MSI-high Cancers Research Articles

Advances in the treatment of gastric cancer.

To review the recent literature regarding treatment of gastric cancer. Addition of postoperative radiation therapy to perioperative chemotherapy offers no survival benefit. Fluoropyrimidines, in particular 5-fluorouracil (5-FU), are the backbone for gastric cancer chemotherapy. S-1, an oral prodrug of 5-FU, has become the mainstay for gastric cancer chemotherapy in Japan. In a Japanese adjuvant chemotherapy trial, addition of docetaxel to standard S-1 chemotherapy improved disease-free survival; this regimen will become their new standard for adjuvant therapy. Microsatellite instability (MSI) high status is emerging as a favorable prognostic marker in resected gastric cancer and may indicate a group of patients who do not gain additional benefit from treatment with adjuvant chemotherapy. In metastatic gastric cancer, the addition of ramucirumab, an antivascular endothelial growth factor receptor 2-targeted antibody, to first-line chemotherapy did not improve survival over chemotherapy alone. Trifluridine/tipiracil treatment in chemotherapy-refractory gastric cancer improved survival compared to placebo and will emerge as a late-line therapy option. Phase II and III trials indicate activity for the immune checkpoint inhibitors pembrolizumab and nivolumab in chemotherapy-refractory gastric cancer and have led to US regulatory approval for pembrolizumab in chemotherapy-refractory programmed death ligand 1-positive or MSI-high gastric cancer, and approval in Japan for nivolumab in chemotherapy-refractory gastric cancer. However, a phase III trial in advanced gastric cancer failed to show a survival benefit for pembrolizumab over conventional paclitaxel. The poly ADP ribose polymerase inhibitor, olaparib, added to second-line paclitaxel in advanced gastric cancer failed to improve overall survival compared with paclitaxel alone. Perioperative or postoperative adjuvant chemotherapy without radiation therapy remains the standard of care in gastric cancer. Addition of docetaxel to adjuvant S-1 will likely emerge as a new care standard. Pembrolizumab and nivolumab improve survival and now are treatment options in chemotherapy-refractory gastric cancer, especially for programmed death ligand 1-positive or MSI-high cancers.

Abstract B011: Immunoediting in untreated mismatch repair deficient colorectal cancer

Abstract A subset of colorectal carcinomas (CRC) with high microsatellite instability (MSI-high) have been shown to respond to immune checkpoint blockade, while the much more common microsatellite stable (MSS) CRC do not usually respond to these immunotherapies. Most MSI-high tumors grow progressively despite a high mutational load, suggesting that the cancer may have developed means to escape from immune recognition, which is termed immunoediting. This immunoediting process includes three phases: an initial phase of nascent cancer cell elimination due to high immunogenicity, then a period of equilibrium with the immune response, finally leading to escape of the cancer cells that have developed genetic or epigenetic mechanisms allowing them to grow progressively in an immunocompetent host. It is likely that MSI-high cancers would go through similar processes to eventually escape from immune recognition. To better understand the differential immunoediting in MSI-high and MSS CRC, we combined tumor exome data from 592 cases from The Cancer Genome Atlas (TCGA) with previously published tumor exome data from 619 cases from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study to yield an unprecedented sample of 1,211 CRC molecularly characterized cases. The large number of samples, including a very large number of MSI-high cases (N = 179), gives us the power to identify the prevalence of the mechanisms of resistance discussed and thereby prioritize downstream efforts. We utilized the MutSigCV algorithm to identify significantly mutated genes in MSS and MSI-high tumors in the TCGA cohort (496 MSS and 75 MSI-high cases), and the NHS/HPFS cohorts (438 MSS and 104 MSI-high cases). We identified a total of 62 significantly mutated genes, of which 9 were identified in MSS tumors only, 40 in MSI-high tumors only, and 13 in both. Twenty-seven of the 53 significantly mutated genes in MSI-high were novel, likely resulting from a large increase in the number of MSI-high tumors relative to previous studies. We identified 13 significantly mutated genes with a documented role in the immune system, specifically in MSI-high tumors, a subtype shown previously to have a high level of T-cell infiltration; ZFP36L2 and B2M were significantly mutated in both MSS and MSI-high. B2M, HLA-A, and HLA-B are significantly mutated antigen presenting genes that were previously reported to be recurrently mutated in MSI-high. Eleven of the significantly mutated immune-related genes had roles in modulating diverse hematopoietic cell types and effects beyond antigen presentation; those genes include XYLT2, a dendritic cell trafficking gene; ZBTB20, a Toll-like receptor mediating immune response; RNF128, a regulator of IL2 and IL4 mediated T-cell maturation; KLF3, a gene involved in B-cell development; ZFP36L2, a gene involved in thymocyte development; CASP8, a gene involved in innate immunity; and CD58, a gene involved in the activation of both T lymphocytes and NK cells. Together, these mutations indicate positive selection for immune escape through other mechanisms beyond mutations in antigen-presenting machinery. Citation Format: Catherine Grasso, Marios Giannakis, Daniel Wells, David Wheeler, Eve Shinbrot, Syed Zaidi, Jeroen Huyghe, Milan Geybels, Stephen Salipante, Gabriel Abril-Rodriguez, Helena Escuin-Ordinas, Cristina Puig-Saus, Daniel Sanghoon Shin, Shuji Ogino, Antoni Ribas, Ulrike Peters. Immunoediting in untreated mismatch repair deficient colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B011.

Intestinal differentiated mucinous adenocarcinoma of the endometrium with sporadic MSI high status: a case report

BackgroundIntestinal differentiation of primary mucinous adenocarcinoma of the uterine corpus is exceedingly rare in comparison to the approximately 25% rate in endocervical and ovarian mucinous carcinoma. Additionally, little is known about the related genetic and epigenetic alterations, even though large-scale molecular characterisation of the different types of endometrial cancer took place in the TCGA project along the entities defined by the recent WHO classification.Case presentationWe present a 62-year-old patient harbouring a primary mucinous carcinoma of the uterine corpus with a morphological resemblance to mucinous colorectal adenocarcinoma. The intestinal differentiation was substantiated by CDX2 and CK20 positivity in the absence of PAX8, p16, WT1, p53, ER, PgR, AFP, SALL4 and Glypican3. A high MSI status with MLH1 hypermethylation was revealed by molecular testing.ConclusionIntestinal differentiation of mucinous adenocarcinoma of the endometrium is a unique observation. Besides morphology, it obviously can share molecular features of sporadic MSI colorectal cancers. It can be speculated that either CDX2 positive morula formation or intestinal metaplasia of the endometrium as rare conditions might be the origin of carcinogenesis for this type II endometrial cancer. Both conditions were not detectable in this case. Of note, categorising endometrial cancers in genetic subgroups like MSI high cancers alone might lead to the integration of likewise morphologically different tumours like the case presented here with intestinal differentiation. Hence, careful genotype-phenotype correlations are warranted for studies of mucinous adenocarcinoma of the endometrium.

Evaluation of microsatellite instability (MSI) status in gastrointestinal (GI) tumor samples tested with comprehensive genomic profiling (CGP).

528 Background: PD-1 inhibitor therapy (pembrolizumab) has demonstrated promising activity in MSI-H (MSI-High) colorectal cancer (CRC) and MSI-H non-CRC compared to MSS tumors, supporting MSI as predictive of anti-PD-1/L1 therapy independent of tumor histology. We developed and validated a novel computational method to assess MSI status using next generation sequencing (NGS) data generated from CGP of clinical cases. We then sought to determine the frequency of MSI in a diverse sample of clinical cases of GI tumors previously assayed with CGP (FoundationOne). Methods: To determine MSI status, 114 intronic homopolymer repeat loci (10-20bp long in the human reference genome) with adequate coverage on the CGP panel were analyzed for length variability and compiled into an overall MSI score via principal components analysis. Translation of the MSI score to MSI-H or MSS (MSI-Stable) was established using a training data set. Results: Our methodology was validated in 69 samples with MSI status (20 MSI-H, 49 MSS) previously determined by standard clinical testing, either PCR or immunohistochemistry staining. Our concordance was 97% (65/67). We then applied our method to 2545 GI cancers assayed with CGP in the course of clinical care, with small bowel carcinoma having the highest rate of MSI-H (Table). The 3.5% frequency of MSI-H in CRC is lower than expected, possibly attributed to sampling bias against MSI-H CRC in the cohort. In CRC, we discovered significant differences in mutational profile: histone methyltransferase MLL2/3 mutations were enriched in MSI-H CRC (P<0.0001, Fisher’s Exact test), while TP53mutations were enriched in MSS CRC (P<0.0001, Fisher’s). Conclusions: CGP can be used to detect MSI with high accuracy. In addition, application of this approach to the 2545 GI cancers demonstrates the use of CGP to identify differences in mutational profiles between MSI-H and MSS cancers. Broadened application of these methods to more tumor types may provide target enrichment for emerging immunotherapies. [Table: see text]

Tumor LINE-1 methylation level and microsatellite instability in relation to colorectal cancer prognosis.

Hypomethylation in long interspersed nucleotide element-1 (LINE-1) and high-degree microsatellite instability (MSI-high) in colorectal cancer (CRC) have been associated with inferior and superior survival, respectively; however, it remains uncertain whether the prognostic association of LINE-1 hypomethylation differs by MSI status. We hypothesized that the adverse prognostic association of LINE-1 hypomethylation might be stronger in MSI-high CRCs than in microsatellite stable (MSS) CRCs. Utilizing 1211 CRCs in the Nurses' Health Study and the Health Professionals Follow-up Study, we examined patient survival according to LINE-1 hypomethylation status in strata of MSI status. A Cox proportional hazards model was used to compute multivariable CRC-specific mortality hazard ratios (HRs) for a 10% decrease in LINE-1 methylation level (range = 23.1-93.1%), adjusting for potential confounders, including CpG island methylator phenotype, and KRAS, BRAF, and PIK3CA mutations. Statistical tests (log-rank test, chi-square test, and likelihood ratio test) were two-sided. In MSI-high cancers, the association of LINE-1 hypomethylation with higher mortality (HR = 2.45, 95% confidence interval [CI] = 1.64 to 3.66, P < .001) was stronger than that in MSS cancers (HR = 1.10, 95% CI = 0.98 to 1.24, P = .11) (P interaction < .001, between LINE-1 and MSI statuses). In MSI-high cases with CRC family history, the association of LINE-1 hypomethylation with higher mortality (HR = 5.13, 95% CI = 1.99 to 13.2; P < .001) was stronger than that in MSI-high cases without CRC family history (HR = 1.62, 95% CI = 0.89 to 2.94, P = .11) (P interaction = .02, between LINE-1 and CRC family history statuses). The association of LINE-1 hypomethylation with inferior survival is stronger in MSI-high CRCs than in MSS CRCs. Tumor LINE-1 methylation level may be a useful prognostic biomarker to identify aggressive carcinomas among MSI-high CRCs.

Risk factors for ovarian cancers with and without microsatellite instability.

In a population-based sample of epithelial ovarian cancers, the objective of this study was to evaluate the association between microsatellite instability (MSI) status and the following factors: (1) ovarian cancer risk factors and (2) the distribution of the specific histologic subtypes. Participants were drawn from 3 population-based studies of primary epithelial ovarian cancer; tumor DNA was analyzed using 5 standardized microsatellite markers to assess the MSI status. Patients were divided into 3 groups (MSI-high, MSI-low, and MSI-stable) according to the National Cancer Institute criteria. We compared the prevalence of specific known risk and protective factors among the 3 subgroups, including body mass index, smoking history, parity, BRCA1 and BRCA2 mutation status, past oral contraceptive use, and tubal ligation. Similarly, we compared the distribution of the histologic subtypes among the 3 subgroups. A total of 917 ovarian cancer patients were included. One hundred twenty-seven cases of cancer (13.8%) were MSI-high. Subgroup analyses according to smoking, body mass index, parity, past oral contraceptive use, and past tubal ligation did not reveal any statistically significance differences among the groups. Among the 29 patients with BRCA1 mutations, 20.7% had MSI-high cancers compared with 5.9% among 17 patients with BRCA2 mutations. The proportions of different ovarian cancer histologies among the various MSI subgroups were similar. The prevalence of risk and protective factors among ovarian cancer patients is similar for cancers with and without MSI. The distributions of MSI do not differ significantly among ovarian cancers with different histologies. Ovarian cancer patients with BRCA1 mutations had a 21% rate of MSI-high tumors compared with 6% among patients with BRCA2 mutations, but this difference was not statistically significant.

Abstract CN06-02: Insight into colorectal cancer etiology through MPE: Unmasking the links with obesity and smoking

Abstract Colorectal cancer is a leading cause of cancer morbidity and mortality worldwide. Epidemiologic studies have identified a host of genetic, lifestyle and demographic factors associated with colorectal cancer incidence, including high body mass index (BMI) and, perhaps less convincingly, cigarette smoking. Epidemiologic studies have often considered colorectal cancer as a singular disease outcome, ignoring potential disease heterogeneity; more recently, however, studies have further investigated whether risk and prognostic factors for colorectal cancer differ by tumor molecular phenotype, including microsatellite instability (MSI) status. MSI is the result of defective DNA mismatch repair capacity and it is a distinct tumor phenotype whereby short repetitive DNA sequences undergo a change in repeat length. Approximately 15% of colorectal tumors display MSI, usually the result of epigenetic modification of MLH1, a gene that encodes a mismatch repair protein, or less often, because the affected individual has a germline mutation in a DNA mismatch repair gene, consistent with Lynch syndrome. The majority of colorectal tumors develop despite having competent mismatch repair; these tumors, known as microsatellite (MS)-stable, arise through chromosomal instability and do not display marked gains or losses in MS regions. Other important molecular phenotypes for colorectal cancer include CpG island methylator phenotype (CIMP), and presence or absence of somatic mutations in the KRAS and BRAF genes. While BMI is a consistent and convincing risk factor for colorectal cancer overall (odds ratios and relative risks in the range of 1.3 to 1.5 are common for an obese BMI relative to a normal BMI), recent studies have suggested the associations are higher, or even restricted to, tumors that are MS-stable. Using the Colon Cancer Family Registry, our group showed that an obese BMI (&amp;gt;30 kg/m^2) relative to a normal BMI (BMI: 18.5-24.99 kg/m^2) was associated with an approximate 2-fold increased risk of MS-stable colorectal cancer while the association with MSI-high colorectal cancer was null. Other recent studies have shown a similar pattern, and other groups have shown that these results might be corroborated with FASN. Current work in the Colon Cancer Family Registry is seeking to address whether the prognostic (i.e., survival) benefit of MSI-high compared to MS-stable tumors further differs by level of obesity. The link between colorectal cancer and cigarette smoking has been more equivocal, with studies generally showing null associations or only modestly higher risks among smokers compared to non-smokers. Herein, tumor molecular phenotype data have been particularly revealing. Data from the Colon Cancer Family Registry showed a null association between ever smoking and colorectal cancer risk overall; however, when stratified by MSI status, risk of MSI-high cancer was about 2-fold higher among long-duration smokers relative to never smokers. Similar findings were reported in the prospective Iowa Women's Health Study where doubling in risks of MSI-high, CIMP-positive and BRAF mutation-positive colorectal cancers were reported for ever smoking while null associations were shown for tumors that lacked these molecular phenotypes. Additional work from one study center involved in the Colon Cancer Family Registry has suggested that the adverse impact of smoking on colorectal cancer survival is limited to patients diagnosed with MSI-high tumors. In addition to presenting published and unpublished results on associations of BMI and smoking with colorectal cancer incidence and survival, this presentation will also share recent experiences with collecting tumor blocks from a prospective cohort study, the American Cancer Society's Cancer Prevention Study-II. Citation Format: Peter T. Campbell. Insight into colorectal cancer etiology through MPE: Unmasking the links with obesity and smoking. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr CN06-02.

Risk Factors for Ovarian Cancers With and Without Microsatellite Instability

The objective of this study was to evaluate the association between microsatellite instability (MSI) status and (1) ovarian cancer risk factors and (2) the distribution of the specific histologic subtypes in a population-based sample of epithelial ovarian cancers. Participants were drawn from 3 population-based studies of primary epithelial ovarian cancer. Tumor DNA was analyzed using 5 standardized microsatellite markers to assess MSI status. Patients were divided into 3 groups (MSI-high, MSI-low, and MSI-stable) according to National Cancer Institute criteria. We compared the prevalence of specific known risk and protective factors among the 3 subgroups, including body mass index, smoking history, parity, BRCA1 and BRCA2 mutation status, past oral contraceptive use, and tubal ligation. Similarly, we compared the distribution of the histologic subtypes among the 3 subgroups. A total of 917 ovarian cancer patients were included. One hundred twenty-seven (13.8%) cancers were MSI-high. Subgroup analyses according to smoking, body mass index, parity, past oral contraceptive use, and past tubal ligation did not reveal any statistically significant differences among the groups. Among the 29 patients with BRCA1 mutations, 20.7% had MSI-high cancers compared with 5.9% among 17 BRCA2-mutation patients. The proportions of different ovarian cancer histologic findings among the various MSI subgroups were similar. The prevalence of risk and protective factors among ovarian cancer patients is similar for cancers with and without MSI. The distributions of MSI do not differ significantly among ovarian cancers with different histologic findings. Ovarian cancer patients with BRCA1 mutations had a 21% rate of MSI-high tumors, compared with 6% among patients with BRCA2 mutations, but this difference was not statistically significant.

Abstract B92: Molecular characterization of colorectal cancer in Ghana

Abstract Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide with significant variation between different parts of the globe. Although colorectal cancer incidence is relatively low in West Africa, the most recent publications from Nigeria and Ghana note significant increase of colorectal cancer incidence in these countries since 1970. These studies also show that colorectal cancer in West Africa has distinctive pattern with young age of onset and predominantly left-sided tumors, yet the spectrum of molecular changes in colorectal tumors has not been characterized in West African populations. The goal of this study was to investigate molecular characteristics of colorectal cancer in Ghana. We retrieved 90 formalin-fixed paraffin embedded (FFPE) colorectal cancer blocks from the University of Ghana Medical School (Accra) diagnosed between 1997 and 2007. Ten 5 μm recuts and H&amp;E slide were prepared for each block and reviewed by the pathologist to determine areas of at least 70% tumor cellularity and areas of adjacent normal tissue. DNA was extracted from the microdissected tumor and normal tissue. Only 71 samples had both tumor and normal tissue within the available specimen. Ten microsatellite marker loci (D10S197, BAT26, beta-catenin, D18S58, BAT40, D2S123, D17S250, BAT25, TGF-b-RIIF, and D5S346F) were used for microsatellite instability (MSI) testing using fluorescently labeled primers and fragment analysis. Tumors with at least one mononucleotide marker and a minimum of three available markers were considered for analysis. The tumors with instability in at least 30% of markers were called MSI-High, less than 30% classified as MSI-Low, and tumors with all stable markers were called microsatellite stable (MSS). Sequencing BRAF and KRAS was repeated twice from both directions and analyzed by two independent readers using Sequencher from GeneCodes (Ann Arbor, MI) and Mutation Surveyor from SoftGenetics (State College, PA) to avoid misinterpretation. Out of 71 colorectal cancer pairs of normal and tumor tissue, MSI testing was informative for 70 pairs. An exceptionally large proportion of cancers were MSI-High (29/70, 41.4%), with 14/70 (20%) MSI-Low tumors, and 27/70 (38.6%) MSS tumors. Sequencing of exons 1 and 2 of KRAS in 75 tumors detected 24 (32%) activating mutations (G12D, G12V, G12C, G12S, G13D, Q61R, and Q61K). Surprisingly, the sequencing of exon 15 of BRAF, the location of frequent activating mutation (V600E), did not show any mutations at codons 599 and 600 in 88 tumor samples. Our study showed a very high frequency of MSI-high colorectal tumors (41.4%), consistent with the higher rates of MSI-High cancers observed in some studies of colorectal cancer in African American patients. The frequency of KRAS mutations is comparable to one found in African Americans, but absence of BRAF mutations is intriguing and requires further analysis of the epidemiology and biology of colorectal cancer in West Africa. Citation Format: Leon Raskin, Jonathan C.B. Dakubo, Nicole Palaski, Joel Greenson, Stephen Gruber. Molecular characterization of colorectal cancer in Ghana. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B92.

Genetic variation in the retinoid X receptor and calcium-sensing receptor and risk of colorectal cancer in the Colon Cancer Family Registry.

Genetic variants in the calcium/vitamin D metabolic pathway may be related to risk for colorectal cancer. While several investigations of vitamin D receptor (VDR) polymorphisms and colorectal cancer have been conducted, no studies to date have evaluated the association of genetic variation in the heterodimer partner for VDR, the retinoid X receptor (RXR). Another important gene in this pathway is the calcium-sensing receptor (CASR). Employing a discordant-sibship case-control design, we examined the association between single nucleotide polymorphisms (SNPs) in RXRA and CASR and risk for colorectal cancer overall and by colorectal subsite and microsatellite instability (MSI) status using data from the Colon Cancer Family Registry. No gene-level relationships between RXRA or CASR and colorectal cancer overall were observed. However, for RXRA SNP rs7861779, a high-interest SNP selected for study a priori, there was a statistically significantly increased risk for proximal colorectal cancer among those with at least one A allele [odds ratio (OR) = 1.42; 95% confidence interval (CI) = 1.03-1.97]. Another selected RXRA SNP, rs12004589, was significantly associated with risk of MSI-high cancers (OR = 2.27; 95% CI = 1.13-4.56). Additionally, CASR SNP rs1801726 was significantly associated with a reduced risk for rectal cancer (OR = 0.53; 95% CI = 0.29-0.96). These results provide support that RXRA SNPs rs7861779 and rs12004589 and CASR SNP rs1801726 may be important markers for colorectal neoplasia. Further work is needed to elucidate their role in the carcinogenic pathway.

Fas ligand and tumour counter-attack in colorectal cancer stratified according to microsatellite instability status.

Expression of membrane-bound Fas ligand (FasL) by colorectal cancer cells may allow the development of an immune-privileged site by eliminating incoming tumour-infiltrating lymphocytes (TILs) in a Fas-mediated counter-attack. Sporadic colorectal cancer can be subdivided into three groups based on the level of DNA microsatellite instability (MSI). High-level MSI (MSI-High) is characterized by the presence of TILs and a favourable prognosis, while microsatellite-stable (MSS) cancers are TIL-deficient and low-level MSI (MSI-Low) is associated with an intermediate TIL density. The purpose of this study was to establish the relationship between MSI status and FasL expression in primary colorectal adenocarcinoma. Using immunohistochemistry and a selected series of 101 cancers previously classified as 31 MSI-High, 30 MSI-Low, and 40 MSS, the present study sought to confirm the hypothesis that increased TIL density in MSI-High cancers is associated with low or absent membrane-bound FasL expression, while increased FasL in MSS cancers allows the killing of host TILs. TUNEL/CD3 double staining was also used to determine whether MSS cancers contain higher numbers of apoptotic TILs in vivo than MSI-High or MSI-Low cancers. Contrary to the initial hypothesis, it was found that MSI-High cancers were associated with higher FasL expression (p = 0.04) and a stronger intensity of FasL staining (p = 0.007). In addition, mucinous carcinomas were independently characterized by increased FasL expression (p = 0.03) and staining intensity (p = 0.0005). Higher FasL expression and staining intensity did not correlate with reduced TIL density or increased numbers of apoptotic TILs. However, consistent with the hypothesis that curtailment of the host anti-tumour immune response contributes to the poor prognosis in MSS cancers, it was found that apoptotic TILs were most abundant in MSS carcinomas and metastatic Dukes' stage C or D tumours (p = 0.004; p = 0.046 respectively). This study therefore suggests that MSS colorectal cancers are killing incoming TILs in an effective tumour counter-attack, but apparently not via membrane-bound FasL.

RIZ, the retinoblastoma protein interacting zinc finger gene, is mutated in genetically unstable cancers of the pancreas, stomach, and colorectum

The retinoblastoma protein interacting zinc finger (RIZ) gene is a candidate tumor suppressor gene on 1p36, a region frequently rearranged in a wide variety of human tumors. As the RIZ gene harbors several microsatellites within its coding region, it is a candidate for an inactivating mutation in microsatellite instability (MSI) mediated carcinogenesis. In this study, we examined mutations of two poly adenine tracts, A8 and A9, within the coding region of the RIZ gene, in MSI-high (MSI-H) primary cancers occurring in the pancreas, stomach, and colorectum. Frameshift mutations were found in one (10%) of 10 pancreatic, four (36%) of 11 gastric, and two (25%) of eight colorectal cancers. These results indicate that mutations of the RIZ gene play an important role in the pathogenesis of some MSI-H cancers. © 2000 Wiley-Liss, Inc.

RIZ, the retinoblastoma protein interacting zinc finger gene, is mutated in genetically unstable cancers of the pancreas, stomach, and colorectum

The retinoblastoma protein interacting zinc finger (RIZ) gene is a candidate tumor suppressor gene on 1p36, a region frequently rearranged in a wide variety of human tumors. As the RIZ gene harbors several microsatellites within its coding region, it is a candidate for an inactivating mutation in microsatellite instability (MSI) mediated carcinogenesis. In this study, we examined mutations of two poly adenine tracts, A(8) and A(9), within the coding region of the RIZ gene, in MSI-high (MSI-H) primary cancers occurring in the pancreas, stomach, and colorectum. Frameshift mutations were found in one (10%) of 10 pancreatic, four (36%) of 11 gastric, and two (25%) of eight colorectal cancers. These results indicate that mutations of the RIZ gene play an important role in the pathogenesis of some MSI-H cancers.