Abstract
The autosomal dominant presentation of trichilemmal cysts is one of the most common single gene familial diseases in humans. However, the genetic basis for the inheritance and genesis of these lesions has remained unknown. We first studied patients with multiple trichilemmal cysts using exome and Sanger sequencing. Remarkably, 21 of 21 trichilemmal cysts from 16 subjects all harbored a somatic p.S745L (c.2234 G > A) mutation in phospholipase C delta 1 (PLCD1), a proposed tumor suppressor gene. In addition to this specific somatic mutation in their tumors, 16 of the 17 subjects with multiple trichilemmal cysts were also heterozygous for a p.S460L (c.1379 G > A) germline variant in PLCD1 which is normally present in only about 6% of this population. The one patient of 17 that did not show the p.S460L germline variant had a germline p.E455K (c.1363 C > T) mutation in the same exon of PLCD1. Among 15 additional subjects, with a history suggesting a single sporadic trichilemmal cyst, six were likely familial due to the presence of the p.S460L germline variant. Of the remaining truly sporadic trichilemmal cysts that could be sequenced, only half showed the p.S745L somatic mutation in contrast to 100% of the familial cysts. Surprisingly, in contrast to Knudsen’s two hit hypothesis, the p.S745L somatic mutation was always on the same chromosome as the p.S460L germline variant. Our results indicate that familial trichilemmal cysts is an autosomal dominant tumor syndrome resulting from two hits to the same allele of PLCD1 tumor suppressor gene. The c.1379 G > A base change and neighboring bases are consistent with a mutation caused by ultraviolet radiation. Our findings also indicate that approximately one-third of apparently sporadic trichilemmal cysts are actually familial with incomplete penetrance. Sequencing data suggests that the remaining, apparently sporadic, trichilemmal cysts are genetically distinct from familial cysts due to a lack of the germline mutations that underlie familial cysts and a decreased prevalence of the p.S745L somatic mutation relative to familial trichilemmal cysts.
Highlights
A region on chromosome 3p24-p21.2 that likely contained the causative gene for inheritance of trichilemmal cysts and termed this locus TRICY1
Samples containing nearly pure cyst were heterozygous for the p.S745L somatic mutation, indicating that trichilemmal cysts are clonal tumors
Our results indicate that familial trichilemmal cysts result from a combination of germline and somatic mutations on the same copy of the phospholipase C delta 1 (PLCD1) gene
Summary
A region on chromosome 3p24-p21.2 that likely contained the causative gene for inheritance of trichilemmal cysts and termed this locus TRICY1. We initially hypothesized that trichilemmal cysts represent clonal proliferations and further conjectured that the familial presentation of these lesions was an example of an autosomal dominant tumor syndrome explained by Knudson’s two-hit hypothesis[8]. According to this model, both alleles of a tumor suppressor gene must be knocked out for a tumor to form. The function of one copy is partially or fully lost due to an inherited genetic variation or mutation This model predicts that a tumor subsequently develops after a cell loses the tumor suppressing activity of the remaining copy through somatic mutation. We applied whole exome sequencing (WES) and Sanger sequencing to identify germline variants and somatic mutations that potentially underlie these cysts and subsequently determined if the two hits were on the same or opposite alleles
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