Microsatellite instability and mutation analysis of candidate genes in urothelial cell carcinomas of upper urinary tract

A subset of upper urinary tract urothelial cell carcinomas (UUC), arising sporadically or as a manifestation of hereditary non-polyposis colorectal cancer, displays microsatellite instability (MSI). MSI tumours are characterized by defective mismatch repair and accumulation of frameshift mutations in numerous genes harbouring repeats in their coding sequences. We have evaluated the incidence of MSI in UUC and the intratumoral distribution of mutations in 13 candidate target genes. A total of 58 unselected UUC were screened for MSI using the panel of five mononucleotide markers recently recommended by the National Cancer Institute for a precise MSI assessment. Four tumours displayed MSI (7%), among which at least three had alterations in the genes MSH3, BAX, MRE11, RAD50. Mutations in genes involved in key cellular pathways (ATR, DNA-PKcs, MBD4, TCF-4, MSH6, and BLM) were further detected. BAX and MRE11 mutations tend to present homogeneously within the three MSI UUC. Immunohistochemistry (MLH1, MSH2, MSH6) showed that loss of mismatch repair protein expression occurred in all MSI UUC defining the gene defect and that MRE11 and RAD50 mutations were associated with their concomitant loss expression. In conclusion, MSI UUC represent a small proportion of UUC in which BAX and MRE11 mutations are frequent and may play a role early in UUC tumorigenesis.     

Microsatellite instability and MBD4 mutation in unselected colorectal cancer

BACKGROUND: We investigated the prognostic significance of microsatellite instability (MSI) and the association with clinicopathological factors in colorectal cancer, and further identified MBD4 mutations and their clinicopathological significance. PATIENTS AND METHODS: MSI was analyzed in 201 colorectal cancers. Sequencing analysis of MBD4 was performed in 26 MSI and 28 microsatellite stable (MSS) tumors. RESULTS: Twenty-seven tumors (13.4%) were MSI but did not correlate with improved survival. MSI was significantly correlated with proximal colon tumors (p < 0.001), poor differentiation or mucinous type (p = 0.005) and multiple tumors (p = 0.04). MBD4 mutations were found in 15% MSI but not in MSS tumors. The mutated cases showed female overrepresentation, proximal site and poorly-differentiated/mucinous type. CONCLUSION: MSI was not correlated with survival, but shared other features associated with MSI in colorectal cancer as demonstrated by others. The clinicopathological variables associated with the MBD4 mutations were probably the reflection of MSI features.     

Microsatellite instability in cervical and endometrial carcinomas

Microsatellite instability has been found preferentially in tumours associated with the hereditary non-polyposis-colorectal-cancer (HNPCC) syndrome. This phenotype, manifested as new alleles at microsatellite loci, and often the result of a defective mismatch-repair gene, is seen as allelic mobility shifts during electrophoretic runs. We examined possible alterations at 8 dinucleotide loci mapping to 6 different chromosomes in endometrial cancers (n = 20) and cervical cancers (n = 82). Overall instability was found in 30% of the endometrial cancers and in 6% of the cervical cancers, including 3 (15%) and 2 (2%) tumours, respectively, unstable at more than one locus. In contrast to the endometrial cancer sub-group, the affected cervical cancers were characterized by one or two new alleles at one or few loci. By DNA ploidy measurements 5 diploid endometrial cancers were microsatellite-unstable vs. one diploid of 6 unaltered cases (p = 0.015; Fisher's exact test). Our data confirm that a sub-set of diploid sporadic endometrial cancers are characterized by a mutator phenotype similar to that found in colorectal cancer. In contrast, among cervical cancers, not characterized by the HNPCC-tumour spectrum, this mutator phenotype is seen infrequently, and positive cases appear to display only minor alterations. Int. J. Cancer 70:499–501. © 1997 Wiley-Liss Inc.     

Microsatellite instability at a tetranucleotide repeat in type I endometrial carcinoma

Background

The paper reports the electric, magnetic and electromagnetic fields (emf) measurements carried out in the Regina Elena National Cancer Institute (NCI). Several devices, used in diagnostics and in medical cures, can represent sources of emf for the workers and for the public subjected to the treatments. The aim is to evaluate their exposition, in order to assess the compliance with the law.

Methods

The investigations have been carried out in the departments of: intensive care, physiotherapy, MR presstherapy and in the surgical rooms. The measurements have been performed using broad band probes in the frequency ranges 5 Hz÷30 kHz and 100 kHz-3 GHz.

Results

The variability of the magnetic induction (B(μT)) levels is between 0,05 μT and 80 μT. The statistical distribution shows that most of the measurements are in the range 0,05<B = 0,5 μT and the 89% of the B(μT) levels are within the 3 μT.

Conclusion

The measurement of the emf levels in the NCI is recommended because of the presence of the oncological patients; their long stay near the equipments and their day-long exposure represent additional risk factors for which a prudent avoidance strategy have to de adopted.     

Microsatellite instability and hMLH1/hMSH2 expression in young endometrial carcinoma patients: associations with family history and histopathology

Endometrial cancer is the second most common malignancy in patients with hereditary nonpolyposis colorectal cancer (HNPCC). The age at diagnosis of HNPCC-associated endometrial cancer is approximately 15 years younger than for sporadic endometrial cancer. Our current study was undertaken to determine the frequency of microsatellite instability (MSI) and absence of hMLH1 or hMSH2 protein expression in young patients with endometrial carcinoma and to correlate these findings with histopathologic and clinical features. Endometrial carcinoma from 62 women (23-52 years, median age 46) were assessed for MSI. Twenty-one of the 62 (34%) tumors demonstrated MSI. Of the 21 tumors demonstrating MSI, 12 showed an absence of hMLH1 expression, 4 showed an absence of hMSH2 expression, and 5 demonstrated normal expression of both proteins. All 41 tumors without MSI demonstrated normal hMLH1 and hMSH2 expression. Two patients with MSI tumors fulfilled the Amsterdam criteria for HNPCC, while 2 had histories suggestive of HNPCC. None of the patients with tumors without MSI had a personal or family cancer history suggestive of HNPCC. The MSI phenotype was associated (p < 0.05) with high FIGO stage and grade, cribriform growth pattern, mucinous differentiation and necrosis. Our findings suggest that the frequency of HNPCC in young endometrial cancer patients is relatively low when compared with the frequency of HNPCC in young colorectal cancer patients. Defects of the MMR proteins hMSH2 or hMLH1 account for MSI in most but not all endometrial cancers from young patients.     

Microsatellite instability and expression of mismatch repair genes in sporadic endometrial cancer coexisting with colorectal or breast cancer

The molecular background of sporadic endometrial cancer coexisting with colorectal or breast cancer is not clear. We investigated microsatellite instability (MSI) and status of mismatch repair (MMR) gene product, MLH1, MSH2 and MSH6, in 63 sporadic endometrial cancers coexisting with colorectal or breast cancer. Sixteen sporadic endometrial cancers with colorectal cancers (EC), 26 sporadic endometrial cancers with breast cancer (EB) and 21 endometrial cancers without a coexisting cancer (control) were analyzed. EC had the highest frequency of MSI among the 3 groups (EC, 69%; EB, 23%; and control, 43%). Incidence of low-frequency MSI was significantly higher in EC (38%). Among endometrial cancer cases diagnosed before age 50, all high-frequency MSI (MSI-H) cases belonged to EC. Interestingly, incidence of MSI-H was significantly higher in tamoxifen-non-treated cases (75%) than that of treated cases (14%). These results suggest that alterations in MMR genes appear to be involved in carcinogenesis of EC but seem to be uncommon in those of EB. Presence of MSI in sporadic endometrial cancer may be a useful marker to predict the risk of colorectal cancer.     

Microsatellite instability in japanese esophageal carcinoma

Recent studies have shown that microsatellite instability (MSI) may play an important role in the development of various types of cancer. However, there have been only 2 reports describing MSI in esophageal carcinoma and the clinicopathologic significance of MSI in this malignancy has not yet been clarified. To better elucidate the role of genetic instability in the development of esophageal carcinoma, we investigated the presence of MSI in 32 cases of esophageal cancer using paired samples of fresh frozen tumor and normal tissue by a method based on the polymerase chain reaction. MSI was defined as occurring in tumors which showed altered banding patterns at one or more microsatellite loci. The incidence of MSI in esophageal carcinoma was 6 out of 32 patients. MSI was observed more frequently in cases with small-cell carcinoma (2 out of 2) than in cases with squamous-cell carcinoma (4 out of 29). No cases with adenocarcinoma or Barrett's metaplasia were included in our series. No significant correlations between MSI and other clinicopathologic parameters were observed. The present study suggests that (I) some Japanese esophageal carcinomas certainly correlate with DNA replication error, and (2) MSI may be more frequent in small-cell carcinoma of the esophagus than in squamous-cell carcinoma of the esophagus. © 1995 Wiley-Liss, Inc.     

Microsatellite instability in Japanese colorectal carcinoma

Recent studies have shown that microsatellite instability (MSI) play an important role in the development of various types of cancer. To clarify the clinicopathologic significance of MSI in colorectal carcinoma (CRC), the presence of MSI was examined in 54 Japanese cases of CRC using the polymerase chain reaction-based method. The incidence of MSI in CRC cases was 13 out of 54 cases (24%). CRC with MSI also showed a significant tendency not to have lymph node metastasis (P<0.05), although neither the survival nor the prognosis of the cases examined in this study were available due to the short period of follow-up. The present study showed that the incidence of MSI in Japanese CRC was 24% and suggests that CRC with MSI may behave in a less malignant manner.     

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     

Variable mutation frequencies in coding repeats of TCF-4 and other target genes in colon, gastric and endometrial carcinoma showing microsatellite instability

Frameshift mutations in genes containing mononucleotide repeats are often observed in cancers exhibiting a high frequency of microsatellite instability (MSI-H). Several tumor types, including colorectal, gastric, and endometrial carcinomas, display this phenotype in a significant proportion of cases. We recently showed in a large series of MSI-H colorectal tumors that approximately 40% of them exhibited frameshift mutations in an (A)9 tract within the coding region of the TCF-4 gene, a crucial member of the APC/beta-catenin/TCF pathway. In the present study, we have examined MSI-H cancers from other primary tumor sites for mutations in this new target gene. Two of 22 (9%) MSI-H primary gastric cancers and none of 23 MSI-H endometrial primary tumors and cell lines were found to have a 1 bp deletion in the TCF-4 repeat. In the same series of tumors we also looked for frameshift mutations in other coding repeats localized within the TGF beta-RII, BAX, IGFIIR, hMSH3 and hMSH6 genes. Our results suggest that the TCF-4 gene, in a similar manner to some of these latter genes, is differentially altered in MSI-H tumors from different primary sites.     

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 colorectal-cancer patients with suspected genetic predisposition

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited syndrome linked to DNA-mismatch-repair (MMR) gene defects, which also account for microsatellite instability (MSI) in tumour tissues. Diagnosis is based mainly on family history, according to widely accepted criteria (Amsterdam Criteria: AC). Aim of this work was to assess MSI in colorectal-cancer patients with suspected genetic predisposition, and to verify whether MSI represents a tool to manage MMR gene (hMSH2 and hMLH1) mutation analysis. We investigated 13 microsatellites (including the 5 NCI/ICG-HNPCC markers) in 45 patients with suspected hereditary predisposition (including 16 subjects from HNPCC families fulfilling the AC). We found MSI-H (high frequency of instability, i.e., in > or =30% of the markers) in 85% of the HNPCC patients and in 16% of the non-HNPCC subjects. The 5 NCI/ICG-HNPCC microsatellites proved to be the most effective in detecting MSI, being mononucleotide repeats the most unstable markers. We investigated the association between hMSH2- and hMLH1 gene mutations and MSI. Our results indicate that AC are highly predictive both of tumour instability and of MMR-gene mutations. Therefore, as the most likely mutation carriers, HNPCC subjects might be directly analyzed for gene mutations, while to test for MSI in selected non-HNPCC patients and to further investigate MMR genes in MSI-H cases, appears to be a cost-effective way to identify subjects, other than those from kindred fulfilling AC, who might benefit from genetic testing.     

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 and mutation analysis among southern Italian patients with colorectal carcinoma: detection of different alterations accounting for MLH1 and MSH2 inactivation in familial cases.

BACKGROUND: Microsatellite instability (MSI) is due to defective DNA mismatch repair (MMR) and has been detected at various rates in colorectal carcinoma (CRC). The role of MSI in colorectal tumorigenesis was assessed further in this study by both microsatellite analysis of two CRC subsets [unselected patients (n = 215) and patients <50 years of age (n = 95)], and mutation screening of the two major MMR genes MLH1 and MSH2 among familial CRC cases. PATIENTS AND METHODS: PCR-based microsatellite analysis was performed on paraffin-embedded tissues. In CRC families, MLH1/MSH2 mutation analysis and MLH1/MSH2 immunostaining were performed on germline DNA and MSI+ tumour tissues, respectively. RESULTS: The MSI+ phenotype was detected in 75 (24%) patients, with higher incidence in early-onset or proximally located tumours. Among 220 patients investigated for family cancer history, MSI frequency was markedly higher in familial [18/27 (67%)] than in sporadic [32/193 (17%)] cases. Three MLH1 and six MSH2 germline mutations were identified in 14 out of 36 (39%) CRC families. Prevalence of MLH1/MSH2 mutations in CRC families was significantly increased by the presence of: (i) fulfilled Amsterdam criteria; (ii) four or more CRCs; or (iii) one or more endometrial cancer. While MSH2 was found mostly mutated, almost all [8/9 (89%)] familial MSI+ cases with loss of the MLH1 protein were negative for MLH1 germline mutations. CONCLUSIONS: Both genetic (for MSH2) and gene-silencing (for MLH1) alterations seem to be involved in CRC pathogenesis.     

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.     

Microsatellite instability in thyroid papillary carcinoma and multinodular hyperplasia

Microsatellite instability (MSI) is a molecular landmark of mutations in DNA mismatch repair genes. The impaired efficiency of DNA repair mechanisms promotes carcinogenesis as well as contributes to tumour progression. Until now, only few studies on MSI in thyroid tumours have been published. Therefore, the aim of the present study was to investigate MSI as a possible characteristic feature of thyroid tumours. The analysis of 12 thyroid papillary carcinomas and 17 multinodular hyperplasias at 13 microsatellite loci showed MSI and loss of heterozygosity (LOH) in both types of lesion, with more alterations noted in the papillary thyroid carcinomas (in 65%) than in multinodular hyperplasia (in 35%). In carcinomas, LOH occurred more frequently than MSI, while in multinodular hyperplasia the LOH/MSI ratio is almost equal.     

肾癌微卫星不稳定性及其机制的研究

目的 探讨微卫星不稳定性（microsatelite instablility,MSI)在肾细胞癌中的表现及与基因突变的关系。方法 用PCR方法分析34例肾细胞癌MSI表现;应用RT－PCR方法检测5种人类错配修复（mismatch repair,MMR)基因在肾细胞癌和肾癌细胞系mRNA转录水平的表达;用PCR－SSCP技术对15例肾细胞癌标本进行MMR基因hMLH1的19个外显子进行筛选,观察基因突变的情况;用PCR方法检查肾癌组织中TGF－βⅡ型受体（TGF－βRⅡ）基因和BAX基因移码突变的情况。结果 34例肾细胞癌中有15例（44．1％）表现为MSI,并多见于晚期肿瘤;15例表达MSI阳性肾癌标本中,3例hMLH1基因mRNA表达缺失,3例表达明显降低,但在正常对照及PCC949细胞系都表达5种MMR基因;PCR－SSCP筛检结果,15例MSI（＋）细胞中3例显示异常电泳带型;40％（6／15）及27％（4／15）分别见TGF－βRⅡ基因及BAX基因移码突变,但不表现在MSI（－）肾肿瘤及正常细胞中。结论 肾细胞癌MSI与MMR基因表达有关,较高的突变率在肿瘤发生中的作用与MSI有关。     

早期子宫内膜癌保留生育功能治疗的临床分析

目的评估早期子宫内膜癌行保留生育功能治疗的可行性、有效性和结局。方法回顾性分析北京协和医院自1998年6月－2004年12月接受保留生育功能治疗的12例早期子宫内膜癌患者的临床资料。结果患者年龄21－35岁,平均29岁。其中33．3％合并不孕,41．7％合并多囊卵巢综合征。高分化11例,高一中分化1例;FIGO Ia期10例,Ib期2例;孕激素受体阳性10例,阴性2例。安宫黄体酮500mg／d或己酸孕酮250mg／d治疗3～10个月,完全缓解9例（75％）,无缓解3例（25％）;完全缓解的9例中复发2例（22．2％）;最后行子宫切除术5例。随诊36—108个月,12例均无瘤存活,无1例妊娠。结论保留生育功能治疗对于仔细选择的年轻子宫内膜癌妇女是可行的。由于病理完全缓解的患者在长期观察中的复发率仍高．故应强调密切随访．     

Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (> or =50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMR-deficient tumors.