Effect of celecoxib on protein expression of FAK and Cx43 in DMBA induced rat tongue carcinoma cells.

OBJECTIVE: The pathogenesis of tongue cancer (TA) has not been fully illustrated. Cyclooxygenase-2 (COX-2) is correlated with the precancerous lesion of oral cavity mucosa and malignant transformation. The focal adhesion kinase (FAK) and gap junction protein connexin 43 (Cx43) are involved in the occurrence and progression of tumors. This study aimed to investigate the effect of celecoxib on the proliferation, malignant transformation, and expression of FAK and Cx43 proteins. MATERIALS AND METHODS: Healthy male Sprague-Dawley (SD) rats (4 months old) were divided into control, model and celecoxib group. 7,12-dimethylbenzanthracene (DMBA) was used to generate tongue mucosal carcinoma, coupled with celecoxib intervention. At 8, 12, 16, and 20 weeks after induction, the rat survival status, the tumor formation rate and the tongue tissue morphology were observed. Meanwhile, the expression of FAK and Cx43 was also evaluated by using immunohistochemistry (IHC). RESULTS: Tumor occurrence rates after induction were 0, 26.67%, 66.67%, and 80% at 8, 12, 16, and 20 weeks, respectively. The celecoxib treatment decreased such rats to 0, 0, 0, and 13.33%, respectively (p<0.05 compared to model group). No significant change was observed in control group, whilst model group had mild to severe hyperplasia and squamous carcinoma with elongated time. Celecoxib treatment significantly improved the tissue morphology (p<0.05). The model group also had elevated FAK and depressed Cx43 protein expression (p<0.05). With elongated time, the FAK expression was further increased whilst Cx43 protein was depressed (p<0.05 compared to model group). CONCLUSIONS: The focal application of celecoxib effectively inhibited the DMBA-induced rat TA, possibly via regulating FAK and CX43 protein expression, and inhibiting oral epidermal hyperplasia.

Circular RNA ITCH suppresses proliferation and promotes apoptosis in human epithelial ovarian cancer cells by sponging miR-10a-α.

OBJECTIVE: To explore the effect of Circular RNA Itchy E3 ubiquitin protein ligase (Circ-ITCH) on regulating epithelial ovarian cancer (EOC) cells proliferation and apoptosis, as well as its potential target microRNAs (miR) in vitro. MATERIALS AND METHODS: Circ-ITCH mimic, blank mimic, Circ-ITCH inhibitor and blank inhibitor plasmids were transfected into SKOV3 cells. Rescue experiments were carried out by transfecting blank mimic, miR-10a mimic, Circ-ITCH mimic and miR-10a mimic/Circ-ITCH mimic plasmids into SKOV3 cells. Quantitative polymerase chain reaction (qPCR) was performed to detect RNA expression. Cells proliferation was determined by Cell Counting Kit-8 (CCK-8) assay, and cells apoptosis rate was detected using Annexin V (AV) / propidium iodide (PI) assay. RESULTS: Circ-ITCH expression was decreased in Human EOC cell lines SKOV3, A-2780, OVCAR-3 and HO-8910 compared with human normal ovarian epithelial cell line IOSE80, and the most significant reduction of Circ-ITCH expression was presented in SKOV3 cells. Cells proliferation was suppressed by Circ-ITCH mimic transfection and promoted by Circ-ITCH inhibitor transfection in SKOV3 cells. Cells apoptosis was enhanced by Circ-ITCH mimic transfection and inhibited by Circ-ITCH inhibitor transfection in SKOV3 cells. In addition, Circ-ITCH adversely regulated miR-10a expression in SKOV3 cells but not miR-4251 or miR-6505. Rescue experiments were subsequently performed, which exhibited that Circ-ITCH adversely regulated miR-10a expression, whereas miR-10a did not affect Circ-ITCH expression. And most importantly, miR-10a mimic attenuated the effect of Circ-ITCH on reducing proliferation and promoting apoptosis in SKOV3 cells. CONCLUSIONS: Circ-ITCH suppresses cells proliferation and promotes cells apoptosis via sponging miR-10a in EOC cells.

Peripheral Blood Leukocyte Telomere Length Is Associated with Age but Not Renal Function: A Cross-Sectional Follow-Up Study.

OBJECTIVES: We aimed to evaluate the relationship between baseline renal function and changes in telomere length in Han Chinese. METHODS: The telomere restriction fragment (TRF) length of leukocytes in the peripheral blood was measured in healthy volunteers recruited in 2014. The estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine (Scr) and serum cystatin C (CysC)-eGFRcys and eGFRScr-cys through the Cockcroft-Gault formula (eGFRC-G) or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI / eGFRCKD-EPI) equation. The correlation between telomere length changes over time and renal function was analyzed. RESULTS: Leukocyte TRF lengths were negatively correlated to age (r = -0.393, p < 0.001) and serum CysC (r = -0.180, p < 0.01), while positively associated with eGFRCKD-EPI, eGFRC-G, eGFRcys, and eGFRScr-cys (r = 0.182, 0.122, 0.290, and 0.254 respectively, p < 0.01). The 3-year change of telomere length was 46 bp/years. When adjusted for age, the associations between telomere length changes and baseline, subsequent TRF lengths, and serum CysC were no longer present. No association was observed between TRF length changes and renal function. CONCLUSION: The rate of telomere length changes was affected by age and baseline telomere length. The telomere length changes might be important markers for aging.

Congenital hydrocephalus and hemivertebrae associated with de novo partial monosomy 6q (6q25.3→qter).

This study was conducted to describe a prenatal case of congenital hydrocephalus and hemivertebrae with a 6q terminal deletion and to investigate the possible correlation between the genotype and phenotype of the proband. We performed an array-based comparative genomic hybridization (aCGH) analysis on a fetus diagnosed with congenital hydrocephalus and hemivertebrae. The deletion, spanning 10.06 Mb from 6q25.3 to 6qter, was detected in this fetus. The results of aCGH, karyotype and fluorescent in situ hybridization (FISH) analyses in the healthy parents were normal, which confirmed that the proband's copy-number variant (CNV) was de novo. This deleted region encompassed 97 genes, including 28 OMIM genes. We discussed four genes (TBP, PSMB1, QKI and Pacrg) that may be responsible for hydrocephalus while the T gene may have a role in hemivertebra. We speculate that five genes in the 6q terminal deletion region were potentially associated with hemivertebrae and hydrocephalus in the proband.

Tuberculoma masked by glioma: a case report.

Tuberculous meningitis (TM), a common infectious disease of the central nervous system that is also seen in other types of tuberculosis infections, has higher mortality rates in young and middle-aged patients. TM is difficult to diagnose and treat owing to its non-specific clinical features and often atypical cerebrospinal fluid changes. Patients who present with focal neurologic signs, cough, low-grade fever and illness duration of more than 5 days, have intracalvarial abnormalities, and do not meet Thwaites' criterion findings should be diagnosed using computed tomography or magnetic resonance imaging. Mycobacterium infections can also be diagnosed by acid-fast staining of smears, cerebrospinal fluid culture, diagnostic polymerase chain reaction for Mycobacterium tuberculosis, and purified protein derivative test. To prevent TM misdiagnosis, clinicians must have sufficient knowledge of the clinical manifestations of tuberculosis. Appropriate application of tuberculosis chemotherapy drug principles, including early diagnosis and treatment, combination therapies, and consistent administration of treatment at appropriate dosages, can greatly reduce TM mortality rates and improve satisfactory treatment outcomes.

Association of Klotho and interleukin 6 gene polymorphisms with aging in Han Chinese population.

Certain gene polymorphisms are associated with human aging. This study investigated polymorphisms of a metabolism-related gene, Klotho, and an inflammatory gene, IL6, for association with the aging process in a healthy Han Chinese population. A total of 482 healthy subjects were recruited and divided into aging and young groups according to chronological age and biological age. Snapshots were used to detect a Klotho gene tag SNP (rs571118) and the F-SNPs rs9536314 (F352V) and rs9527025 (C370S), and an interleukin 6 (IL-6) gene tag SNP (rs1524107) and the F-SNPs rs1800795 (-174G/C) and rs1800796 (-572G/C). Klotho F352V and IL-6-174G/C was G homozygous, C370S was T homozygous while IL-6-572G/C MAF less than 5%. There was a statistically significant difference in the Klotho rs571118 SNP between chronological age groups, but not biological age groups. However, other SNPs, including IL-6 gene SNPs, didn't correlate with age in the Han Chinese population. Human aging is a complex process that includes chronological and biological aging. Our current data showed that Klotho gene rs571118 SNP was associated with chronological aging, but not biological aging, in a Han Chinese population. Further study will investigate genetic build up for the difference between chronological and biological aging.

AEG-1 expression is an independent prognostic factor in rectal cancer patients with preoperative radiotherapy: a study in a Swedish clinical trial.

BACKGROUND: Preoperative radiotherapy (RT) is widely used to downstage rectal tumours, but the rate of recurrence varies significantly. Therefore, new biomarkers are needed for better treatment and prognosis. It has been shown that astrocyte elevated gene-1 (AEG-1) is a key mediator of migration, invasion, and treatment resistance. Our aim was to analyse the AEG-1 expression in relation to RT in rectal cancer patients and to test its radiosensitising properties. METHODS: The AEG-1 expression was examined by immunohistochemistry in 158 patients from the Swedish clinical trial of RT. Furthermore, we inhibited the AEG-1 expression by siRNA in five colon cancer cell lines and measured the survival after irradiation by colony-forming assay. RESULTS: The AEG-1 expression was increased in the primary tumours compared with the normal mucosa independently of the RT (P<0.01). High AEG-1 expression in the primary tumour of the patients treated with RT correlated independently with higher risk of distant recurrence (P=0.009) and worse disease-free survival (P=0.007). Downregulation of AEG-1 revealed a decreased survival after radiation in radioresistant colon cancer cell lines. CONCLUSIONS: The AEG-1 expression was independently related to distant recurrence and disease-free survival in rectal cancer patients with RT and could therefore be a marker to discriminate patients for distant relapse.

Construction of an integral formula of biological age for a healthy Chinese population using principle component analysis.

BACKGROUND: Whereas chronological age (CA) cannot distinguish functional differences among individuals of the same age, the biological age (BA) may be used to reflect the functional state of the body. The purpose of this study was to construct an integral formula of the BA, by using principle component analysis (PCA). METHODS: The vital organ function of 505 healthy individuals of Han origin (age 35-91 years) was examined. A total of 114 indicators of cardiovascular, pulmonary, and brain functions, and clinical, inflammatory, genetic, psychological, and life habit factors were assessed as candidate indicators of aging. Candidate indicators were submitted with CA to correlation and redundancy analyses. The PCA method was used to build an integral formula of the BA for the population. RESULTS: Seven biomarkers were selected in accordance with a certain load standard. These biomarkers included the trail making test (TMT), pulse pressure (PP), mitral valve annulus ventricular septum of the peak velocity of early filling (MVES), minimum carotid artery intimal-medial thickness (IMTmin), maximum internal diameter of the carotid artery (Dmax), maximal midexpiratory flow rate 75/25 (MMEF75/25), and Cystatin C (CysC). The formula for the BA was: BA = 0.0685 (TMT) + 0.267 (PP) - 1.375 (MVES) + 22.443 (IMTmin) + 2.962 (Dmax) - 2.332 (MMEF75/25) + 16.104 (CysC) + 0.137 (CA) + 0.492. CONCLUSION: Several genetic and lifestyle indicators were considered as candidate markers of aging. However, ultimately, only markers reflecting the function of the vital organs were included in the BA formula. This study represents a useful attempt to employ multiple indicators to build a comprehensive BA evaluation formula of aging populations.

Cancer-initiating cells derived from human rectal adenocarcinoma tissues carry mesenchymal phenotypes and resist drug therapies.

Accumulating evidence indicates that cancer-initiating cells (CICs) are responsible for cancer initiation, relapse, and metastasis. Colorectal carcinoma (CRC) is typically classified into proximal colon, distal colon, and rectal cancer. The gradual changes in CRC molecular features within the bowel may have considerable implications in colon and rectal CICs. Unfortunately, limited information is available on CICs derived from rectal cancer, although colon CICs have been described. Here we identified rectal CICs (R-CICs) that possess differentiation potential in tumors derived from patients with rectal adenocarcinoma. The R-CICs carried both CD44 and CD54 surface markers, while R-CICs and their immediate progenies carried potential epithelial-mesenchymal transition characteristics. These R-CICs generated tumors similar to their tumor of origin when injected into immunodeficient mice, differentiated into rectal epithelial cells in vitro, and were capable of self-renewal both in vitro and in vivo. More importantly, subpopulations of R-CICs resisted both 5-fluorouracil/calcium folinate/oxaliplatin (FolFox) and cetuximab treatment, which are the most common therapeutic regimens used for patients with advanced or metastatic rectal cancer. Thus, the identification, expansion, and properties of R-CICs provide an ideal cellular model to further investigate tumor progression and determine therapeutic resistance in these patients.

Cutaneous adverse drug reactions in a hospital-based Chinese population.

BACKGROUND: Cutaneous adverse drug reactions (CADRs) are common skin adverse reactions associated with drugs. AIM: To assess recent trends in CADRs and the drugs associated with them, using data from the past 5 years in the largest single database available on a hospital-based population in China. METHODS: All clinical records of inpatients admitted with a diagnosis of CADR to the Dermatology Ward, Huashan Hospital from January 2004 to December 2008 were retrospectively studied. RESULTS: In the 734 patients, the three most common types of CADRs were nonsevere reactions, erythema multiforme (EM)-like eruptions (n = 255), urticaria (n = 192) and exanthematous reactions (n = 159), followed by three severe reactions: Stevens-Johnson syndrome (n = 58), toxic epidermal necrolysis (n = 29) and exfoliative dermatitis (n = 22). The most common single drug associated with the development of all drug eruptions was allopurinol, followed by amoxicillin, cephalosporins, antiepileptic agents and antipyretic/analgesic agents. However, the most common single drugs associated with severe reactions were antiepileptic agents, followed by allopurinol, antipyretic/analgesic agents and cephalosporins. In contrast to patients with nonsevere reactions, patients with severe reactions were more likely to be male (P < 0.001) and to have a greater mean age of onset (P < 0.001), a longer latency period (P < 0.001) and a longer duration of hospitalization (P < 0.001). CONCLUSION: In contrast to previous studies, we found allopurinol to be the most common single drug associated with CADRs followed by antibiotics (amoxicillin and cephalosporins), and antiepileptic, especially carbamazepine. A higher incidence of EM-like eruptions and urticaria was also seen.

Gene expression profile of colon cancer cell lines treated with SN-38.

AIM: Colorectal cancer is the third most common form of cancer in the industrial countries. Due to advances regarding the treatments, primarily development of improved surgical methods and the ability to make the earlier diagnosis, the mortality has remained constant during the past decades even though the incidence in fact has increased. To improve chemotherapy and enable personalised treatment, the need of biomarkers is of great significance. In this study, we evaluated the gene expression profiles of the colon cancer cell lines treated with SN-38, the active metabolite of topoisomerase-1 inhibitor irinotecan which leads to cell cycle arrest and apoptosis. MATERIAL AND METHODS: The study included 3 colon cancer cell lines: KM12C, KM12SM and KM12l4a. The 3 cell lines were treated with SN-38, and samples were obtained after 24 and 48 hour treatments. The gene expression analyses were performed using oligonucleotide microarrays comprising of approximately 27,000 spots where the untreated controls were compared to the SN-38-treated samples. RESULTS: Unsupervised clustering clearly distinguished the treated cell lines from the untreated. Supervised analysis identified 3,974 significant genes (p = 0.05) differentiating the treated samples from the untreated, majority of which were down-regulated after treatment. The top-ranked down-regulated genes in the treated cell lines included those related to receptor and kinase activity, signal transduction, apoptosis, RNA processing, protein metabolism and transport, cell cycle and transcription. A smaller number of genes were up-regulated in the cell lines after treatment and included genes involved in apoptosis, transcription, development and differentiation. CONCLUSIONS: These results demonstrate that the expression of the genes involved in cell proliferation and apoptosis as well as RNA, DNA and protein metabolism were affected by SN-38. The impact of certain genes on colorectal cancer development needs to be further evaluated; however, these results could serve as a basis for further studies in order to find targets for irinotecan treatment.

Knockdown of peroxisome proliferator-activated receptor-beta induces less differentiation and enhances cell-fibronectin adhesion of colon cancer cells.

The role of peroxisome proliferator-activated receptor-beta/delta (PPAR-beta/delta) in the pathogenesis of colon cancer remains highly controversial. This study specifically silenced the PPAR-beta expression in three colon cancer cell lines with different metastatic potentials. Although PPAR-beta knockdown resulted in more malignant morphological changes, bigger colony sizes and lower carcinoembryonic antigen (CEA) secretion, and enhanced the cell-fibronectin adhesion, cell invasion and migration were unaffected. These effects were stronger in poorly metastatic cell lines compared with highly metastatic ones. Simultaneously, PPAR-beta knockdown decreased the mRNAs encoding adipocyte differentiation-related protein and liver fatty acid binding protein, and increased the mRNA of ILK, whereas the mRNAs encoding integrin-beta1 and angiopoietin-like 4 were unchanged. Using immunohistochemistry, we determined that the intensity of PPAR-beta expression was stronger in rectal cancers with better differentiation than in those with poor differentiation, and was stronger in early-stage tumors than in advanced ones. Together, these findings consistently indicate that PPAR-beta may facilitate differentiation and inhibit the cell-fibronectin adhesion of colon cancer, having a role as an inhibitor in the carcinogenesis and progression of colorectal cancer. Interestingly, PPAR-beta seems to have a more important role in poorly metastatic cells than in highly metastatic ones.

The location of lymphangiogenesis is an independent prognostic factor in rectal cancers with or without preoperative radiotherapy.

BACKGROUND: Lymphangiogenesis and angiogenesis are essential for tumour development and progression. The lymphatic vessel density (LVD) and blood vessel density (BVD) and their relationship to outcome have been studied extensively, however the clinical significance of the location of LVD/BVD in tumour is not known. In the present study, the location and degree of LVD/BVD and their relationship to preoperative radiotherapy (RT), clinicopathological, histopathological and biological factors were studied in rectal cancer patients participating in a Swedish clinical trial of preoperative RT. PATIENTS AND METHODS: The location and degree of LVD/BVD were analysed in primary tumours (n = 138/140) and in their subgroups of non-RT (n = 74) and RT (n = 64/66). Further, the degree of LVD/BVD was examined in the corresponding distant normal mucosa (n = 35/31) and adjacent normal mucosa (n = 72/91). All sections were immunohistochemically examined by using D2-40 and CD34 antibodies. RESULTS: In the whole series of the patients, a higher LVD at the periphery was related to negative p53 expression (P = 0.03) and favourable survival independent of tumour-node-metastasis stage, differentiation and p53 expression (P = 0.03). LVD was increased in p53-negative tumours after RT (P = 0.01). CONCLUSION: LVD at the periphery of the tumour was an independent prognostic factor in rectal cancer patients.

Downregulation of caspase-9 is a frequent event in patients with stage II colorectal cancer and correlates with poor clinical outcome.

OBJECTIVE: To evaluate the clinical significance of caspase-9 mRNA expression and investigate its prognostic value in stage II colorectal cancer. METHOD: Quantitative real-time RT-PCR was used to analyse caspase-9 mRNA expression in cancer tissue and corresponding normal mucosa from 120 patients. RESULTS: Compared with normal mucosa, the expression of caspase-9 mRNA was found to be downregulated in cancer tissue (P = 0.001). Poorly differentiated cancer showed lower mRNA expression than cancer with greater differentiation (P = 0.031). The Kaplan-Meier survival analysis demonstrated that patients with downregulated caspase-9 showed a worse overall survival (P = 0.012) and disease-free survival (P = 0.022). Cox's proportional hazards regression model confirmed that expression of caspase-9 was the strongest prognostic factor in stage II colorectal cancer. CONCLUSION: The mRNA expression of caspase-9 can be used as an independent prognostic factor for patients with stage II colorectal cancer.

Genotype <21CAs/≥21CAs and allele <21CAs of the MANBA gene in melanoma risk and progression in a Swedish population.

Cutaneous melanoma is characterized by poor patient outcome in its later stages. The search for genetic markers is therefore crucial for the identification of populations at risk for melanoma. Highly polymorphic CA repeats in 3' proximity in the MANBA gene were examined by PCR-capillary electrophoresis in 185 Swedish melanoma patients and 441 tumor-free age- and gender-matched individuals. The associations of the polymorphisms with melanoma risk, the pigment phenotypes of the patients and tumor characteristics were analyzed. A significant difference in allelic distribution between melanoma patients and tumor-free individuals was observed. The frequency of the MANBA genotype <21CAs/≥21CAs was significantly higher in melanoma patients than in the controls. When comparing allele distribution in patients and their matched controls, the allele <21CAs was found to be associated with the female gender (39.8 vs. 31.2%, P=0.041, OR=1.46, 95% CI 1.02-2.10), but not with male gender (34.4 vs. 30.9%, P%0.39). Within the melanoma group, there were no differences in the distribution of the MANBA alleles associated with patient gender or age before or after 55 years at diagnosis, nor was there any association between the MANBA genotype and pigment phenotype or tumor sites. The MANBA allele <21CAs was, however, associated with thin melanomas at diagnosis (Breslow thickness ≤1.5 mm and Clark levels I and II). In conclusion, these data suggest that MANBA polymorphisms might be an indicator of tumor growth and progression and, together with other markers, could be used to identify individuals at increased risk of melanoma.

RECK, a novel matrix metalloproteinase regulator.

Extracellular matrix (ECM) macromolecules are important for creating the cellular environments required during development and morphogenesis of tissues. Matrix metalloproteinases (MMPs) are a family of Zn-dependent endopeptidases that collectively are capable of cleaving virtually all ECM substrates, and play an important role in some physiological and pathological processes. MMP activity can be inhibited by some natural and artificial inhibitors. A newly found membrane-anchored regulator of MMPs, the reversion-inducing-cysteine-rich protein with kazal motifs (RECK), is downregulated when the cells undergo a process of malignant transformation, and is currently the subject of considerable research activity because of its specific structure and function. In this review, we have chosen to concentrate our efforts on the structure, function, regulation, and future prospect of RECK in order to provide a new target for prevention and treatment of tumours.

NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases.

Nuclear factor-kappaB (NF-kappaB) is responsible for the expression by regulating many genes for immune response, cell adhesion, differentiation, proliferation, angiogenesis and apoptosis. The function of NF-kappaB is inhibited by binding to NF-kappaB inhibitor (IkappaB), and imbalance of NF-kappaB and IkappaB has been associated with development of many diseases, including tumours. In this review, we focus on polymorphisms of the NFKB and NFKBI genes in relation to development of common inflammatory diseases including ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, giant cell arthritis, type 1 diabetes, multiple sclerosis, celiac disease, and Parkinson's disease, as well as susceptibility of several cancers, such as oral squamous cell carcinoma, colorectal cancer (CRC), hepatocellular carcinoma, breast cancer and myeloma.

Significance of glutathione S-transferases M1, T1 and P1 polymorphisms in Swedish melanoma patients.

Polymorphisms of GSTM1, GSTT1 and GSTP1 were examined in melanoma patients and tumor-free individuals. Relationships between the polymorphisms and tumor characteristics and pigment phenotypes of the patients were analyzed. There was no significant difference in GSTM1 null and GSTT1 null genotypes nor GSTP1 GG genotype between melanoma patients and controls. In melanoma patients, these polymorphisms were not correlated with early or later onset of melanomas or gender of the patients. Frequency of GSTM1 null genotype was higher in patients with melanoma >2.5 mm than in those with tumors <1.0 mm, and higher frequency was found in nodular melanoma than in the other tumor types. GSTP1 GG genotype was more often found in the patients with brown and mixed eye color or brown and black hair than those with blue and green eyes or blond hair. It is unlikely that polymorphisms of GSTM1, GSTT1 and GSTP1 are general risk factors for melanoma in the Swedish population. GSTM1 null genotype was correlated with Breslow thickness and tumor type, which might serve as an additional biomarker for a rapid tumor progression. GSTP1 GG increases risk for melanoma in the subgroup of individuals with dark eyes or hair.

Germline mutations in the MYH gene in Swedish familial and sporadic colorectal cancer.

Biallelic germline mutations in the base excision repair gene MYH have been shown to predispose to a proportion of multiple colorectal adenomas and cancer. To evaluate the contribution of MYH mutations to non- FAP, non-HNPCC familial colorectal cancer, 84 unrelated Swedish individuals affected with colorectal cancer from such families were screened for germline mutations in the coding sequence of the gene. None of the cases was found to carry any pathogenic sequence change. We then determined the prevalence of the two most common pathogenic MYH mutations found in Caucasians, Y165C and G382D, in 450 Swedish sporadic colorectal cancer cases and 480 Swedish healthy controls. The frequency of both variants in Swedish cases and controls was similar to those previously reported. In addition, we found that previously unknown sequence variations at the position of amino acid 423 (R423Q, R423P, and R423R) appear to occur more frequently in cases than in controls (p = 0.02), a finding that warrants future studies.