Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome

Abstract

Background Muir‐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. Methods Whole 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. Results Signature 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. Conclusion Tumor mutational signatures 6 and 15 and somatic mutation burden were effective in differentiating Lynch‐related from non‐Lynch sebaceous lesions.

Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

“…LOH in the tumor across MUTYH was determined by identifying germline heterozygous variants with homozygous somatic equivalents (see Supplementary Methods) 4 . Copy number loss was assessed in PCAWG and TCGA CRC cohorts with available consensus data 37 and copy number segment data 38 , respectively (see Supplementary Methods).…”

“…Genome-wide tumor profiling and associated computational approaches can provide a historical record of the mutational processes, both endogenous and exogenous, that were active during tumor initiation and progression, providing a tumor mutational signature (TMS) profile 1 , 2 . Several of these TMSs have been mechanistically shown to result from genetic defects related to homologous recombination repair deficiency 3 , DNA mismatch repair deficiency 4 , and base excision repair deficiency 5 , 6 , including in colorectal cancer (CRC) 7 , 8 . Therefore, TMSs can represent a functional manifestation of specific alterations in DNA repair pathways, with the potential application for not only identifying tumors caused by inherited defects in DNA repair genes but also providing functional evidence to support variant classification approaches in these DNA repair genes.…”

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

“…Signature 6 is strongly associated with MSI/MMR deficiency in CRC, but several other signatures have been associated with MMR deficiency in a variety of cancers [ 294 , 295 ]. Signatures 6 and 15 have been shown to be more prevalent in MMR-deficient sebaceous tumors from patients with LS compared with MMR-proficient tumors [ 296 ]. However, whether these tumor mutational signatures are able to distinguish LS-related from sporadic MSI/dMMR tumors is currently unknown.…”

Molecular pathology of skin adnexal tumours

“…5,10, Sporadic sebaceous adenomas and sebaceomas are less well characterised, but show similar aberrations to SC, including mutations of MMR genes, HRAS/ KRAS and/or TP53 (Table 2). 9,12 Tumours with follicular differentiation…”