Somatic MMR Gene Mutations as a Cause for MSI-H Sebaceous Neoplasms in Muir-Torre Syndrome-Like Patients

Joly, Marie‐Odile; Attignon, Valéry; Saurin, Jean‐Christophe; Desseigne, Françoise; Leroux, Dominique; Martin-Denavit, Tanguy; Giraud, Sophie; Bonnet-Dupeyron, Marie-Noëlle; Faivre, Laurence; Auclair, Jessie; Grand-Masson, Chloé; Audoynaud, Carole; Wang, Qing

doi:10.1002/humu.22740

Cited by 21 publications

(22 citation statements)

References 11 publications

(12 reference statements)

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“…Indel-rich MSI SeC appear to be initiated by inactivating mutations in mismatch-repair genes (which can be either germline or somatic), while SeC with UV-damage-associated mutational signatures develop on heavily sun-damaged skin. Although sebaceous neoplasms have been reported anecdotally to harbor somatic mutations in mismatch-repair genes 8 , 22 , our results show that virtually all MSI class SeC arise from either a germline or somatic mutation in this pathway. A third, previously undescribed pauci-mutational class is primarily represented by facial SeC.…”

Section: Discussionmentioning

confidence: 49%

Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma

North

Golovato²,

Vaske³

et al. 2018

Nat Commun

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Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.

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Section: Discussionmentioning

confidence: 49%

Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma

North

Golovato²,

Vaske³

et al. 2018

Nat Commun

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“…Smaller studies have suggested that universal tumor testing with MMR IHC also may be effective in screening for Lynch syndrome among individuals with less common forms of Lynch syndrome‐associated cancer, such as upper tract urothelial cancer (ie, renal pelvis and ureter) . Caution should be used when interpreting MMR IHC results from sebaceous neoplasms of the skin, which, compared with other Lynch‐associated neoplasms, appear disproportionately likely to demonstrate sporadic MSI‐H/MMR deficiency in the absence of underlying Lynch syndrome . It is also important to note that, for rectal cancers, when radiotherapy is administered before surgery, the MMR IHC assay can be inaccurate, primarily because of artifactual loss of MSH6 in the surgical specimen .…”

Section: Current Status Of Germline and Somatic Dna Testingmentioning

confidence: 99%

“…69 Caution should be used when interpreting MMR IHC results from sebaceous neoplasms of the skin, which, compared with other Lynch-associated neoplasms, appear disproportionately likely to demonstrate sporadic MSI-H/MMR deficiency in the absence of underlying Lynch syndrome. [70][71][72] It is also important to note that, for rectal cancers, when radiotherapy is administered before surgery, the MMR IHC assay can be inaccurate, primarily because of artifactual loss of MSH6 in the surgical specimen. 73 Thus, pretherapy tissue or polymerase chain reaction-based MSI testing should be the preferred approach in this situation.…”

Section: Variants) Including Some Rare Individuals With Pathogenic Gmentioning

confidence: 99%

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes

Boland

Yurgelun

Boland

2018

CA A Cancer J Clinicians

130

106

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The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm-shifting approaches to treatment of Lynch-syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217-231. © 2018 American Cancer Society.

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“…The remaining MSI-H tumors were, until recently, believed to be the indication of the presence of a germline mutation in the context of Lynch or Lynch-related syndromes. However, recent studies have shown that a small subset of those MSI-H tumors can be the consequence of a pure somatic MMR inactivation through two somatic hits 16 , 17 . Still, because the majority of the MSI-H tumors are germline-related, the testing for the MSI-H phenotype combined with immunostaining for a loss-of-expression of one of four MMR proteins (MLH1, MSH2, MSH6 and PMS2) is considered to be an efficient way to screen for Lynch or related syndromes.…”

Section: Genetics and Clinical Impact Of Predisposition To Lynch Syndmentioning

confidence: 99%

Cancer predisposition genes: molecular mechanisms and clinical impact on personalized cancer care: examples of Lynch and HBOC syndromes

Wang

2015

Acta Pharmacol Sin

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Up to 10% of cancers occur through the inherited mutation of a group of genes called cancer predisposition genes. Individuals who carry a mutant allele of these genes have an increased susceptibility to cancer. A growing number of cancer susceptibility genes are being identified, and the physiopathology of germline mutation-based cancer development is also being elucidated with accumulating clinical and molecular data. More importantly, the identification of familial mutations has become routine practice, which is a perfect example of bench-to-bed translational medicine. Recently, other clinical applications of predisposition genes have been exploited, especially as efficient biomarkers predicting prognosis or response to treatment. Thus, it appears interesting to give an overview of the advances and impacts of predisposition genes in personalized cancer care by taking representative and common cancer syndromes as examples: Lynch syndrome for the first example, which is related to cancer susceptibility, and breast and ovary cancer syndrome for the second example, which involves BRCA deficiency-related targeted therapy.

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Somatic MMR Gene Mutations as a Cause for MSI-H Sebaceous Neoplasms in Muir-Torre Syndrome-Like Patients

Cited by 21 publications

References 11 publications

Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma

Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes

Cancer predisposition genes: molecular mechanisms and clinical impact on personalized cancer care: examples of Lynch and HBOC syndromes

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