B Humar

Publications (7)34.7 Total impact

• Source

  Available from: PubMed Central

  Article: Slow proliferation as a biological feature of colorectal cancer metastasis.

  A Anjomshoaa, S Nasri, B Humar, J L McCall, A Chatterjee, H-S Yoon, L McNoe, M A Black, A E Reeve
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  ABSTRACT: We have recently reported an inverse relationship between colon cancer progression and tumour proliferative activity. Here, we extend our findings by evaluating the proliferative activity of liver metastatic lesions and primary colorectal cancers (CRC) that differ in their metastatic potential. Using an earlier established multi-gene proliferation signature (GPS), proliferative levels were analysed in 73 primary CRCs and 27 liver metastases. Compared with primary CRCs, we observed a significantly lower expression of the GPS in liver metastases and confirmed their lower proliferative levels by quantitative RT-PCR and Ki-67 immunostaining. No difference could be detected in apoptotic indices as assessed by M30 immunostaining, indicating that the net growth rate is lower in metastases relative to primary tumours. Notably, relapsed primaries or those with established metastases had significantly lower proliferative activity than CRCs that were non-metastatic and did not relapse. Our results suggest that slow proliferation is a biological characteristic of both liver metastases and those primary tumours with the ability to metastasise. The delineation of the mechanisms underlying the inverse association between proliferation and CRC aggressiveness may be important for the development of new therapeutic strategies.
  British Journal of Cancer 09/2009; 101(5):822-8. · 5.04 Impact Factor
• Article: Variations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectal cancer.

  F Graziano, A Ruzzo, E Canestrari, F Loupakis, D Santini, E Rulli, B Humar, N Galluccio, R Bisonni, I Floriani, P Maltese, A Falcone, G Tonini, V Catalano, A Fontana, L Giustini, G Masi, B Vincenzi, P Alessandroni, M Magnani
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  ABSTRACT: The interleukin-1 receptor antagonist (IL-1RA) cytokine is thought to counteract tumor angiogenesis/metastasis. Two single nucleotide polymorphisms in the IL-1RA gene (rs4251961 T/C and rs579543 C/T) influence IL-1RA circulating levels with highest production in carriers of the homozygous rs4251961 T/T and rs579543 T/T genotypes. A total of 180 patients with metastatic colorectal cancer were categorized as high IL-1RA producers if they were carriers of at least one of the rs4251961 T/T or rs579543 T/T genotypes (T/T carriers). Median survival times were 35.8 months (95% confidence interval: 29.7-43.7 months) and 28.6 months (95% confidence interval: 25.6-30 months) in 56 T/T carriers and in 124 non-T/T carriers, respectively. The favorable association between T/T carriers' status and survival was significant in the multivariate analysis (P=0.018). Also, T/T carriers and non-T/T carriers were prevalent among patients with Karnofsky performance status 90-100 and 70-80, respectively (P=0.002). These findings encourage additional studies in this field and the evaluation of a recombinant-IL-1RA for anticancer activity.
  The Pharmacogenomics Journal 01/2009; 9(1):78-84. · 4.54 Impact Factor
• Source

  Available from: Andre M van Rij

  Article: Reduced expression of a gene proliferation signature is associated with enhanced malignancy in colon cancer.

  A Anjomshoaa, Y-H Lin, M A Black, J L McCall, B Humar, S Song, R Fukuzawa, H-S Yoon, B Holzmann, J Friederichs, A van Rij, M Thompson-Fawcett, A E Reeve
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  ABSTRACT: The association between cell proliferation and the malignant potential of colon cancer is not well understood. Here, we evaluated this association using a colon-specific gene proliferation signature (GPS). The GPS was derived by combining gene expression data obtained from the analysis of a cancer cell line model and a published colon crypt profile. The GPS was overexpressed in both actively cycling cells in vitro and the proliferate compartment of colon crypts. K-means clustering was used to independantly stratify two cohorts of colon tumours into two groups with high and low GPS expression. Notably, we observed a significant association between reduced GPS expression and an increased likelihood of recurrence (P < 0.05), leading to shorter disease-free survival in both cohorts. This finding was not a result of methodological bias as we verified the well-established association between breast cancer malignancy and increased proliferation, by applying our GPS to public breast cancer data. In this study, we show that reduced proliferation is a biological feature characterizing the majority of aggressive colon cancers. This contrasts with many other carcinomas such as breast cancer. Investigating the reasons underlying this unusual observation may provide important insight into the biology of colon cancer progression and putative novel therapy options.
  British Journal of Cancer 10/2008; 99(6):966-73. · 5.04 Impact Factor
• Article: Identification of seven novel germline mutations in the human E-cadherin (CDH1) gene.

  H More, B Humar, W Weber, R Ward, A Christian, C Lintott, F Graziano, A-M Ruzzo, E Acosta, B Boman, M Harlan, P Ferreira, R Seruca, G Suriano, P Guilford
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  ABSTRACT: Hereditary diffuse gastric cancer (HDGC) is a cancer predisposition syndrome caused by germline mutation of the gene encoding the tumour-suppressor E-cadherin (CDH1). We describe the search for CDH1 mutations in 36 new diffuse gastric cancer families. All 16 CDH1 exons, neighbouring intronic sequence and an essential promoter region were screened by DNA sequencing. We detected nine different mutations, seven of which were novel. Of the seven novel mutations, five were identified in families who met the IGCLC clinical criteria for HDGC. Two mutations resulted in a premature stop codon and truncation of the protein. Three mutations affected splice sites; two of the splice-site mutations were shown by RT-PCR to disturb normal CDH1 splicing, while the third splice-site mutation was present in two unrelated HDGC families. The remaining two mutations resulted in amino acid substitutions and impaired the ability of E-cadherin protein to form cellular aggregates and suppress invasion in vitro. Together with the occurrence of extra-gastric tumours such as lobular breast and colorectal cancer, these findings further extend the types of CDH1 mutations and the spectrum of tumours associated with HDGC.
  Human Mutation 03/2007; 28(2):203. · 5.69 Impact Factor
• Source

  Available from: Antonio Ramos-De la Medina

  Article: Single nucleotide polymorphisms (SNPs) at CDH1 promoter region in familial gastric cancer.

  A Ramos-de la Medina, H More, H Medina-Franco, B Humar, A Gamboa, L J Ortiz, J H Donohue, P Guilford
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  ABSTRACT: Gastric cancer is the most frequent gastrointestinal malignancy in Mexico and the proportion of patients younger than 40 years is one of the highest reported in the world literature. Recently several families with familial diffuse gastric cancer have been identified at the National Institute of Medical Sciences and Nutrition. Germline mutations in the E-cadherin gene (CHD1) have been described that result in the development of diffuse hereditary gastric cancer in young patients. The complete coding sequence at exons 1 to 16 and the promoter region of CDH1 was amplified by polymerase chain reaction in peripheral blood samples of two patients with early onset familial diffuse gastric cancer. No germline inactivating mutations of CHD1 were found on either patient. Single nucleotide polymorphisms -160 C->A were detected in the promoter region of CDH1 in both patients. The polymorphism -160 C->A theoretically confers an increased risk of developing diffuse gastric cancer. The relatives of these patients may an increased risk of gastric cancer among other tumors. There is presently not enough evidence to consider the -160 C->A polymorphism an etiologic factor of diffuse gastric cancer in these patients since the frequency and type of genetic alterations of CDH1 are largely unknown in the Mexican population. It will be necessary to conduct epidemiologic studies in the Mexican population to determine the influence that genetic alterations have on the genesis of diffuse gastric carcinoma.
  Revista espanola de enfermedades digestivas: organo oficial de la Sociedad Espanola de Patologia Digestiva 01/2006; 98(1):36-41. · 1.55 Impact Factor
• Article: Interleukin 1B gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in Helicobacter pylori-negative gastric cancer of intestinal and diffuse histotype.

  A Ruzzo, F Graziano, F Pizzagalli, D Santini, V Battistelli, S Panunzi, E Canestrari, V Catalano, B Humar, R Ficarelli, I Bearzi, S Cascinu, N Naldi, E Testa, M Magnani
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  ABSTRACT: Polymorphisms in the interleukin 1beta gene (IL-1B-31T/C and IL-1B-511C/T single nucleotide changes) and in the interleukin 1 receptor anatagonist gene (IL-1RN2 variable number of tandem repeats) have been studied with respect to gastric cancer susceptibility. Available data support an aetiologic role of these genetic variants in the presence of concomitant Helicobacter pylori infection. Their contribution without H. pylori infection is still an open field of investigation. IL-1B and IL-1RN polymorphisms were investigated in 138 H. pylori-negative Italian patients with sporadic gastric cancer and 100 H. pylori-negative controls. Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with disease. In all gastric cancer cases, carriers of the homozygous IL-1B-511T/T genotype showed a significant risk for the development of the disease (OR 3.2 with 95% CI 1.27-8.05). In cases with intestinal-type gastric cancer, however, both IL-1B-511T and IL-1RN2 alleles were associated with disease. In this subgroup, the odds ratio for carriers of both IL-1B-511T and IL-1RN2 was 6.49 (95% CI 2.07-20.4). Haplotype analysis supported the aetiologic contribution of these alleles in gastric cancer of the intestinal histotype. In conclusion, IL-1B-511T and IL-1RN2 may contribute to intestinal gastric cancer risk in the absence of concomitant H. pylori infection. In this setting, future epidemiologic studies should consider dietary habits and exposure to carcinogens interacting with pro-inflammatory host genotypes.
  Annals of Oncology 07/2005; 16(6):887-92. · 6.43 Impact Factor
• Article: The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice.

  F Graziano, B Humar, P Guilford
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  ABSTRACT: Loss of function of the E-cadherin gene (CDH1) has been linked with diffuse gastric cancer susceptibility, and germline inactivating mutations in CDH1 characterise the hereditary diffuse gastric cancer (HDGC) syndrome. Hypermethylation in the CDH1 promoter region is a frequent phenomenon in poorly differentiated, diffuse gastric carcinomas and it was identified as the main mechanism for the inactivation of the remaining wild-type allele in HDGC cases. Specific criteria are used to identify patients with suspected HDGC and who should be investigated for CDH1 germline mutations. Accurate screening is mandatory for unaffected carriers of CDH1 mutations and selected high-risk individuals could be considered for prophylactic gastrectomy. Also, germline CDH1 mutations may predispose to lobular breast carcinoma and prostate cancer. Germline CDH1 mutations are not always detectable in patients who meet the HDGC criteria and the aetiological role of this gene is still under investigation. Families without recognised inactivating CDH1 mutations may have undisclosed CDH1 mutations or mutations in its regulatory sequences or germline mutations in unidentified genes that also contribute to the disease. In recent years, several germline missense CDH1 mutations have been identified, some of which showed a marked negative influence on E-cadherin function in experimental models. CDH1 promoter hypermethylation seems a key event in the carcinogenetic process of poorly differentiated, diffuse gastric cancer and it deserves further investigation as a new target for anticancer therapies with demethylating agents.
  Annals of Oncology 01/2004; 14(12):1705-13. · 6.43 Impact Factor