Microsatellite instability and aneuploidy rate in young colorectal-cancer patients do not differ significantly from those in older patients

DNA and chromosomal instabilities are thought to promote colorectal carcinogenesis. Mismatch repair (MMR) deficiency affects DNA-sequence integrity, resulting in microsatellite instability (MI). Tumor aneuploidy (AN) has been shown to reflect underlying chromosomal instability (CI). This study aimed at assessing the MI and AN rate of Singapore's colorectal-cancer (CRC) patients, who are predominantly Chinese, in association with age group, tumor site, Dukes' staging and gender. In contrast to a Caucasian series, the MI rate for our younger patients aged 40 or less without family history (23%) is not significantly different from that for older, sporadic patients (13%) aged 60 or more, suggesting that population screening for germline MMR mutations is unlikely to be cost-effective. Our MI-positive patients also show no significant differences from the MI-negative patients with respect to tumor site, staging, ploidy status and gender. This implies that the local MI-positive individuals may have a different profile from that of the Caucasians, indicating the possibility of underlying genetic differences. AN is also not significantly more prevalent in younger patients. In addition, a significant 21% of our patients (p < 0.00005) show no evidence of either the MI or CI pathways, implying that there is at least a third pathway driving colorectal carcinogenesis, involving neither genes that maintain DNA sequence stability nor genes that cause gross chromosomal segregation defects.     

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

Germline anomalies of the INK4a-ARF and Cdk4 genes were sought in a series of 89 patients suspected of having a genetic predisposition to melanoma. Patients were selected based on the following criteria: (a) familial melanoma (23 cases), (b) multiple primary melanoma (MPM; 18 cases), (c) melanoma and additional unrelated cancers (13 cases), (d) age at diagnosis less than 25 years (21 cases), and (e) nonphoto-induced melanoma (NPIM; 14 cases). Mutations of INK4a-ARF and Cdk4 were characterised by automated sequencing, and germline deletions of INK4a-ARF were also examined by real-time quantitative PCR. Seven germline changes of INK4a-ARF, five of which were novel, were found in seven patients (8%). Four were very likely to be pathogenic mutations and were found in three high-risk melanoma families and in a patient who had a pancreatic carcinoma in addition to melanoma. Three variants of uncertain significance were detected in one MPM patient, one patient <25 years, and one NPIM patient. No germline deletion of INK4a-ARF was found in 71 patients, and no Cdk4 mutation was observed in the 89 patients. This study confirms that INK4a-ARF mutations are infrequent outside stringent familial criteria, and that germline INK4a-ARF deletions are rarely involved in genetic predisposition to melanoma.     

Microsatellite instability in patients with gastric remnant cancer

Background. About 2% of patients who undergo partial distal gastrectomy for gastroduodenal diseases develop gastric remnant cancer 10 to 30 years after the gastrectomy. It is important in clinical practice to determine a molecular marker to identify patients susceptible to gastric remnant cancer. Methods. We investigated nine gastric remnant cancers (from nine individuals who had gastrectomies for primary gastric cancer or gastroduodenal ulcer) for microsatellite instability (MSI) at six loci, using the polymerase chain reaction (PCR). A control group of ten patients with sporadic gastric cancers in the upper third of the stomach was also similarly analyzed. Results. MSI was demonstrated in eight of nine cancers from the individuals who had had primary gastric cancer or gastroduodenal ulcer (88.9%) compared with two of ten cancers from the individuals with sporadic gastric cancer in the upper third of the stomach (20%). Conclusion. These results suggest that one or more MSI is associated with remnant gastric cancer after gastrectomy. Received on Sept. 6, 1999; accepted on Dec. 20, 1999     

Microsatellite instability in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a relatively common disease, affecting mainly males in the western world. Although substantial data are available as regards the clinicopathological characterization of COPD, little is known of the molecular basis of the disease. In the present study we analysed the incidence of microsatellite instability (MI) in cytological specimens from patients with COPD. MI reflects increased mutational rate and is associated with decreased accuracy in the DNA repair, resulting in the accumulation of somatic mutations in cells manifesting this genetic alteration. Among 31 specimens tested, 7 (23%) exhibited MI in at least one among 6 microsatellite markers tested. 5 cases were affected in only one marker while the remaining two cases exhibited evidence of MI in two microsatellite markers. These data suggest that an elevated mutational rate as reflected by the increased incidence of MI is associated with the development of the disease.     

Microsatellite instability in patients with chronic B-cell lymphocytic leukaemia

The purpose of our study was to evaluate the microsatellite instability (MSI) at selected loci with known involvement in the oncogenesis of chronic B-cell lymphocytic leukaemia (B-CLL). DNA from B cells (tumour cells) and from T cells (normal controls) of 27 samples of 26 patients with previously untreated B-CLL was extracted. Microsatellite instability in six microsatellite markers was tested using GeneScan Analysis Software. The rate of replication errors positive phenotype (RER+) was determined (MSI in more than 30% of examined loci). RER+ was found in four out of 27 patients (14.8%). A larger proportion of patients with stage C B-CLL exhibited RER+ than those with stage A or B (P < 0.05). A higher prevalence of RER+ was demonstrated in a subgroup of patients with additional malignancies (three out of eight patients) in comparison with patients with B-CLL alone (1/19) (P = 0.031). In conclusion, our study demonstrated that MSI might have a more prominent role in pathogenesis of B-CLL than reported to date. This may result from a selection of microsatellite markers adjacent to chromosomal loci, which are involved in B-cell malignancies, and using GeneScan Analysis Software, which is most modern and precise method of microsatellite analysis.     

Microsatellite instability testing in Korean patients with colorectal cancer

Microsatellite instability (MSI) testing is useful for identifying patients with hereditary nonpolyposis colorectal cancer and detecting sporadic colorectal cancer that develops through replication error pathways. A pentaplex panel is recommended by the National Cancer Institute for MSI testing, but simplified mononucleotide panels and immunohistochemistry of mismatch repair proteins are widely employed for convenience. This study was to evaluate the MSI status of colorectal cancer in Korean patients. This study included 1,435 patients with colorectal adenocarcinoma subjected to surgical resection. The pentaplex Bethesda panel was used for MSI testing. Seventy nine (5.5?%) carcinomas were classified as MSI-high (MSI-H) and 95 (6.6?%) as MSI-low (MSI-L). BAT-26 and BAT-25 were unstable in 73 and 75 of 79 MSI-H carcinomas, respectively. With the panel comprising these 2 mononucleotide markers, 72 carcinomas were diagnosed as MSI-H, compared to the Bethesda panel data (72/79, 91.1?%). In contrast, BAT-26 or BAT-25 were unstable in only 7 (7.4?%) of the 95 MSI-L tumors. In the panel with 2 dinucleotide markers, D17250 linked to p53 and D2S123 to hMSH2, detection rates were 89.9?% (71/79) for MSI-H and 80.0?% (76/95) for MSI-L carcinomas, compared to the Bethesda panel. Moreover, we compared the frequency of MSI tumor in our patients with those reported previously from Western countries. In conclusion, the frequency of MSI-H appears lower in colorectal cancer patients in Korea. A simplified panel for MSI testing with BAT-26 and BAT-25 seems not effective for the accurate evaluation of MSI status, particularly in MSI-L colorectal carcinomas, in our patients.     

Microsatellite instability in sporadic-colon-cancer patients with and without liver metastases

Microsatellite instability (MSI) is intrinsic to most colorectal carcinomas (CRC) from patients with hereditary non-polyposis colorectal cancer (HNPCC), reflecting germline mutations in the mismatch-repair (MMR) genes. Its occurrence and chronological sequence of development in sporadic CRC appears less well defined. To explore the time sequence in acquisition of MSI, and the role it plays during tumor progression in sporadic CRC, we compared the incidence of MSI in tissue samples from 40 Dukes'-B and 30 Dukes'-D CRC patients with liver metastases, at 4 different microsatellite loci, representing sites on the APC, DCC and p53 genes respectively as well as the D2S123 site. Among the 30 patients with hepatic metastases, MSI was found in 9 (30%) of the primary, and 13 (43.3%) of the metastatic tumors. In comparison, among the 40 Dukes'-B CRC, MSI was found in only 8 cases (20%). CRC with MSI were more frequently located in the right colon, less frequently on the left side, and seldom in the rectum. Tumor ploidy analysis shows that 46.2% of Dukes'-D primary tumors with MSI are diploid (χ² = 4.46, p = 0.035). With a mean follow-up time of 4.2 years for the Dukes'-B CRC, there were no recurrences in the 8 patients with MSI, whilst 6 (18.8%) relapses occurred amongst the 32 patients without MSI, average time to recurrence being 15 months. In Dukes'-D CRC, mean survival time for patients with MSI was 37 months (95% CI, 24 to 51 months), for those without MSI 26 months (95% CI, 18 to 35 months), although this was not statistically significant. Our data suggest that tumor progression may involve increased genetic instability. Int. J. Cancer 74:470–474, 1997. © 1997 Wiley-Liss, Inc.     

Local-regional control in breast cancer patients with a possible genetic predisposition

PURPOSE: Local control rates for breast cancer in genetically predisposed women are poorly defined. Because such a small percentage of breast cancer patients have proven germline mutations, surrogates, such as a family history for breast cancer, have been used to examine this issue. The purpose of this study was to evaluate local-regional control following breast conservation therapy (BCT) in patients with bilateral breast cancer and a breast cancer family history. METHODS AND MATERIALS: We retrospectively reviewed records of all 58 patients with bilateral breast cancer and a breast cancer family history treated in our institution between 1959 and 1998. The primary surgical treatment was a breast-conserving procedure in 55 of the 116 breast cancer cases and a mastectomy in 61. The median follow-up was 68 months for the BCT patients and 57 months for the mastectomy-treated patients. RESULTS: Eight local-regional recurrences occurred in the 55 cases treated with BCT, resulting in 5- and 10-year actuarial local-regional control rates of 86% and 76%, respectively. In the nine cases that did not receive radiation as a component of their BCT, four developed local-regional recurrences (5- and 10-year local-regional control rates of BCT without radiation: 49% and 49%). The 5- and 10-year actuarial local-regional control rates for the 46 cases treated with BCT and radiation were 94% and 83%, respectively. In these cases, there were two late local recurrences, developing at 8 years and 9 years, respectively. A log rank comparison of radiation versus no radiation actuarial data was significant at p = 0.009. In the cases treated with BCT, a multivariate analysis of radiation use, patient age, degree of family history, margin status, and stage revealed that only the use of radiation was associated with improved local control (Cox regression analysis p = 0.021). The 10-year actuarial rates of local-regional control following mastectomy with and without radiation were 91% and 89%, respectively. CONCLUSIONS: Patients with a possible genetic predisposition to breast cancer had low 5-year rates of local recurrence when treated with breast conserving surgery and radiation, but the local failure rate exceeded 50% when radiation was omitted. Our data are consistent with the hypothesis that patients with an underlying genetic predisposition develop cancers with radiosensitive phenotypes.     

A deficiency in chromatin repair, genetic instability, and predisposition to cancer

This review traces steps leading to malignant neoplastic transformation of rodent and human cells in culture and in vivo. Emphasis is placed on an abnormal response characterized by persistent chromatid damage following irradiation of cells in culture with X-rays or fluorescent light during G2 phase of the cell cycle. Evidence is presented that deficient or unbalanced DNA repair during G2 accounts for the abnormal response. This G2 repair deficiency can be inherited or acquired by normal tissue cells during the process of or following attainment of infinite lifespan. It appears as an early, possibly initiating step in neoplastic transformation. It characterizes all human tumor cells examined irrespective of histopathology or tissue of origin. It has a genetic basis. In an animal model, the BALB/c mouse, this phenotype is associated with genes on chromosomes 1 and 4. It characterizes skin fibroblasts and blood lymphocytes from individuals with genetic or familial conditions predisposing to cancer and can be used to identify clinically normal family members carrying a gene(s) for any one of the three cancer-prone genetic disorders studied to date. Furthermore, it can provide the basis of a test for carriers of genes predisposing to a high risk of cancer. We conclude that the G2 repair deficiency, whether inherited or acquired, is a prerequisite for cancer development and that it accounts for the genetic instability of the cancer cell.     

Microsatellite DNA instability in nasal cytology of COPD patients

Genetic alterations in the microsatellite DNA level have been successfully detected in sputum samples of patients with COPD and have been shown to be disease specific. Furthermore, previous studies have shown that inflammation coexists in the nasal mucosa of patients with COPD. The aim of this study was to assess the presence of MSI in nasal cytological samples of patients with COPD comparing the results with sputum samples of the same individuals. Nasal brush samples, sputum samples obtained by induction, and peripheral blood from 20 patients with COPD were analyzed. DNA was extracted and analyzed for MSI using the following microsatellite markers: RH70958, D5S207, D6S344, D6S263, G29802, D13S71, D14S588, D14S292 and D17S250. Microsatellite analysis was also performed in 8 healthy non-smokers. MSI was detected in the sputum samples of 7 patients with COPD (35%). In contrast, no microsatellite DNA instability was noted in the nasal cytological samples of the same COPD patients. In addition, no genetic alteration was detected in the control group. These results suggest that MSI is a specific finding for the target organ of COPD, i.e. the lungs, despite the fact that inflammation coexists in the nasal mucosa of COPD patients. Our study supports the hypothesis that MSI could be an index of the somatic-acquired genetic alterations in the lungs of COPD patients.     

Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan

BackgroundInherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated.Patients and methodsWe conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT.ResultsAmong the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands.ConclusionsOur study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.     

Correlation between tps and cea in patients with colorectal-cancer

Serum TPS and CEA levels were measured in 173 cancer patients with various disease stages. The patients were divided into 4 groups: preoperative group, 16 patients in whom TPS and CEA were measured pre- and postoperatively; group I, 66 newly diagnosed patients up to 40 days post surgery; group II, 86 patients whose blood was taken 40-365 days post surgery, and group III, 47 patients on long-term follow-up in whom blood was taken more than one year after surgery. The median preoperative TPS levels were significantly higher (p<0.01) than the postoperative levels. Patients with Dukes' D had significantly higher TPS (p<0.01) and CEA levels as compared to patients with Dukes' B or C. For both Dukes' B and C stages there was a significant increase in median TPS level between group I and II and III. There was no similar increase in median CEA level. Serial measurements in individual patients show a significant increase in TPS levels between groups I, II and III. In Dukes' D patients, individual TPS levels decreased in response to therapy. There was a significant correlation between TPS and CEA levels. These results suggest that TPS measurement is additive to CEA in follow-up of asymptomatic patients, and to monitor response to therapy in patients with metastatic disease.     

结直肠癌的微卫星不稳定与染色体不稳定

结直肠癌中存在微卫星不稳定（MSI）和染色体不稳定（CIN）。微卫星不稳定指微卫星序列中重复单位的获得或丢失，多由于DNA错配修复系统改变所致。染色体不稳定包括整条染色体的获得或缺失，染色体易位、重排等，结直肠癌中常见有1p和8p的删除、17p和18q的杂合性缺失以及20q的扩增。两种类型的结直肠癌具有不同的临床病理特征，在基因表达、疗效和预后等方面的差异性有待进一步研究。     

Microsatellite instability in esophageal adenocarcinoma

The frequency of microsatellite instability (MSI), a result of defective mismatch repair during DNA replication, has been reported inconsistently in primary esophageal adenocarcinoma (EADC). Using a panel of 15 markers, the primary aim of this study was to analyze the frequency of MSI in a well-characterized series of 27 primary EADCs, defined according to strict clinicopathologic criteria. Polymerase chain reaction was used to amplify the following microsatellite repeat loci: D2S123, D10S197, D2S119, D11S904, D2S147, D3S1764, D7S1830, D7S1805, D2S434, D9S299, BAT25, BAT26, D5S346, D17S250, and TGF-beta-RII. Tumors were classified as microsatellite-stable (MSS) when no alterations were seen in tumor DNA compared to matched normal tissues, low-level MSI (MSI-L) when 1-5 of 15 markers were altered, and high-level MSI (MSI-H) when more than five markers were altered. Using these stringent criteria, 9/27 (33%) tumors were MSS, 18/27 (67%) tumors were MSI-L, and no tumor was MSI-H. Immunohistochemistry demonstrated cell nuclear expression of DNA mismatch repair proteins (both hMLH1 and hMSH2) in 78% (21/27) of tumors. No associations were seen between MSI and immunohistochemical expression of hMLH1, hMSH2, alterations in p53 or MBD4, tumor grade, pathologic stage, or patient survival. In conclusion, the finding of low levels of MSI in most tumors suggests an inherent baseline genomic instability, and potentially increased susceptibility to mutations during the progression of esophageal adenocarcinoma.     

Microsatellite instability in colorectal cancer

Approximately 20 percent of right-sided colon cancers and 5 percent of left-sided colon and rectal cancers have a deficient DNA mismatch repair system. This results in the widespread accumulation of mutations to nucleotide repeats, some of which occur within the coding regions of cancer-related genes such as TGFβRII and BAX. A standardized definition for microsatellite instability (MSI) based on the presence of deletions to mononucleotide repeats is gaining widespread acceptance in both research and the clinic. Colorectal cancer (CRC) with MSI are characterized histologically by an abundance of tumor-infiltrating lymphocytes, poor differentiation and a signet ring or mucinous phenotype. In younger patients these tumors usually develop along the chromosomal instability pathway, in which case the mismatch repair genes are inactivated by germline mutation, somatic mutation and loss of heterozygosity. In older patients MSI CRC usually develops against a background of widespread hypermethylation that includes methylation-induced silencing of the mismatch repair gene MLH1. The overall biological and clinical phenotype of MSI CRC that arise in these two pathways is likely to be different and may account for some of the discordant results reported in the literature relating to the clinical properties of these tumors. The available evidence indicates that MSI is unlikely to be a clinically useful marker for the prognostic stratification of early-stage CRC. The predictive value of MSI for response to 5-fluorouracil-based chemotherapy remains controversial, while for other agents the predictive value is difficult to assess because they are used in combination regimens. The MSI phenotype is being actively investigated for novel therapeutic approaches based on the principle of synthetic lethality. Finally, the MSI status of CRC is an extremely useful marker for population-based screening programs that aim to identify individuals and families with the hereditary cancer condition known as Lynch syndrome.     

Microsatellite instability in oral cancer

Generalized genomic instability, detected as somatic changes in allele sizes at microsatellite loci in tumors compared to peripheral lymphocyte DNA, is a recently recognized mechanism of mutation in cancer. Such instability results from the Somatic loss of DNA mismatch repair capability. Germ-line mutations at DNA mismatch repair loci confer susceptibility to colon cancer in hereditary non-polyposis colorectal cancer. Somatic loss of DNA mismatch repair has been reported in a large variety of other tumor types. Our goal was to determine the frequency of microsatellite instability in a large series of oral tumors. Out of 91 tumors analyzed for microsatellite instability, 6 (7%) showed microsatellite instability. Instability was observed at multiple loci with a range of 50-74% of loci affected. Alterations include both increase (74%) and decrease (26%) in allele sizes. The proportion of alleles affected ranged from 30-58% of all alleles. Our data suggest that somatic genomic instability plays a role in the pathogenesis of a small subset of oral tumors. © 1995 Wiley-Liss, Inc.     

Microsatellite instability in hematological malignancies

The replication error (RER+) phenotype, characterized by microsatellite instability (MSI) has been recently related to mutations of genes involved in DNA mismatch repair pathway. These genetic alterations were first described in hereditary non polyposis colorectal cancer (HNPCC). We examined 44 patients with hematological malignancies (27 AML, 9 MDS, 2 CML-BP and 6 T-ALL) for evidence of MSI. Twenty seven percent of our patients showed differences for only one marker. In four cases (9.1%) MSI was observed in multiple markers and these cases were described as RER+ phenotype. Presented data suggest that this phenomenon may play a role in at least a subset of patients with hematological malignancies.     

Microsatellite instability in sacral chordoma

BACKGROUND AND OBJECTIVES: Microsatellite instability (MIN) is an indirect marker of globally defective DNA mismatch repair in the neoplastic cells of cancer patients. Chordomas are rare, primary skeletal malignancies for which few characteristic molecular genetic markers have been identified. Is MIN demonstratable in chordoma? METHODS: We evaluated sacral chordomas from 12 patients with sacral chordomas for the presence of MIN at 9 different genetic loci from chromosomes 1p, 5q, 7q, 9p, 11p, 12p, 13q, 17p, and 18q. Cells were scraped from glass slides so that tumor and control DNA could be isolated and then amplified by polymerase chain reaction (PCR). Heterozygosity indices were >/= 0.70. RESULTS: Six patients (50%) demonstrated MIN for at least 1 locus, and 2 patients demonstrated loss of heterozygosity (LOH) for at least 1 locus. Only 1 individual's chordoma manifested microsatellite instability (MIN) and loss of heterozygosity (LOH). Another patient manifested no MIN but LOH at 9p and 18q. Interestingly, this individual had the most aggressive clinical cancer course, presenting with lymph node metastasis and succumbing to widespread metastatic disease. CONCLUSIONS: Chordomas can be added to the list of malignancies demonstrating MIN. LOH may prove to portend a worse prognosis than MIN when more tumors are examined.     

Microsatellite instability in colorectal cancer

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the world. In 75% CRC develops sporadically, in 25% hereditary or as a consequence of inflammatory bowel disease. CRC carcinogenesis develops over many years. The cause of CRC in 85% is chromosomal instability (CIN) and in 15% microsatellite instability (MSI-H), where hereditary nonpolyposis colorectal cancer (HNPCC) represents 10-20%. Microsatellite sequences (MS) are repeated sequences of short stretches of DNA all over the genome. Microsatellite stability (MSS) means MS are the same in each cell of an individual, whereas microsatellite instability (MSI-H) means MS differ in normal and cancer cells of an individual. The cause of MSI-H is a damaged mismatch repair mechanism (MMR), with the most important MMR proteins being MSH2, MLH1 and MSH6. CONCLUSIONS: MSI-H seems to be an important prognostic factor in CRC and an important predictive factor of CRC chemotherapeutic treatment efficacy. Clinical trials conducted until now have shown contradictory findings in different chemotherapeutic settings, adjuvant and palliative; therefore MSI-H is going to be the object of the future research. The future of cancer treatment is in the individualized therapy based on molecular characteristics of the tumour, such as MSI-H in CRC.