Clinical characteristics and registry-validated extended pedigrees of germline <i>TP53</i> mutation carriers in Denmark

<div><p>Introduction</p><p><i>TP53</i> mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration.</p><p>Methods</p><p>We performed a nation-wide exploration of <i>TP53</i> 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.</p><p>Results</p><p>We identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three <i>de novo</i> 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 <i>TP53</i> mutation carriers than the 300–1,100 expected based on estimated background population frequencies.</p><p>Conclusion</p><p>Germline <i>TP53</i> 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.</p></div

Clinical characteristics and registry-validated extended pedigrees of germline <i>TP53</i> mutation carriers in Denmark - Fig 1

<p>(A) Pedigrees of three Danish families harboring germline <i>TP53</i> mutations. (B) NM_000546 isoform of the <i>TP53</i> gene protein product showing the mutations found in this study (upper track) and all published mutations from the IARC database (lower track). In the upper track, 5 novel germline mutations described in this study are expanded. In the lower track, mutations from 9 loci in the IARC database are expanded, corresponding to the 9 non-novel mutation sites described in this study. 14 IARC mutations were left out as they were either complex (13) or not classified (1). Variant colors: blue, missense, orange, nonsense, purple, splice region, red, frameshift, green, silent, grey, protein deletion.</p

Clinical and mutational data of families with 36 confirmed or <i>obligate</i> germline <i>TP53</i> mutations carriers.

<p>Clinical and mutational data of families with 36 confirmed or <i>obligate</i> germline <i>TP53</i> mutations carriers.</p

IARC database characteristics of germline <i>TP53</i> mutations observed in both IARC and in this study (families with more than 10 confirmed carriers in the IARC database are in bold).

<p>IARC database characteristics of germline <i>TP53</i> mutations observed in both IARC and in this study (families with more than 10 confirmed carriers in the IARC database are in bold).</p

Co-segregation analysis of a <i>BAP1</i> splice mutation in a Danish family.

<p>In the pedigree individuals that have uveal melanoma (UMM) are represented by black circles (female) or boxes (male) and individuals with cutaneous melanoma (CMM) are indicated by grey circles or boxes. The age of diagnosis of each melanoma is indicated in brackets. A line through a symbol indicates that the person is now deceased. If a person carries the <i>BAP1</i> splice mutation it is indicated by an ‘M’ and if they are wild type for this variant it is indicated with a ‘WT’. Where the mutation status is indicated in brackets, the person is a presumed obligate carrier, ‘(M)’. Other cancer types are also indicated in the pedigree with the age of diagnosis in brackets. Asterisks indicate the two individuals that were exome sequenced. Unaffected siblings are represented by diamonds, with the number in the centre indicating the number of people.</p

Clinical phenotypes of current and published UMM cases or their families with <i>BAP1</i> mutations.

<p>na is not available; a has been observed for 41 years without metastatic disease; b has been observed for 16 years without metastatic disease; c has been observed for 1, 4 and 8 years without metastatic disease; d has no information regarding the 4 other UMM cases;</p>*<p>refers to UMM case with unknown age of onset;</p>∧<p>refers to values from columns 1–3;</p>∼<p>refers to values from columns 4–9;</p>§<p>refers to values from columns 1–9.</p

Sanger sequencing trace and amino acid alignment showing the truncated BAP1 protein.

<p>(A) The left panel shows the wild type chromatogram while the right panel shows that of the <i>BAP1</i> splice mutation. (B) Wild type nucleotide and amino acid sequences are shown in the upper panel while the lower panel shows part of the truncated BAP1 protein resulting from the loss of exon 8.</p

RT-PCR showing the aberrantly spliced <i>BAP1</i> transcript.

<p>From the left, the first lane shows a size marker, the next two lanes show wild type <i>BAP1</i> RT-PCR products, and the last two lanes show the aberrantly spliced product resulting from the c.581-2A>G mutation.</p

Additional file 1 of Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Additional file 1