Ylermi Soini

A recurrent mutation in PALB2 in Finnish cancer families

BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer. Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified. The BRCA2–PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity. Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.

Reactive oxygen species and antioxidant mechanisms in human tissues and their relation to malignancies

Reactive oxygen species (ROS) are formed in mammalian cells as a consequence of aerobic respiration. Despite multiple conserved redox modulating systems, a given proportion of ROS continuously escape from the mitochondrial respiratory chain, being sufficiently potent to damage cells in various ways, including numerous carcinogenic DNA mutations. Oxidative stress resulting from an imbalanced ratio between ROS production and detoxification may also disturb physiological signal transduction, lead to chain reactions in lipid layers, and damage DNA repair enzymes. The significance of ROS and antioxidant systems in carcinogenesis is still complicated and in many ways contradictory. Enhanced antioxidant mechanisms in tumor cells in vivo have been implicated in chemoresistance and lead to poor prognosis, whereas most in vitro studies have reported tumor‐suppressing properties of antioxidant enzymes. The present review aims to clarify the significance of oxidative stress and the role of cell redox state modulating systems in human malignancies in light of the current literature.

Overexpression of peroxiredoxins I, II, III, V, and VI in malignant mesothelioma

Peroxiredoxins (Prxs) are a recently characterized group of thiol‐containing proteins with efficient antioxidant capacity, capable of consuming hydrogen peroxide in living cells. Altogether six distinct Prxs have been characterized in mammalian tissues. Their expression was investigated in histological samples of mesothelioma and in cell lines established from the tumours of mesothelioma patients. Four cases with histopathologically healthy pleura from non‐smokers were used as controls. Healthy pleural mesothelium was negative or very weakly positive for all Prxs. In mesothelioma, the most prominent reactivity was observed with Prxs I, II, V, and VI. Prx I was highly or moderately expressed in 25/36 cases, the corresponding figures for Prxs II–VI being 27/36 (Prx II), 13/36 (Prx III), 2/36 (Prx IV), 24/36 (Prx V), and 30/36 (Prx VI). Positive staining was observed both in the cytosolic and the nuclear compartment, with the exception of Prx III, which showed no nuclear reactivity. The staining pattern of Prxs III and V was granular. Immunoelectron microscopic localization of Prxs was in accordance with the immunohistochemical findings, showing diffuse cytoplasmic localization for Prxs I, II, IV, and VI and distinct mitochondrial labelling for Prxs III and V. There was no significant association between the extent of staining and different Prxs. It appeared that Prxs may not have prognostic significance, but being prominently expressed in most mesotheliomas these proteins, at least in theory, may play a role in the primary drug resistance of this disease. Copyright

Carbonic anhydrase IX in oligodendroglial brain tumors

BackgroundCarbonic anhydrase IX is a hypoxia-induced enzyme that has many biologically important functions, including its role in cell adhesion and invasion.MethodsThis study was set out to investigate the role of CA IX in a series of 86 oligodendroglial brain tumors (71 primary and 15 recurrent; 48 pure oligodendrogliomas and 40 mixed oligoastrocytomas).Results80% of the tumors showed CA IX expression by immunohistochemistry. Tumors with moderate or strong CA IX expression had decreased level of cell proliferation compared to weak or no CA IX expression (median 2.9 vs. 5.8, p = 0.015). CA IX correlated with two antioxidative enzymes, manganese superoxide dismutase (MnSOD) and regulatory gammaglutamylcysteine synthetase (GLCL-R): CA IX expression was significantly higher in MnSOD-positive tumors (p = 0.008) and decreased in GLCL-R-positive tumors (p = 0.044). In Cox multivariate analysis CA IX expression, patient age and histological component (pure oligodendroglioma vs. mixed oligoastrocytoma) showed independent prognostic values (p = 0.009, p = 0.003 and p = 0.022, respectively), CA IX positivity predicting poorer outcome.ConclusionCA IX was proved to be an independent prognostic indicator in oligodendroglial brain tumors, and it also correlates reversely with cell proliferation. It may have a role in the biology of oligodendrogliomas, and most interestingly, as it is mainly expressed in tumor tissue, CA IX could serve as a target molecule for anticancer treatments.

Histopathological Evaluation of Apoptosis in Cancer

The first observations of programmed cell death were made more than a century ago, and the term apoptosis was coined for this widely occurring phenomenon as early as 2 decades ago 1,2 . However, it is only during the past few years that serious mechanistic studies on it have been launched, leading to a revelation of its basic molecular intricacies. Along with this, investigators also working with clinical tumor material have obtained new analytical tools to study the role of apoptosis in cancer. Indeed, during the past years, there have been numerous papers in which the occurrence and extent of apoptosis and its association with the growth and progression of cancer have been studied in various types of neoplasms. This is not surprising, because, in essence, tumor growth is the net result of cell proliferation and cell loss. Rather, one may wonder why it is that, after so many years of meticulous use of not only mitotic count but also of more sophisticated proliferation markers as pointers of cell growth, it is only now that apoptotic index is becoming to be included among the parameters used to measure tumor growth. In the following, we first give a brief overview of the molecular mechanisms of apoptosis. We then look at the role of apoptosis in cancer. Finally, we review studies done on the occurrence and extent of apoptosis in various types of tumors, and on the apoptotic index as a prognostic marker. We also reflect on, as extracted from the literature and based on our own experience, the currently used methods to determine the number of apoptotic cells in tumor samples and their limitations.

Expression of claudins 1, 2, 3, 4, 5 and 7 in various types of tumours

Aims : Claudins are adhesion molecules present in tight junctions. To evaluate their usefulness as differentiation markers claudins 1, 2, 3, 4, 5 and 7 were studied in 116 epithelial and 92 non‐epithelial tumours.

Peroxiredoxins, a novel protein family in lung cancer

Cigarette smoke, the major risk factor for lung cancer, induces an accumulation of reactive oxygen species. These have multiple effects on cell defense, cell proliferation and cell death. Thus, compounds involved in the regulators of redox balance can be hypothesized to play a fundamental role in both carcinogenesis and tumor progression. Here, we have evaluated the expressions of all 6 peroxiredoxins (Prxs I–VI) in lung carcinomas. Prxs represent a protein family with the capability of breaking down hydrogen peroxide; thus, they can participate in cellular antioxidant defense, regulate cell proliferation and increase drug resistance of cultured cells. Altogether 92 cases were investigated by immunohistochemistry, including 32 adenocarcinomas, 45 squamous cell, 9 small cell and 6 other carcinomas. Additionally, 11 cases with adenocarcinoma or squamous cell carcinoma were studied by Western analysis and/or by RT‐PCR. Prxs I, II, IV and VI were particularly elevated in lung carcinomas as assessed by immunohistochemistry and/or RT‐PCR. Western analysis revealed that Prxs I and IV were significantly elevated in tumors compared to nonmalignant tissue (p = 0.04 and 0.002, respectively). There were remarkable variations in Prx expression in various tumor subtypes, the most striking being Prx IV expression, which was mainly associated with adenocarcinoma. Elevated Prx VI expression was associated with high‐grade squamous cell carcinoma (p = 0.03) and Prx II expression, with advanced tumor stage (p = 0.01). Our results suggest that Prxs may have effects on the progression of lung cancer.

Prognostic factors in tongue cancer – relative importance of demographic, clinical and histopathological factors

The incidence of and mortality from squamous cell carcinoma (SCC) of the tongue have increased during the recent decades in the Western world. Much effort has been made to predict tumour behaviour, but we still lack specific prognostic indicators. The aim of our study was to evaluate the relative importance of the known demographic, clinical and histological factors in a homogeneous population-based group of patients with SCC of the mobile tongue. The demographic and clinical factors were reviewed retrospectively from primary and tertiary care patient files. Histological prognostic factors were determined from pre-treatment biopsies. The TNM stage was found to be the most important prognostic factor. In particular, local spread outside the tongue rather than spread to regional lymph nodes was related to poor prognosis. Several demographic and histopathological factors were closely related to TNM stage. When the cases were divided into stage I–II carcinomas and stage III–IV carcinomas, it appeared that the patient’s older age (> 65 years), a high malignancy score and an absence of overexpressed p53 protein were associated with a poorer prognosis in stage I–II carcinomas. Such cases may require more aggressive treatment. Among patients with stage III–IV carcinomas, heavy use of alcohol was significantly associated with a poor disease-specific survival time.

Prognostic evaluation of oral tongue cancer: Means, markers and perspectives (I)

Oral (mobile) tongue squamous cell carcinoma (OTSCC) is the most common cancer diagnosed within the oral cavity. Due to the inherent disadvantages of the mobile tongue OTSCC behaves aggressively and is generally associated with higher rates of occult metastasis and neck nodal metastasis than any other cancer of the oral cavity. The prognosis remains relatively poor and is still heavily reliant on TNM (tumor, node, metastasis) staging of the tumor despite a vast array of literature on possible prognostic indicators. This is a two-part article which examines the methods by which the behavior and prognosis of OTSCC has been studied, the prognostics markers, and the relevance and future direction of prognostic studies. In this first part, we discuss the relative merits of the methods used in prognostic studies and the clinicopathologic prognostic factors.

Angiogenesis is involved in the pathogenesis of nonrheumatic aortic valve stenosis

Angiogenesis is an essential biological process not only in embryogenesis, but also in the progression of several major diseases, including cancer, diabetes, and inflammation. Excessive vascularization can also contribute to some cardiovascular pathologies, such as atherosclerosis, but contradictory reports still prevail regarding its impact on aortic stenosis. Using immunohistochemical techniques, we assessed the vascular density and distribution of angiogenesis (FVIII) and vascular endothelial growth factor (VEGF) expression as well as the expression of 2 VEGF receptors, Flt-1 and Flk-1, in 55 nonrheumatic and 6 control aortic valves. In the light of the fact that the angiogenic effect of VEGF is mediated by sustained formation of nitric oxide, the samples were also immunostained with 3 nitric oxide synthase (eNOS, iNOS, and nNOS) antibodies. The immunohistochemical findings of VEGF and its receptors were verified by immunoblotting techniques. Vascular density was highest in the cases with moderate valve stenosis, and the mean number of FVIII-positive blood vessels was 1.7 +/- 1.9 vessels/mm(2) in the diseased valves, whereas the normal valves contained no blood vessels. Vascular density was significantly higher in the cases showing chronic inflammation (P = 0.007). Interestingly, the patients receiving statin therapy had significantly lower vascular densities than those not receiving such therapy (P = 0.001). Diseased valves showed distinct VEGF, Flt-1, Flk-1, and eNOS positivity of activated endothelial, stromal fusiform myofibroblastic, and histocytic cells. In contrast, immunoreactivity for iNOS and nNOS was seen only in nonendothelial stromal cells, and their expression was weaker. Enhanced vascular density was significantly associated with increased expression of Flk-1 (P = 0.028 for endothelial and P = 0.009 for stromal cells) and with endothelial eNOS expression (P = 0.024). A similar tendency was also observed for VEGF, but not for Flt-1. Our results show a distinct angiogenic response and the presence of angiogenic factors in nonrheumatic aortic valve stenosis, suggesting that angiogenesis may influence on the evolution of this disease.