K-ras, BRCA1/2, and CHEK2 mutations and loss of heterozygosity at 9p, 17p, and 18q in sporadic adenocarcinoma of the pancreas

Amosenko, F. A.; Kazubskaya, T. P.; Gromyko, O E; Matveeva, T. I.; Korchagina, E. L.; Наседкина, Т. В.; Gar'kavtseva, R F; Kalinin, Viacheslav

doi:10.1134/s0026893309030054

Cited by 6 publications

(5 citation statements)

References 21 publications

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“…In studies from the Czech Republic the I157T and other alterations in its proximity, del5395 and 1100delC in CHEK2 mutations did not appear to predispose to pancreatic cancer risk in the Czech population . CHEK2 mutations were also not found in a Russian study, although they only analyzed the presence of the 1100delC in a group of 37 patients . In a German study, the CHEK2 1100delC mutation was identified in 1 of 35 (3%) Familial Pancreatic Cancer cases.…”

Section: Discussionmentioning

confidence: 93%

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Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?

et al. 2016

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Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among PaCa patients and assessed their possible association with the risk of disease in Poland. In the study 383 PaCa patients and 4,000 control subjects were genotyped for founder mutations in: BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2 + 1G > A, del5395, I157T), NBS1 (657del5) and PALB2 (509_510delGA, 172_175delTTGT). A statistically significant association between the 657del5 mutation and an increased risk of pancreatic cancer was observed for NBS1 gene. The Slavic NBS1 gene mutation (657delACAAA) was detected in 8 of 383 (2.09%) unselected cases compared with 22 of 4,000 (0.55%) controls (OR: 3.80, p = 0.002). The PALB2 509_510delGA and 172_175delTTGT mutations combined were seen in 2 (0.52%) unselected cases of PaCa and in 8 (0.20%) of 4,000 controls (OR: 2.61, p = 0.49). For BRCA1, the three mutations combined were detected in 4 of 383 (1.04%) PaCa patients and in 17 of 4,000 (0.42%) controls (OR: 2.46, p = 0.20). CHEK2 mutations were not associated with the risk of pancreatic cancer (OR: 1.11, p = 0.72). The founder mutation in NBS1 (657del5) was associated with an increased risk of PaCa in heterozygous carriers, indicating that this mutation appears to predispose to cancer of the pancreas. By identifying pancreatic cancer risk groups, founder mutation testing in Poland should be considered for people at risk for PaCa.

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Section: Discussionmentioning

confidence: 93%

“…29 CHEK2 mutations were also not found in a Russian study, although they only analyzed the presence of the 1100delC in a group of 37 patients. 30 In a German study, the CHEK2 1100delC mutation was identified in 1 of 35 (3%) Familial Pancreatic Cancer cases.…”

Section: Discussionmentioning

confidence: 97%

Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?

et al. 2016

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“…Both these are macroscopic lesions in contrast to the microscopic nature of PanIN. PanIN is associated with chromosomal instability such as telomere shortening, aneuploidy, loss of heterozygosity, and DNA damage triggered by activation of the ATM‐Chk2 checkpoint pathway . A telomere present at each end of a chromosome protects each chromosomal end from deterioration.…”

Section: Age‐related Neoplastic Changes In the Pancreasmentioning

confidence: 99%

Age‐related morphological changes in the pancreas and their association with pancreatic carcinogenesis

Matsuda

2019

Pathology International

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Age-related pathological changes in the pancreas have been unclear because they are often minor and nonspecific. However, recent studies have shown that they are closely related to various pathological conditions such as pancreatic cancer and diabetes mellitus. Knowledge of age-related changes is important to determine appropriate prevention, detection, and treatment strategies for various diseases observed in elderly patients. We present a review of the pathological age-related non-neoplastic changes in the exocrine pancreas such as pancreatic fatty replacement, lobulocentric pancreatic atrophy, pancreatic duct ectasia, and metaplasia of exocrine pancreas, as well as changes in islet cells. We have discussed common pancreatic neoplasms in elderly patients, such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMNs), and pancreatic ductal adenocarcinoma (PDAC). Age-related pathological changes play a key role in pancreatic carcinogenesis via telomere dysfunction. Further studies are warranted to clarify molecular mechanisms of pancreatic carcinogenesis in elderly patients. K E Y W O R D S aging, autopsy, carcinogenesis, pancreas, telomere

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“…Pancreatic cancer is characterized by genomic complexity and instability; telomere shortening, loss of TP53, K-RAS mutation, abnormal mitosis and nuclear abnormalities are all contributors to this phenotype [ 17 ]. PanIN also harbors chromosomal instability such as telomere shortening [ 18 ], aneuploidy [ 19 ], loss of heterozygosity [ 20 ], and a DNA damage response triggered by activation of the ataxia-telangiectasia-mutated (ATM)-cell cycle checkpoint kinase-2 (Chk2) checkpoint pathway [ 21 ]. Telomere shortening appears to precede the development of TP53 mutations during pancreatic carcinogenesis [ 18 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Gradual Telomere Shortening and Increasing Chromosomal Instability among PanIN Grades and Normal Ductal Epithelia with and without Cancer in the Pancreas

et al. 2015

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A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence in situ hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with invasive ductal carcinoma (n = 36), as well as control autopsy cases (n = 150). In comparison with normal ducts, telomere length was decreased in PanIN-1, −2 and −3 and cancer. Furthermore, telomeres were shorter in cancer than in PanIN-1 and −2. Telomere length in cancer was not associated with histological type, lesion location, or cancer stage. PanINs with or without cancer showed similar telomere lengths. The incidences of atypical mitosis and anaphase bridges, which are morphological characteristics of chromosomal instability, were negatively correlated with telomere length. The telomeres in normal duct epithelium became shorter with aging, and those in PanINs or cancers were shorter than in age-matched controls, suggesting that telomere shortening occurs even when histological changes are absent. Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium might be associated with carcinogenesis of the pancreas. Determination of telomere length in pancreatic ductal lesions may be valuable for accurate detection and risk assessment of pancreatic cancer.

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K-ras, BRCA1/2, and CHEK2 mutations and loss of heterozygosity at 9p, 17p, and 18q in sporadic adenocarcinoma of the pancreas

Cited by 6 publications

References 21 publications

Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?

Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?

Age‐related morphological changes in the pancreas and their association with pancreatic carcinogenesis

Gradual Telomere Shortening and Increasing Chromosomal Instability among PanIN Grades and Normal Ductal Epithelia with and without Cancer in the Pancreas

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