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. 2016 Aug 25:6:32038.
doi: 10.1038/srep32038.

Werner syndrome through the lens of tissue and tumour genomics

Mari Tokita  1 , Scott R Kennedy  2 , Rosa Ana Risques  2 , Stephen G Chun  3 , Colin Pritchard  4 , Junko Oshima  2   5 , Yan Liu  2 , Peter K Bryant-Greenwood  6 , Piri Welcsh  2 , Raymond J Monnat  2   7
Affiliations

Werner syndrome through the lens of tissue and tumour genomics

Mari Tokita et al. Sci Rep. .

Abstract

Werner syndrome (WS) is the canonical adult human progeroid ('premature aging') syndrome. Patients with this autosomal recessive Mendelian disorder display constitutional genomic instability and an elevated risk of important age-associated diseases including cancer. Remarkably few analyses of WS patient tissue and tumors have been performed to provide insight into WS disease pathogenesis or the high risk of neoplasia. We used autopsy tissue from four mutation-typed WS patients to characterize pathologic and genomic features of WS, and to determine genomic features of three neoplasms arising in two of these patients. The results of these analyses provide new information on WS pathology and genomics; provide a first genomic characterization of neoplasms arising in WS; and provide new histopathologic and genomic data to test several popular models of WS disease pathogenesis.

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Figures

Figure 1
Figure 1. Histopathological features of neoplasms in Werner patients.
(A) H&E staining of pancreatic adenocarcinoma liver metastasis in Patient 3. Arrows indicate mitotic figures. Scale bar, 50 μm. Inset shows liver (L) and adjacent metastasis (M) separated by a sharp boundary (dark line). Inset scale bar, 500 μm. (B) H&E staining of pancreatic adenocarcinoma lymph node metastasis in Patient 4 growing in and expanding the subcapsular sinus of an abdominal lymph node (LN). Scale bar, 500 μm. (C) H&E staining of pancreatic adenocarcinoma perineural invasion in Patient 4. Arrows mark invading carcinoma. N, nerve. Scale bar, 500 μm. (D) H&E staining of a pulmonary carcinoid in Patient 4. Scale bar, 100 μm.
Figure 2
Figure 2. Frequency and spectrum of specific base substitution mutations in mtDNA from WS patient and control liver.
Frequency and spectrum of specific base substitution mutations as determined by Duplex Sequencing in mtDNA isolated from liver tissue of two WS patients (WS patients 1 and 2) and two control donors (Control donors 1 and 2).
Figure 3
Figure 3. Immune staining detects senescent cell markers in Werner Syndrome patient tissue.
(A) DEC1 x WS. Left panel: DEC1 immunostaining in an ulcerative colitis tissue sample (positive control). Note gradient of positive staining (basal/bottom to apical/top) typically observed in colonic crypts. Middle and right panels show DEC1 immunostaining in autopsied abdominal wall skin from WS patient 1 (middle panel) and WS patient 2 (right panel). (B) DEC1 x Age. DEC1 immunostaining of control skin from 4 month old control donor (left panel), a 49 year old control donor (middle panel) and a 50 year old control donor (right panel).(C) p16 x WS. Panels show irregular p16 immunostaining typically observed in high grade ovarian serous carcinomas (positive control, left panel); in abdominal wall skin from WS patient 1 (middle panel); and in abdominal wall skin from WS patient 2 (right panel). Arrows in middle and right panels indicate small clusters of p16-immunostained cells. All images are 40 X with scale bars representing 50 μm.
See this image and copyright information in PMC

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References

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