Search

Multiple endocrine neoplasia type 2 (MEN2) syndromes are inherited in an autosomal dominant fashion with high penetrance. There are three subtypes, namely, MEN2A (multiple endocrine neoplasia type 2A), MEN2B (multiple endocrine neoplasia type 2B), and familial medullary thyroid carcinoma. The variations in the RET gene play an important role in the MEN2 syndromes. In this work, we have developed a RET oligonucleotide microarray of 67 oligonucleotides to quickly detect RET mutations in MEN2 syndromes. The predominant RET mutations are missense mutations and are restricted to nine codons (codons 609, 611, 618, 620, 630, 634, 768, 804, and 918) in MEN2 syndromes. Missense mutations at codons 609, 611, 618, 620, and 634 have been identified in 98% of MEN2A families and in 85% of familial medullary thyroid carcinoma families. More than 95% of MEN2B patients also had a predominant mutation type at codon 918 (Met--Thr). RET oligonucleotide microarray can detect RET missense mutations at these nine codons. Theoretically, a total of 55 missense mutation types can occur at eight codons (codons 609, 611, 618, 620, 630, 634, 768, and 804). RET oligonucleotide microarray is designed to detect all of these 55 missense mutation types at these eight codons and one predominant type at codon 918. Fifty-six oligonucleotides were designed for the 56 mutation types at nine codons, and 11 oligonucleotides were designed for the wild types and positive controls. We found RET mutations in all eight of the Korean MEN2A families (a total of 75 members; 27 affected members, 19 gene carriers, and 29 unaffected members) using the developed RET oligonucleotide microarray and an automatic sequencing. Because we found only five mutation types from eight MEN2A families, the international collaborations are required to see whether the RET oligonucleotide microarray may be used as a genetic diagnostic tool. Taken together, the RET oligonucleotide microarray can function as a fast and reliable genetic diagnostic device, which simplifies the process of detecting RET mutations.

AIM:To investigate the characteristics of newly established four hepatocellular carcinoma cell lines (SNU-739, SNU-761, SNU-878 and SNU-886) from Korean hepatocellular cancer patients.METHODS:Morphologic and genetic studies were done.RESULTS:All four lines grew as a monolayer with an adherent pattern, and their doubling times ranged from 20 to 29 hours. The viability rate was relatively high (88%-94%).Neither mycoplasmal nor bacterial contamination was present.The lines showed different patterns in fingerprinting analysis. The hepatitis B virus (HBV) DNA was integrated in the genomes of all four lines, and in all of them HBx,HBc and HBs transcripts were detected by reverse transcriptase-PCR methods. Among the three cell lines used as control (Hep 3B, SK Hep1 and Hep G2),only Hep 3B showed HBx expression, and this line was used as a HBV integrated control.The RNA of albumin was detected in three lines (SNU-761, SNU-878 and SNU-886), that of transferrin in two lines (SNU-878, SNU-886), and that of IGF-II was detected in none of the cell lines.CONCLUSION:These well characterized cell lines may be very useful for studying the biology of hepatocellular carcinoma in association with the hepatitis Bvirus.

In the process of developing individualized cancer therapeutics, tumor derived cell line based preclinical (in vitro and in vivo) methods have been widely used. Patient derived genome analysis revealed significant cancer biomarkers for targeted drug development. Classic cancer biomarker, HER2, overexpression was discovered as a cancer biomarker and as a druggable target in breast cancer, which lead to the development of Trastuzumab. HER2 is overexpressed in 10-25% of gastric cancer, and treatment with Trastuzumab showed positive yet limited activity in advanced gastric cancer treatment in the ToGA study. These results present HER2 as an attractive target for gastric cancer. However, Gillet and colleagues reported the challenges in the use of in vitro and in vivo studies for drug validation and development. They reported variance in gene expression patterns between the in vitro and in vivo context within a single cancer cell line. In our study using gastric cancer derived cell lines, we observed differences in HER2 expression between in vitro and in vivo xenograft model. Also, we show the potential promising in vivo xenograft model in the development of HER2 targeting agents for gastric cancer. Eleven out of 25 gastric cancer cell lines showed HER2 expression, which was demonstrated using the IHC assay on a cell microarray. Sixteen out of 25 cell lines successfully produced xenograft models. Gastric cancer cell lines (SNU-5, SNU-16, SNU-638, SNU-1967, MKN-1, MKN-28, and NUGC-3) that had no HER2 expression when cultured in vitro showed HER2 expression in vivo. Two cell lines (NCC-19 and NCI-N87) that had HER2 expression in vitro showed a decrease in HER2 expression in vivo. Three cell lines (SNU-484, SNU-668, and SNU-719) showed various levels of increase in HER2 expression. Two cell lines showed minor to no changes in HER2 expression. NUGC-4 had consistent significant HER2 expression levels in both assays, while MKN-45 had consistent insignificant to no HER2 expression. Our study demonstrates inconsistency in HER2 gene expression between in vitro and in vivo cancer cell line models for the first time in gastric cancer. Citation Format: Youme Gim, Hee Seo Park, Hae Rim Jung, Hae Ryung Chang, Seungyoon Nam, Yong Doo Choi, Ja-Lok Ku, Yon Hui Kim. Variability of HER2 expression between in vitro and in vivo models within gastric cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2783. doi:10.1158/1538-7445.AM2014-2783

Colorectal cancer (CRC) is the third most common cancer and estimated cancer related death is high in worldwide. 5-Fluorouracil (5-Fu) is common used chemotherapeutic agent for colorectal cancer. Nevertheless the use frequency, the resistance to 5-Fu is still a critical problem. To improvement of therapeutic effects of 5-Fu, there are the new chemotherapeutic strategies like FOLFOX and FORFIRI, combination treatment 5-Fu with oxaliplatin or irinotecan. However, it is arguable that the side effects and efficiency of these strategies. Metformin is widely used therapeutic agent for type II diabetics, obesity, and polycystic ovarian syndrome with limited side effects. Recently, there are some evidence that metformin has anticancer effects for some types of cancers e.g. breast, pancreases, prostate, and colon. Recently, correlation of metformin and cancer stem cell population was proved. Here, we examined that metformin effects on parental colorectal cancer cells and their 5-Fu-resistant colorectal cancer cells. Metformin has the anticancer effects in parental cells and their 5-Fu-resistant cells in both cell lines. As treated with metformin, wound healing ability is decreased in both cell lines. Cell proliferation was 41.7% decreased in parental cells and 30.6% in 5-Fu-resistant cells. Also, expression of PARP and caspase-3 were induced by metformin dose dependent manner in both cell lines. It is suggested that metformin induces inhibition of cell proliferation and increased apoptosis. In addition, metformin treatment affects cell cycle; subG1 stage was increased to 1.7 fold and G2/M stage was increased to 1.6 fold in both cell lines. It means that metformin induces cell death and leads cell cycle arrest. However, there are no significant synergistic effect in cell proliferation, apoptosis, and cell cycle change with combination treatment of 5-Fu and metformin. CD133+ cancer stem cell population was decreased in 20 to 40 % as treated with 5-Fu and low dose of metformin to parental cells. On the other hand, CD133+ population in 5-Fu-resistant cells was affected in only low dose of metformin not 5-Fu. In sum, metformin has anticancer effects via inhibition of cell proliferation, cell cycle changes and metformin decreases CD133+ cancer stem cell population. Further studies will be necessary to verify the mechanisms that metformin decreases CD133+ cancer stem cell population in colorectal cancer cell lines. Citation Format: Sunghee Kim, Ja-Lok Ku. Metformin induces apoptotic cell death and inhibits CD133+ cancer stem cells in 5-Fu-resistant colorectal cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 780. doi:10.1158/1538-7445.AM2014-780

To elucidate RB1 germline mutations in Korean retinoblastoma patients, DNA samples from 14 children with bilateral (including three familial cases) and 19 children with unilateral retinoblastoma were analyzed. We found germline mutations in three out of 14 bilateral cases and one out of 19 unilateral cases. There were no germline mutations in the three familial cases. PCR-SSCP from each exon showed bandshifts in four patients which, upon sequencing, were shown to be K616E in exon 19 (c.1846A>G), an AA insertion in exon 7 (c.684-685insAA), R500G in exon 16 (c.1498A>G), and an A insertion in exon 23 (c.2391-2392insA), respectively. Hum Mutat 18:252, 2001.

We characterized four pancreatic carcinoma cell lines (designated SNU-213, SNU-324, SNU-410, and SNU-494) established from histopathologically varied primary or liver metastatic tumor samples of Korean patients. Three cell lines grew as adherent monolayers and one as adherent and floating cell clumps. All lines had: (1) relatively high viability; (2) an absence of mycoplasma or bacterial contamination; (3) genetic heterogeneity as assessed by DNA-fingerprinting analysis; (4) an absence of MADH4 mutation. Among the lines, three lines had mutations in codon 12 in K- ras, two lines harbored p53 mutations within the DNA-binding domain; two lines had homozygous deletions in both p16 and p15 genes; and one line had a missense mutation. Two lines (SNU-324 and SNU-410) had genetic alterations in the TGFBR2 gene: the SNU-324 line had a -1-bp or +1-bp mutation in 10-bp polydeoxyadenine repeat tracts; the SNU-410 line had a genomic deletion in this gene. Mutation analysis of mismatch repair genes demonstrated that SNU-324 has two heterozygous missense mutations in different exons of the hMLH1 gene. In addition, this line showed microsatellite instability and harbored frameshift mutations in simple repeated sequences of the coding regions of the TGFBR2, BAX, and hMSH3 genes. These defects of microsatellite instability and mismatch repair genes suggest the possibility of a new mutator phenotype for pancreatic carcinogenesis. These cell lines should be very useful for studying the biology of pancreatic carcinoma, particularly those related to mutator phenotype and genetic alterations in the TGFBR2 gene.

Microsatellite instability (MSI) at simple repeated sequences characterises a distinct mechanism of carcinogenesis in hereditary nonpolyposis colorectal cancer (HNPCC), as well as sporadic colorectal cancers displaying MSI. Such MSI is associated with mutations of hMSH2 and hMLH1, and somatic frameshift mutations in TGF-beta RII, IGFIIR, BAX, hMSH3 and hMSH6 at simple repeated sequences in coding regions. The aim of this study was to look for a correlation between mutations in mismatch repair genes and frameshift mutations in colorectal cancer cell lines with MSI. Using 22 colorectal cancer cell lines, we examined the MSI status at mononucleotide repeat microsatellite markers and mutations in hMSH2 and hMLH1, TGF-beta RII, IGFIIR, BAX, hMSH3 and hMSH6. Thirteen of 22 lines (59%) displayed MSI. In these 13 lines showing MSI, 10 lines (77%) had mutations in TGF-beta RII, nine lines (69%) in BAX, seven lines (54%) in hMSH6, and six lines (46%) in hMSH3, while mutations in the IGFIIR gene were identified in only two lines (15%). Of the 13 lines with MSI, six lines (46%) harboured mutations/deletions in hMSH2 (two nonsense mutations, three deletions and one no expression of transcripts) and three of these cell lines (50%) had mutations both in the hMSH2 and hMSH3 genes. Two cell lines (15%) had mutations/deletions in hMLH1 (one missense mutation and one deletion) and these two cell lines also had mutations in hMSH3. One line had a mutation in hMSH3 only, although this line showed MSI and had mutations in TGF-beta RII, IGFIIR and BAX. All lines with mutations in hMLH1, hMSH2, TGF-beta RII, IGFIIR, BAX and hMSH3 genes showed MSI. However, of the nine lines without MSI, two (22%) had homozygous mutations in hMSH6. In these two cell lines, no mutations were identified in hMLH1, hMSH2, TGF-beta RII, IGFIIR, BAX and hMSH3. Our results indicate that mutations in hMLH1, hMSH2 and hMSH3 are associated with MSI, but mutations in hMSH6 are not. We conclude that mutations in hMSH6 alone are not sufficient to cause MSI, although protein functional effects of these mutations should still be examined.

Objectives: Six human laryngeal squamous cell carcinoma cell lines (SNU-46, -585, -899, -1066, -1076, -1214) established from Korean patients are reported. Study Design: In vitro culture of six squamous cell carcinoma cell lines derived from primary tumors of the larynx. Description of the cell line phenotypes and determination of molecular characteristics. Methods: Six laryngeal squamous cell carcinoma cell lines were cultured. The cell phenotypes, including the histopathology of the primary tumors and in vitro growth characteristics, were determined. Molecular characterization was also performed, including DNA fingerprinting analysis and abnormalities of p15, p16, p53, and TGF-βRII genes by polymerase chain reaction-based single strand conformation polymorphism and sequencing analysis. Results: All cell lines grew as adherent cells; five lines grew as monolayers and one other line grew as stratifying colonies. All lines showed 1) high viability (75%–92%) with various doubling times (36–96 h); 2) absence of Mycoplasma and other bacteria; and 3) genetic heterogeneity by DNA profile analysis. p53 Mutations were found in three lines and p16 mutations were observed in five cell lines. TGF-βRII mutations were found in two lines: one line had frameshift mutation and another line had a missense mutation at the kinase domain. Conclusions: These newly established and characterized laryngeal squamous cell carcinoma cell lines will be useful for investigating the biologic characteristics of laryngeal cancer. Key Words: Laryngeal squamous cell carcinoma, cell lines, p53, p16, TGF-βRII.

Gastric cancer is the most common cancer in Korea. Germline mutations of the E-cadherin gene have recently been identified in familial gastric cancer patients. We screened five Korean familial gastric cancer patients to investigate germline mutations of the E-cadherin gene. These patients fulfilled the following criteria: presence of at least two gastric cancer patients within first-degree relatives and one patient diagnosed before the age of 50 years. Abnormal band patterns were found in exons 6 and 10 in two familial gastric cancer patients by polymerase chain reaction-single strand conformation polymorphism analysis (probands from the SNU-G2 and SNU-G1001 families, respectively). DNA sequencing analysis of the E-cadherin gene of these two patients revealed missense mutations in each exon. The SNU-G2 proband harbored a missense mutation from aspartic acid (GAT) to glycine (GGT) at codon 244 in exon 6 of the E-cadherin gene, and the SNU-G1001 proband had a missense mutation from valine (GTG) to alanine (GCG) at codon 487 in exon 10. The SNU-G2 proband was diagnosed with gastric cancer at the age of 38; three brothers and two sisters had died of gastric cancer under the age of 50, and their mother had died of gastric cancer at the age of 63. The SNU-G1001 proband was diagnosed with gastric cancer at the age of 42 and one brother had died of gastric cancer at the age of 49. In summary, we found germline mutations of the E-cadherin gene in two of five Korean familial gastric cancer patients screened.

Colorectal cancer (CRC) is the third most common type of cancer in developed countries. Proper radiotherapy with chemotherapy is the worldwide treatment for CRC patients. It has been reported that chemoradiotherapy is related to chemical and radiation resistance and may cause local recurrence. To investigate features in resistant tumors, various cancer cell lines that have resistance to chemo and radiotherapy have been established. In this study, three radio-resistant human colorectal cancer cell lines (SNU-61R80GY, SNU-283R80GY, and SNU-503R80GY) were induced by exposing them to a total of 80 greys of Cs-137 to define their characteristics compared to their parental cell lines (SNU-61, SNU-283, and SNU-503). In order to explain cellular properties of parental and induced radio-resistant cell lines, cell proliferation assay, soft agar colony forming assay, cell cycle analysis, and apoptotic assay were performed. Interestingly, remarkable increases of cell proliferation and colony forming abilities on the induced radio-resistant cell line (SNU-503R80GY) were observed compared to the parental cell line (SNU-503) without irradiation although there was no significant change with cell cycle and apoptotic assay using FACS and western blot analysis. Gene expression microarray analysis was then conducted to identify genetic differences between the induced radio-resistant cell lines and the parental cell lines and thirty-three genes with more than 2-fold up-regulated upon induced radio-resistant cell lines were analyzed. According to the gene ontology analysis of these genes, most of them were associated with responses to hypoxia and oxygen levels, oxidation reduction, regulation of epithelial cell differentiation, and cell-cell adhesion. Five genes with more than 3-fold up-regulated upon all three induced radio-resistant cell lines were also sorted out as candidate marker genes for radio-resistance. Furthermore, various genes that are related with cell migration, growth, differentiation, adhesion, and ERBB signaling pathways were screened by RT-PCR. In conclusion, induced radio-resistant human colorectal cancer cell lines have different features such as differential gene expression patterns, and a great ability of cell proliferation, and colony forming compared to the parental cell lines. These results suggest that the induced radio-resistant cell lines are more tumorigenic than the parental cell lines. These cellular and genetic characteristics on the induced radio-resistant cell lines could be considered markers for radio-resistance. The genes that were 3-fold up-regulated on the induced radio-resistant cell lines could be also regarded as candidate markers for radio-resistance. In order to verify our hypothesis, we are in the process of performing the same experiments using other human colorectal cancer cell lines. Citation Format: Ye-Ah Kim, Sang-Geun Jang, Young-Kyoung Shin, Ja-Lok Ku. Identification of genes with differential expression in induced radio-resistant human colorectal cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 441. doi:10.1158/1538-7445.AM2013-441

Background Granulocyte-colony stimulating factor (G-CSF) is extensively used to improve neutrophil count during anti-cancer chemotherapy. We investigated the effects of G-CSF on several leukemic cell lines and screened for the expression of the G-CSF receptor (G-CSFR) in various malignant cells. Methods We examined the effects of the most commonly used commercial forms of G-CSF (glycosylated lenograstim and nonglycosylated filgrastim) on various leukemic cell lines by flow cytometry. Moreover, we screened for the expression of G-CSFR mRNA in 38 solid tumor cell lines by using real-time PCR. Results G-CSF stimulated proliferation (40-80% increase in proliferation in treated cells as compared to that in control cells) in 3 leukemic cell lines and induced differentiation of AML1/ETO+ leukemic cells. Among the 38 solid tumor cell lines, 5 cell lines (hepatoblastoma, 2 breast carcinoma, squamous cell carcinoma of the larynx, and melanoma cell lines) showed G-CSFR mRNA expression. Conclusion The results of the present study show that therapeutic G-CSF might stimulate the proliferation and differentiation of malignant cells with G-CSFR expression, suggesting that prescreening for G-CSFR expression in primary tumor cells may be necessary before using G-CSF for treatment.

Abstract 1009 Poster Board I-31 We previously reported that the increased expression of G-CSFR in AML1/ETO+ AML cell, suggesting that cells with G-CSFR expression might easily proliferate in response to therapeutic G-CSF. To confirm the association of AML/ETO gene and increased expression of G-CSFR, we transfected AML1/ETO specific small interfering RNAs (siRNAs) to AML/ETO+ cell line and G-CSFR expression was decreased on transfection by siRNA AML1/ETO gene suggesting a strong association between AML1/ETO gene and G-CSFR up-regulation. To assess the effect of G-CSF on G-CSR expressing leukemic cells, we treated the most commonly used two forms of G-CSF on various leukemic cell lines. Both forms of G-CSF significantly stimulated the cell proliferation (40-80% increment compared to control) and the differentiation of AML1/ETO+ leukemic cells. Western blot showed marked increased signals of JAK2/STAT3 after treatment of G-CSF on AML/ETO+ Kasumi-1 cell line, while there was no increased signals in AML/ETO- CTV-1 cell line. To search the malignant tumors with increased G-CSFR, we screened the expressions of G-CSFR mRNA in 32 kinds of solid tumor cell lines and % kinds of leukemic cell lines, using real-time PCR. Among 32 kinds of solid tumor cell lines, 3 cell lines [hepatoblastoma (HepG2), squamous cell carcinoma of larynx (SNU-899), and breast carcinoma cell line (MCF 10A)] expressed G-CSFR mRNA and amount of G-CSFR expression of HepG2 cell was comparable to Kasumi-1 cell lines. In summary, association of G-CSFR and AML/ETO gene is strongly suggested. Expression of G-CSFR in some tumor cells is suspected, requiring pre-screening of G-CSFR expression before treatment of G-CSF. The present study shows that therapeutic G-CSF might stimulate the proliferation and differentiation of malignant cells with G-CSFR expression (AML/ETO+ AML cell and solid tumor cell lines) and we suggest the prescreening of G-CSFR expression primary tumor cells before treatment of G-CSF. Disclosures: No relevant conflicts of interest to declare.

SNU (Seoul National University) cell lines have been established from Korean cancer patients since 1982. Of these 109 cell lines have been characterized and reported, i.e., 17 colorectal carcinoma, 12 hepatocellular carcinoma, 11 gastric carcinoma, 12 uterine cervical carcinoma, 17 B-lymphoblastoid cell lines derived from cancer patients, 5 ovarian carcinoma, 3 malignant mixed Mllerian tumor, 6 laryngeal squamous cell carcinoma, 7 renal cell carcinoma, 9 brain tumor, 6 biliary tract, and 4 pancreatic carcinoma cell lines. These SNU cell lines have been distributed to biomedical researchers domestic and worldwide through the KCLB (Korean Cell Line Bank), and have proven to be of value in various scientific research fields. The characteristics of these cell lines have been reported in over 180 international journals by our laboratory and by many other researchers from 1987. In this paper, the cellular and molecular characteristics of SNU human cancer cell lines are summarized according to their genetic and epigenetic alterations and functional analysis.

Gastric cancer is one of the most deadly cancers world wide. Although its incidence has declined in recent years, it is still the most prevalent cancer in Asian countries such as Korea and Japan.1 Germline mutations of the cell to cell adhesion molecule E-cadherin ( CDH1 ) have been reported in patients with the diffuse type of familial gastric cancer.2,3 However, the frequency of CDH1 mutations is low overall4 and the observed mutations differ between western and Asian patients.5 Truncating mutations (that is, nonsense, frameshift, and alternative splicing mutations) predominate in patients of western origin,2,3 whereas only a few missense mutations have been found in patients of Asian extraction.5,6 This suggested that CDH1 does not play a major role in gastric cancer development in Asian countries, and prompted researchers to investigate other gastric cancer causing genes. One such gene is that for the MET receptor tyrosine kinase. MET transduces motility, proliferation, and morphogenic signals of hepatocyte growth factor/scatter factor (HGF/SF) in epithelial cells.7 Similar to other receptor tyrosine kinase genes such as RET , the MET gene encodes a protein with an extracellular domain (exon 2–13), a transmembrane domain (exon 13), and a tyrosine kinase domain (exon 15–21).8,9 MET germline mutations have been reported in patients with hereditary papillary renal carcinoma (HPRC).7 Most of the MET mutations associated with HPRC or sporadic papillary renal carcinomas7 were missense mutations in the tyrosine kinase domain,10,11 and overexpression of MET has been reported in human diseases such as breast, prostate, gastric, and ovarian cancers.12,13 In the specific context of gastric cancers, a MET germline missense mutation was found in a Korean patient suffering from intestinal gastric cancer.11 The mutation, located at the juxtamembrane domain (exon 14), …

Birt-Hogg-Dube (BHD) syndrome, an inherited autosomal genodermatosis characterised by benign tumours of the hair follicle, is associated with renal neoplasia, lung cysts, and spontaneous pneumothorax.1 The novel causative gene, identified by linkage analysis in BHD families, is localised on chromosome 17p11.2.2 Protein truncating germinal mutations within a hypermutable (C)8 tract occur in patients with BHD syndrome and lead to an increased risk of kidney cancer.3 Microsatellite repeats are widely distributed throughout the genome. Owing to a defect in the DNA mismatch repair gene, a subset of tumours accumulates frequent deletion and insertion mutations in these repetitive DNA sequences.4–6 Most microsatellite instability (MSI) has so far been described in non-coding DNA within introns of intergenic regions in the genome. However, in some cancer related genes and mismatch repair genes, MSI has been identified in protein coding regions. The first target sequence identified within a coding region was a poly (A)10 nucleotide tract of the TGFBR2 gene.7 The other mutational targets of MSI have been found in repetitive sequences of IGF2R 8 and BAX 9 genes involved in the regulation of cell growth and in the promotion of apoptosis, respectively. Furthermore, frameshift mutations in repeat sequences of the DNA mismatch repair genes MSH3 and MSH6 have been reported.10 In tumours with MSI, the mechanism of tumorigenesis is believed to involve frameshift mutations of microsatellite repeats within the coding regions of genes, the inactivation of which is considered to contribute to tumorigenesis. Early reports suggested that BHD syndrome was associated with a predisposition to colon neoplasms,11–13 but Zbar et al 14 reported that colon cancer and colon polyps are not related to BHD syndrome. Recently, Khoo et al 15 reported that colorectal neoplasia is an associated feature of BHD in some families. …

Background “Biomarker-driven targeted therapy,” the practice of tailoring patients’ treatment to the expression/activity levels of disease-specific genes/proteins, remains challenging. For example, while the anti-ERBB2 monoclonal antibody, trastuzumab, was first developed using well-characterized, diverse in vitro breast cancer models (and is now a standard adjuvant therapy for ERBB2-positive breast cancer patients), trastuzumab approval for ERBB2-positive gastric cancer was largely based on preclinical studies of a single cell line, NCI-N87. Ensuing clinical trials revealed only modest patient efficacy, and many ERBB2-positive gastric cancer (GC) patients failed to respond at all (i.e., were inherently recalcitrant), or succumbed to acquired resistance. Method To assess mechanisms underlying GC insensitivity to ERBB2 therapies, we established a diverse panel of GC cells, differing in ERBB2 expression levels, for comprehensive in vitro and in vivo characterization. For higher throughput assays of ERBB2 DNA and protein levels, we compared the concordance of various laboratory quantification methods, including those of in vitro and in vivo genetic anomalies (FISH and SISH) and xenograft protein expression (Western blot vs. IHC), of both cell and xenograft (tissue-sectioned) microarrays. Results The biomarker assessment methods strongly agreed, as did correlation between RNA and protein expression. However, although ERBB2 genomic anomalies showed good in vitro vs. in vivo correlation, we observed striking differences in protein expression between cultured cells and mouse xenografts (even within the same GC cell type). Via our unique pathway analysis, we delineated a signaling network, in addition to specific pathways/biological processes, emanating from the ERBB2 signaling cascade, as a potential useful target of clinical treatment. Integrated analysis of public data from gastric tumors revealed frequent (10 – 20 %) amplification of the genes NFKBIE, PTK2, and PIK3CA, each of which resides in an ERBB2-derived subpathway network. Conclusion Our comprehensive bioinformatics analyses of highly heterogeneous cancer cells, combined with tumor “omics” profiles, can optimally characterize the expression patterns and activity of specific tumor biomarkers. Subsequent in vitro and in vivo validation, of specific disease biomarkers (using multiple methodologies), can improve prediction of patient stratification according to drug response or nonresponse. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2232-2) contains supplementary material, which is available to authorized users.