In cis TP53 and RAD51C pathogenic variants may predispose to sebaceous gland carcinomas

Rami Abou Jamra,Mirjana Ziemer,Mathias Stiller,Johannes R Lemke,Hendrik Bläker,Astrid Monecke,Elisabeth Jäger,Julia Hentschel,Sonja Neuser,Aleksander Markovic,Carolin Meier,Diana Le Duc,Konrad Platzer

doi:10.1038/s41431-020-00781-x

Abstract

Pathogenic variants in TP53 have been classically thought to cause Li-Fraumeni syndrome (LFS), a cancer predisposition with high risks for various childhood- and adult-onset malignancies. However, increased genetic testing has lately revealed, that pathogenic variant carriers exhibit a broader range of phenotypes and that penetrance may be dependent both on variant type and modifiers. Using next generation sequencing and short tandem repeat analysis, we identified germline pathogenic variants in TP53 and RAD51C located in cis on chromosome 17 in a 43-year-old male, who has developed a rare sebaceous gland carcinoma (SGC) but so far no tumors of the LFS spectrum. This course mirrors a Trp53-Rad51c-double-mutant cis mouse-model, which similarly develops SGC, while the characteristic Trp53-associated tumor spectrum occurs with significantly lower frequency. Therefore, we propose that co-occurent pathogenic variants in RAD51C and TP53 may predispose to SGC, reminiscent of Muir-Torre syndrome. Further, this report supports the diversity of clinical presentations associated with germline TP53 alterations, and thus, the proposed expansion of LFS to heritable TP53-related cancer syndrome.

Highlights

Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited multicancer predisposition covering a spectrum of five core malignancies: breast cancer, soft tissue or bone sarcoma, brain tumors, and adrenocortical carcinoma [1, 2]
The deletion of exons 5–9 in RAD51C was validated by Multiplex Ligation-dependent Probe Amplification (MLPA) (Kit P260, MRC-Holland) and the TP53 variant was validated by Sanger sequencing
We evaluated the probability of recombination for the TP53 and RAD51C variants to be 31.6%, using d 1⁄4 50lnð1À2Pr1⁄2reco1mbinationÞ, where d represents the distance in centimorgans

Summary

Introduction

Carriers have a 58% risk of developing cancer before age 40 and about 80% before age 70 [4]. Penetrance is higher in males than in females during childhood and adolescence, but by age 35 the initial male bias is offset by the burden of breast cancer in women [4]. Lifetime risk of developing cancer has been estimated to 70% or higher for men, while women’s risk is close to 100% [4,5,6,7]. Estimating the cancer risk for TP53 variant carriers remains a great challenge [1]. The fact that about 20% of carriers detected in a familial context do not develop cancer until the age of 70 years, suggests that additional genetic or nongenetic factors may create an environment that is either promoting, or

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