Abstract
BackgroundMuir‐Torre syndrome is defined by the development of sebaceous skin lesions in individuals who carry a germline mismatch repair (MMR) gene mutation. Loss of expression of MMR proteins is frequently observed in sebaceous skin lesions, but MMR‐deficiency alone is not diagnostic for carrying a germline MMR gene mutation.MethodsWhole exome sequencing was performed on three MMR‐deficient sebaceous lesions from individuals with MSH2 gene mutations (Lynch syndrome) and three MMR‐proficient sebaceous lesions from individuals without Lynch syndrome with the aim of characterizing the tumor mutational signatures, somatic mutation burden, and microsatellite instability status. Thirty predefined somatic mutational signatures were calculated for each lesion.ResultsSignature 1 was ubiquitous across the six lesions tested. Signatures 6 and 15, associated with defective DNA MMR, were significantly more prevalent in the MMR‐deficient lesions from the MSH2 carriers compared with the MMR‐proficient non‐Lynch sebaceous lesions (mean ± SD=41.0 ± 8.2% vs. 2.3 ± 4.0%, p = 0.0018). Tumor mutation burden was, on average, significantly higher in the MMR‐deficient lesions compared with the MMR‐proficient lesions (23.3 ± 11.4 vs. 1.8 ± 0.8 mutations/Mb, p = 0.03). All four sebaceous lesions observed in sun exposed areas of the body demonstrated signature 7 related to ultraviolet light exposure.ConclusionTumor mutational signatures 6 and 15 and somatic mutation burden were effective in differentiating Lynch‐related from non‐Lynch sebaceous lesions.
Highlights
Individuals who carry germline mutations in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) have a high risk of developing cancer of the colon and rectum, and endometrium, among others, referred to as Lynch syndrome (Win et al, 2012)
The number of somatic mutations identified in the six sebaceous lesion exomes called by both variant callers and with sufficient allele frequency and read depth, and falling in the capture region, ranged from 80 to 2,421 which translates to tumor mutation burdens ranging from 1.2 to 36.0 mutations per megabase
MMR‐deficient sebaceous lesions from MSH2 gene mutation carriers demonstrated a significantly higher tumor mutation burden, increased numbers of indels in exonic microsatellite repeats and the highest proportion of tumor mutational signatures 6 and 15 compared with MMR‐proficient non‐Lynch sebaceous lesions, features which are consistent with other cancer types demonstrating MMR‐deficiency
Summary
Individuals who carry germline mutations in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) have a high risk of developing cancer of the colon and rectum, and endometrium, among others, referred to as Lynch syndrome (Win et al, 2012). Lynch syndrome related tumors, including sebaceous skin lesions (Cesinaro et al, 2007), develop characteristic features namely widespread somatic DNA replication errors occurring within microsatellite repeats, referred to as microsatellite instability (MSI), and loss of expression of one or more of the MMR proteins determined by immunohistochemical (IHC) staining, collectively referred to as tumor MMR‐deficiency. We report on whole exome sequencing (WES) derived tumor mutational signatures present in sebaceous skin lesions in people with and without Lynch syndrome. Muir‐Torre syndrome is defined by the development of sebaceous skin lesions in individuals who carry a germline mismatch repair (MMR) gene mutation. Signatures 6 and 15, associated with defective DNA MMR, were significantly more prevalent in the MMR‐deficient lesions from the MSH2 carriers compared with the MMR‐proficient
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