Targeted therapy of cancer: new roles for pathologists in colorectal cancer

Hamilton, Stanley R.

doi:10.1038/modpathol.2008.14

Cited by 54 publications

(30 citation statements)

References 71 publications

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“…Histological grading of the tumors and diagnosis of PanINs were performed according to the WHO classification system. 23 On the basis of the greatest degree of dysplasia present, IPMN lesions were classified as adenoma, borderline neoplasm or carcinoma. IPMNs were also classified into four groups, gastric, intestinal, pancreatobiliary and oncocytic types, in accordance with the recently suggested subclassification system.…”

Section: Clinical Samplesmentioning

confidence: 99%

REG4 is associated with carcinogenesis in the ‘intestinal’ pathway of intraductal papillary mucinous neoplasms

et al. 2009

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Subclassification of intraductal papillary mucinous neoplasms of the pancreas (IPMNs), based on morphological features and immunohistochemical profiles, has been proposed. Intestinal-type IPMNs frequently show moderate to severe dysplasia. Regenerating islet-derived family, member 4 (REG4) is associated with the adenoma-carcinoma sequence in colon cancer and it is also associated with intestinal phenotype. Therefore, to identify REG4 expression in IPMNs may be helpful to detect high-grade IPMNs. We also investigated REG4 expression and CDX2 expression in IPMNs. To investigate the expressions of REG4 and CDX2 in IPMNs and in invasive ductal adenocarcinoma derived from IPMN, we used immunohistochemical staining and microdissection-based quantitative real-time reverse transcription-polymerase chain reaction. Among 125 IPMNs, 43 (34%) were positive for REG4 and most of the intestinal-type IPMNs showed its expression (35/38). The positive ratio of REG4 expression in colloid carcinoma (5/7) was significantly higher than that in tubular carcinoma (1/17; P ¼ 0.003). Most of CDX2-positive cases (31/33) expressed REG4 protein, whereas only 12 of 92 CDX2-negative cases did (Po0.001). The levels of REG4 mRNA in intestinal-type IPMN were significantly higher compared to those in gastric-type IPMN or to normal pancreatic ductal epithelium (P ¼ 0.005, P ¼ 0.004, respectively). REG4 expression was observed more frequently in borderline lesions (14/28) and carcinoma (21/45) compared to adenoma (8/52). Using the Ki-67 labeling index, REG4 expression was significantly correlated with proliferative activity in borderline lesions. We conclude that REG4 is involved in the 'intestinal' pathway of carcinogenesis in IPMN. Intraductal papillary mucinous neoplasms (IPMNs) show a wide spectrum of histological differentiation from hyperplasia, adenoma and borderline neoplasm to carcinoma, and the existence of an adenoma-carcinoma sequence is documented. [1][2][3] IPMNs are considered to be precursors of invasive cancer of either tubular ductal adenocarcinoma or colloid (mucinous noncystic) carcinoma. [4][5][6][7] Recently, subclassification of IPMNs, based on morphological features and immunohistochemical profiles, has been proposed. Intestinal-type IPMNs frequently show moderate to severe dysplasia and the intestinal-type associated invasive cancer tends to be colloid carcinoma. [8][9][10][11][12] Meanwhile, most gastric-type IPMNs show low-grade dysplasia and rarely associated with invasive cancer. [8][9][10] IPMNs arising from branch ducts often show gastric-type differentiation and have a less aggressive clinical course. 1,9 Pancreatobiliary-type IPMNs show severe atypia corresponding to in situ carcinoma and is often associated with an invasive tubular type of ductal adenocarcinoma. These findings suggest that each type of IPMN follows a different pathway of carcinogenesis. Adsay et al suggested that the intestinal-type IPMN to colloid carcinoma sequence is a distinct pathway of carcinogenesis involving intestinal-related genes CDX2 an...

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Section: Clinical Samplesmentioning

confidence: 99%

REG4 is associated with carcinogenesis in the ‘intestinal’ pathway of intraductal papillary mucinous neoplasms

et al. 2009

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“…It is tempting to speculate that, as for other biomarker routinely assessed in pathology laboratories (KRAS mutation or EGFR by immunohistochemistry and/or ISH), VEGFA assessment will deserve a predictive role in colorectal cancer. 34 Further studies are needed to elucidate the potential role of amplification as a prognostic or predictive biomarker in patients with both metastatic and nonmetastatic disease. …”

Section: Discussionmentioning

confidence: 99%

VEGFA gene locus (6p12) amplification identifies a small but highly aggressive subgroup of colorectal patients

et al. 2011

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The aim of this study was to determine: (1) the frequency of VEGFA gene locus (6p12) amplification in colorectal cancers, (2) the effect of gene amplification on clinical outcome using two independent colorectal cancer patient cohorts and (3) the relationship between amplification and KRAS or BRAF gene mutation as well as with other RAS/MAPK signalling proteins. Single-punch (n ¼ 1280; cohort 1) and multiple-punch (n ¼ 195; cohort 2) tissue microarrays were used for dual-labelling fluorescence in situ hybridization (FISH). Amplification was defined as a ratio 42 times for 6p12/centromere 6 signals. Mutation analysis of KRAS (codons 12 and 13) and BRAF (codon V600E) and immunohistochemistry for p-MAPK3/MAPK1, PEBP1, HMMR, p-AKT, PLAU, PLAUR, TP53 and VEGFA were performed on cohort 1. In cohort 1, VEGFA amplification was found in 39/1280 (3%) cases and linked to higher pT stage (P ¼ 0.022), higher tumor grade (P ¼ 0.024) and vascular invasion (P ¼ 0.003).The 5-year disease-specific survival rates were 31% (95% CI 17-46) and 57% (95% CI 54-60) for amplified and nonamplified cases, respectively (Po0.001). Results were confirmed in cohort 2. In multivariable analysis, the relative risk for amplification was 2.09 (95% CI 1.4-3.1; Po0.001) and linked to more frequent BRAF mutation (P ¼ 0.015), overexpression of p-MAPK3/MAPK1 (P ¼ 0.012) and PLAU (P ¼ 0.048) and loss of metastasis suppressor protein PEBP1 (P ¼ 0.047). VEGFA gene locus amplification highlights a small but remarkably aggressive subgroup of colorectal cancers. Further studies are needed to elucidate the potential role of amplification as a prognostic or predictive biomarker in both metastatic and nonmetastatic patients.

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“…phosphorylation is continuous) and acts independently from EGFR (and other physiological signaling pathways). As a consequence, despite the signals reaching the cell surface being "blocked" by monoclonal antibodies at the receptor level, signaling tracks regulated by EGFR under normal conditions remain (chronically) activated (Amado et al, 2008;Benvenuti et al, 2007;Dahabreh et al, 2011;De Roock et al, 2010;(Engstrom et al, 2011a, b;Esteller et al, 2001;EMA, 2009;EMA 2011b;Hamilton, 2008;Heinemann et al, 2009;Malumbres & Barbacid, 2003;Normanno et al, 2009). As the estimated incidence of K-ras mutation in CRC is 30-50%, it is expected that in about half to two thirds of patients the regulation of signal effect and signal transmission are preserved and drugs acting via the K-ras route can be used with success.…”

Section: Correlation Between the Therapeutic Effect Of Egfr Inhibitormentioning

confidence: 99%

“…EGF activation can initiate cell division, proliferation, development of metastases and inhibition of apoptosis. Apparently, this leads to tumour progression (Cohenuram & Saif, 2008;Coutinho & Rocha Lima, 2003;EMA, 2009;EMA 2011b;Harari, 2004;Hamilton, 2008;Herbst & Shin, 2002;(Ritter & Arteaga, 2003;van Cutsem et al, 2009). EGFR inhibitors (cmab and pmab) are licensed for the treatment of mCRC patients.…”

Section: Correlation Between the Therapeutic Effect Of Egfr Inhibitormentioning

confidence: 99%

“…Differential diagnosis can be challenging in such cases to rule out headaches, mental disorders, and possible cortical blindness frequently caused by cerebral metastases. (Allen et al, 2006;BC Cancer Agency Cancer Management Guidelines, 2006;Benson et al, 2003;EMA, 2011a;Fakih & Lombardo, 2006;Giantonio et al, 2004;Hamilton, 2008;Kilickap et al, 2003;Martel et al, 2006;Pereg & Lishner, 2008;Scappaticci et al, 2007;Traina et al, 2006;van Heeckeren et al, 2007;Widakowich et al, 2007).…”

Section: Brief Description Of Drugs Affecting Biological Targetsmentioning

confidence: 99%

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