Oncogenic mutations in histologically normal endometrium: the new normal?

Lac, Vivian; Nazeran, Tayyebeh M.; Tessier‐Cloutier, Basile; Aguirre-Hernández, Rosalía; Albert, Arianne; Lum, Amy; Khattra, Jaswinder; Praetorius, T; Mason, Marcia A.; Chiu, Derek S.; Köbel, Martin; Yong, Paul J.; Gilks, Blake; Anglesio, Michael S.; Huntsman, David G.

doi:10.1002/path.5314

Cited by 120 publications

(118 citation statements)

References 41 publications

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“…KRAS mutations occur in a high proportion of pancreatic ductal adenocarcinoma, colorectal cancer, and non‐small cell lung cancer cases 15 . In addition to malignant neoplasms , KRAS mutations have been reported in different entities, including benign lesions such as endometriosis, sinonasal oncocytic papillomas and squamous cell papillomas of the head and neck, odontogenic and bone tumors, 8,9,17‐20 vascular malformations, 21 and even histologically normal endometrial tissue 22 . Notably, KRAS mutations have been previously identified in other giant cell‐rich tumors, including giant cell tumors of the pancreas and liver 23 and in teno‐synovial giant cell tumor 24 .…”

Section: Discussionmentioning

confidence: 99%

KRAS mutations in brown tumor of the jaws in hyperparathyroidism

Guimarães

Gomes

Pereira

et al. 2020

J Oral Pathology Medicine

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Background Brown tumors are giant cell‐rich lesions that result from abnormal bone metabolism in hyperparathyroidism, one of the most common endocrine disorders worldwide. Brown tumors occasionally affect the jaws and, despite well‐known clinical and microscopic features, their molecular pathogenesis remains unclear. We investigated the presence of pathogenic activating mutations in TRPV4, FGFR1, and KRAS in a cohort of brown tumors since these have recently been reported in giant‐cell lesions of the jaws and non‐ossifying fibromas of the bones (FGFR1 and KRAS), which are histologic mimics of brown tumors. Methods We target sequenced 13 brown tumors of the jaws associated with primary or secondary hyperparathyroidism. As mutations in these genes are known to activate the MAPK/ERK signaling pathway, we also assessed the immunostaining of the phosphorylated form of ERK1/2 (pERK1/2) in these lesions. Results KRAS pathogenic mutations were detected in seven cases (p.G12V n = 4, p.G12D n = 1, p.G13D n = 1, p.A146T n = 1). KRAS variants of unknown significance (VUS), p.A134T and p.E37K, were also detected. All samples showed wild‐type sequences for FGFR1 and TRPV4 genes. The activation of the MAPK/ERK signaling pathway was demonstrated by pERK1/2 immunohistochemical positivity of the brown tumors´ mononuclear cells. Conclusion Mutations in KRAS and activation of the MAPK/ERK signaling pathway were detected in brown tumors of hyperparathyroidism of the jaws, expanding the spectrum of giant cell lesions whose molecular pathogenesis involve RAS signaling.

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Section: Discussionmentioning

confidence: 99%

KRAS mutations in brown tumor of the jaws in hyperparathyroidism

Guimarães

Gomes

Pereira

et al. 2020

J Oral Pathology Medicine

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“…SBS10a and SBS10b were responsible for the increase in SBS rate compared to normal individuals (Fig 3b). Somatic driver mutations in cancer genes are common in normal human endometrium 25,29,30 and were found in a similar repertoire of genes in all but one gland from this individual (Extended Data Fig. 6e, Extended Data Table 3).…”

Section: Mutagenesis In Other Tissuesmentioning

confidence: 81%

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

Robinson

Coorens

Palles

et al. 2020

Preprint

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Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases Pol e and Pol d replicate DNA with high fidelity during normal cell divisions. However, in some cancers defective proofreading due to acquired mutations in the exonuclease domains of POLE or POLD1 causes markedly elevated somatic mutation burdens with distinctive mutational signatures. POLE and POLD1 exonuclease domain mutations also cause familial cancer predisposition when inherited through the germline. Here, we sequenced normal tissue DNA from individuals with germline POLE or POLD1 exonuclease domain mutations. Increased mutation burdens with characteristic mutational signatures were found to varying extents in all normal adult somatic cell types examined, during early embryogenesis and in sperm. Mutation burdens were further markedly elevated in neoplasms from these individuals. Thus human physiology is able to tolerate ubiquitously elevated mutation burdens. Indeed, with the exception of early onset cancer, individuals with germline POLE and POLD1 exonuclease domain mutations are not reported to show abnormal phenotypic features, including those of premature ageing. The results, therefore, do not support a simple model in which all features of ageing are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.POLE and POLD1 exonuclease domain mutations can also be inherited through the germline causing a rare autosomal dominant familial cancer predisposition syndrome, known as Polymerase Proofreading Associated Polyposis (PPAP), characterised primarily by early-onset colorectal and endometrial tumours 16,17 . It is plausible that an increased somatic mutation rate underlies this cancer predisposition and high somatic mutation loads have been reported in the small number of neoplasms analysed from such individuals 17 . However, whether the mutation rate is elevated in normal cells, or just in neoplastic cells, is not known. If elevated in normal cells, the magnitude of the increase, whether it is raised over the whole lifespan, the range of tissues and fraction of cells in each tissue it affects, and the impact of subsequent neoplastic change are important questions to address in elucidating the pathogenesis of neoplastic transformation.Accrual of somatic mutations has been proposed as the primary biological mechanism underlying ageing 18-21 . This hypothesis is based on the premises that a) mutations accumulate throughout life; and b) higher mutation loads cause widespread malfunction of cell biology. Recent reports have confirmed that the somatic mutation burden in normal cells does increase during life in a more or less linear manner 22-30 , compatible with a causal role for somatic mutations in ageing. However, somatic mutations could, in principle, accumulate without significant biological consequences. Thus, study of individuals with inherited POLE or POLD1 exonuclease domain mutations could provide insi...

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“…Taken together, our data and the literature available, we can hypothesize that the inflammatory environment of the peri‐implant tissue could trigger KRAS mutations and MAPK/ERK activation, which can contribute to IA‐PGCG development. Despite the increasing number of reports of pathogenic mutations in normal and inflammatory tissues (Lac et al, ; Martincorena et al, ), there are no data regarding peri‐implant inflammatory tissues. Thus, further studies are necessary to test these assumptions.…”

Section: Discussionmentioning

confidence: 99%

“…The pro-inflammatory cytokine overproduction in chronic inflammation can enhance the production of reactive oxygen species that, in turn, contribute to highly mutagenic molecule formation that are able to promote mutations (Khansari, Shakiba, & Mahmoudi, 2009;Grivennikov, Greten, & Karin, 2010). Chronic inflammation may amplify the activity of the RAS at pathological levels (Daniluk et al, 2012;Ji et al, 2009) (Lac et al, 2019;Martincorena et al, 2018), there are no data regarding peri-implant inflammatory tissues. Thus, further studies are necessary to test these assumptions.…”

Section: Discussionmentioning

confidence: 99%

KRAS mutations in implant‐associated peripheral giant cell granuloma

et al. 2019

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Objectives To investigate the molecular pathogenesis of implant‐associated peripheral giant cell granuloma (IA‐PGCG). Methods A convenience sample of 15 IA‐PGCG cases was selected. Hotspot mutations of KRAS, FGFR1, and TRPV4 genes, previously reported in conventional giant cell lesions of the jaws, were investigated by Sanger sequencing. As these mutations could activate MAPK/ERK pathway, the expression of phospho‐ERK1/2 was also evaluated by immunohistochemistry. Results KRAS mutations were detected in 8/15 (53.4%) samples. Similar to conventional peripheral giant cell granuloma, the KRAS mutations most frequently occurred in codon 146 (p.A146V, n = 3), followed by codon 12 (p.G12A and p.G12D, n = 1 each) and codon 14 (p.V14L, n = 1). Variants of unknown significance (VUS) were also detected in two cases, affecting codons 37 (p.E37K) and 127 (p.T127I). All samples showed wild‐type (WT) sequences for FGFR1 and TRPV4 genes. Consistent with MAPK/ERK pathway activation, all mononuclear cells of the lesion showed strong staining for phospho‐ERK1/2 protein in the immunohistochemical analysis. Conclusions KRAS mutations and activation of the MAPK‐ERK signaling pathway occur in IA‐PGCG. This is the first study to demonstrate cancer‐associated gene mutations in a non‐neoplastic reactive condition associated with dental implants.

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Oncogenic mutations in histologically normal endometrium: the new normal?

Cited by 120 publications

References 41 publications

KRAS mutations in brown tumor of the jaws in hyperparathyroidism

KRAS mutations in brown tumor of the jaws in hyperparathyroidism

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

KRAS mutations in implant‐associated peripheral giant cell granuloma

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