debut age; 29.1 y., median 33.0 y., n = 26 (17F, 9M), range 1-54 y]]. Cancer was the primary cause of all deaths [average age at death; 34.5 years]. Two tumors were identified through registry data alone. Two independent families harbored novel c.80delC mutations shown to be related through an ancestor born in 1907. This exhaustive national collection yielded markedly fewer TP53 mutation carriers than the 300-1,100 expected based on estimated background population frequencies.CONCLUSION: Germline TP53 mutations in Denmark are likely to be drastically underdiagnosed despite their severe phenotype. Following recent advances in surveillance options of LFS patients, lack of pre-symptomatic testing may lead to the mismanagement of some individuals.",
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Stoltze, U, Skytte, A-B, Roed, H, Hasle, H, Ejlertsen, B, Overeem Hansen, TV, Schmiegelow, K, Gerdes, A-M & Wadt, K 2018, 'Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark', PLOS ONE, bind 13, nr. 1, e0190050. https://doi.org/10.1371/journal.pone.0190050

Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark. / Stoltze, Ulrik; Skytte, Anne-Bine; Roed, Henriette; Hasle, Henrik; Ejlertsen, Bent; Overeem Hansen, Thomas van; Schmiegelow, Kjeld; Gerdes, Anne-Marie; Wadt, Karin.

I: PLOS ONE, Bind 13, Nr. 1, e0190050, 01.01.2018.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark

AU - Stoltze, Ulrik

AU - Skytte, Anne-Bine

AU - Roed, Henriette

AU - Hasle, Henrik

AU - Ejlertsen, Bent

AU - Overeem Hansen, Thomas van

AU - Schmiegelow, Kjeld

AU - Gerdes, Anne-Marie

AU - Wadt, Karin

PY - 2018/1/1

Y1 - 2018/1/1

N2 - INTRODUCTION: TP53 mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration.METHODS: We performed a nation-wide exploration of TP53 mutation carrier families identified through all clinical genetics departments in Denmark. Pedigrees were expanded and verified using unique national person identification, cancer, cause of death, pathology, and church registries.RESULTS: We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three de novo germline mutations. All but two (96%) developed cancer by age 54 years [mean debut age; 29.1 y., median 33.0 y., n = 26 (17F, 9M), range 1-54 y]]. Cancer was the primary cause of all deaths [average age at death; 34.5 years]. Two tumors were identified through registry data alone. Two independent families harbored novel c.80delC mutations shown to be related through an ancestor born in 1907. This exhaustive national collection yielded markedly fewer TP53 mutation carriers than the 300-1,100 expected based on estimated background population frequencies.CONCLUSION: Germline TP53 mutations in Denmark are likely to be drastically underdiagnosed despite their severe phenotype. Following recent advances in surveillance options of LFS patients, lack of pre-symptomatic testing may lead to the mismanagement of some individuals.

AB - INTRODUCTION: TP53 mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration.METHODS: We performed a nation-wide exploration of TP53 mutation carrier families identified through all clinical genetics departments in Denmark. Pedigrees were expanded and verified using unique national person identification, cancer, cause of death, pathology, and church registries.RESULTS: We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three de novo germline mutations. All but two (96%) developed cancer by age 54 years [mean debut age; 29.1 y., median 33.0 y., n = 26 (17F, 9M), range 1-54 y]]. Cancer was the primary cause of all deaths [average age at death; 34.5 years]. Two tumors were identified through registry data alone. Two independent families harbored novel c.80delC mutations shown to be related through an ancestor born in 1907. This exhaustive national collection yielded markedly fewer TP53 mutation carriers than the 300-1,100 expected based on estimated background population frequencies.CONCLUSION: Germline TP53 mutations in Denmark are likely to be drastically underdiagnosed despite their severe phenotype. Following recent advances in surveillance options of LFS patients, lack of pre-symptomatic testing may lead to the mismanagement of some individuals.

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1371/journal.pone.0190050

DO - 10.1371/journal.pone.0190050

M3 - Journal article

C2 - 29324801

VL - 13

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 1

M1 - e0190050

ER -

Stoltze U, Skytte A-B, Roed H, Hasle H, Ejlertsen B, Overeem Hansen TV et al. Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark. PLOS ONE. 2018 jan 1;13(1). e0190050. https://doi.org/10.1371/journal.pone.0190050