Association of MUTYH and colorectal cancer

Mutations in the MUTYH gene have been reported to be associated with increased risk of developing colorectal cancer. In this study, we confirmed this association using original data on 928 colorectal cancer cases and 845 healthy controls from Scotland. We then conducted a meta-analysis from published data on the association between mutations at MUTYH and colorectal cancer risk. We show for the first time a small but significant mono-allelic effect with a genotype relative risk (GRR) of 1.27 (95% confidence interval (CI): 1.01-1.61), and confirm and give a more precise estimate of the strong bi-allelic effect with an estimated GRR of 117 (95% CI: 74-184). This study underscores the need for large sample sizes in order to identify small gene effects when the disease allele frequency is low.     

Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer

Cancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first- and second-degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country-, age- and sex-specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56-2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18-4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07-12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18-5.08; p = 0.02) for endometrial cancer. Age-specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5-8%) for men and 4% (95%CI 3-6%) for women; for gastric cancer, 2% (95%CI 1-3%) for men and 0.7% (95%CI 0.5-1%) for women; for liver cancer, 1% (95%CI 0.3-3%) for men and 0.3% (95%CI 0.1-1%) for women and for endometrial cancer, 4% (95%CI 2-8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple-case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers.     

Alterations of the base excision repair gene MUTYH in sporadic colorectal cancer

The base excision repair gene MUTYH encodes glycosylase which removes adenine residues mispaired with 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHG). Biallelic germline mutations of the MUTYH gene are known to cause multiple colorectal adenomas including polyposis and cancer, mostly due to G:C?T:A transversions in proto-oncogenes or tumor suppressor genes. The risk of colorectal cancer (CRC) in monoallelic mutation carriers of MUTYH is estimated to be higher in comparison with non-carriers. To investigate the possible role in sporadic CRC, we examined alterations of the MUTYH gene including somatic mutations and allelic loss in 101 cases of sporadic CRC, together with the KRAS mutation in some cases. MUTYH mutations in cancer DNA were detected in 3 cases, while mutations were also found in DNA samples from normal tissues, indicating that all were germline mutations. Allelic loss at the MUTYH locus was found in 10 of 51 (20.0%) CRC cases and KRAS mutations were found in 33 of the 101 (32.7%) samples. There was no significant difference in the rate of G:C?T:A transversion in KRAS between cases with allelic loss (1 of 10, 10.0%) and without allelic loss (9 of 41, 22.0%). Investigation of quantitative allelic imbalance at SNP rs3219489 of MUTYH showed that CRC cases with C allele dominance (minor type corresponding to His) were more frequently detected with G:C?T:A transversions than in those with G allele dominance (major type corresponding to Gln). In conclusion, somatic alterations of MUTYH in sporadic CRC were rare, similar to other DNA repair genes. However, it is possible that unknown mutations of regions not analyzed in this study and epigenetic changes of the promoter region of MUTYH may contribute to the disease.     

芥菜籽对氧化偶氮甲烷诱导小鼠结直肠癌的影响

背景与目的:结直肠癌是常见的恶性肿瘤之一,在我国发病率和死亡率呈不断上升趋势.文献报道芥菜籽具有抗肿瘤的活性,本研究旨在观察在氧化偶氮甲烷(azoxymethane,AOM)诱发昆明种小鼠发生结直肠癌的过程中,通过芥菜籽(mustard seed,MS)进行饮食干预能否预防肿瘤的发生.方法:选择6周龄昆明种雌性小鼠,随机分为AOM组、AOM+5%MS干预组、AOM+10%MS干预组和正常对照组.小鼠皮下注射AOM(10 mg/kg体质量),每周1次,连续3周.32周时颈椎脱臼处死小鼠,分离结直肠,用预冷的0.9%NaCl溶液冲洗肠内容物.观察记录各组小鼠有无肿瘤发生及发生数目、大小和位置,计算肿瘤发生率.结果:正常对照组小鼠未发现肿瘤,AOM模型组小鼠结直肠肿瘤发生率为86.7%,5%MS干预组及10%MS干预组小鼠结直肠肿瘤发生率分别为60.0%和41.7%,与模型组相比差异均有统计学意义(P＜0.05).AOM模型组小鼠荷瘤数为(2.2±1.2)个,而5%MS干预组和10%MS干预组小鼠荷瘤数分别为(1.1±1.1)个和(0.7±0.9)个,与AOM模型组相比差异均有统计学意义(P＜0.05).结论:通过芥菜籽饮食干预能够抑制UAOM诱导的小鼠结直肠癌的发生发展,可进一步用于结直肠癌防治的研究.     

Investigation of pathogenic mechanisms in multiple colorectal adenoma patients without germline APC or MYH/MUTYH mutations

Patients with multiple (5-100) colorectal adenomas (MCRAs) often have no germline mutation in known predisposition genes, but probably have a genetic origin. We collected a set of 25 MCRA patients with no detectable germline mutation in APC, MYH/MUTYH or the mismatch repair genes. Extracolonic tumours were absent in these cases. No vertical transmission of the MCRA phenotype was found. Based on the precedent of MYH-associated polyposis (MAP), we searched for a mutational signature in 241 adenomatous polyps from our MCRA cases. Somatic mutation frequencies and spectra at APC, K-ras and BRAF were, however, similar to those in sporadic colorectal adenomas. Our data suggest that the genetic pathway of tumorigenesis in the MCRA patients' tumours is very similar to the classical pathway in sporadic adenomas. In sharp contrast to MAP tumours, we did not find evidence of a specific mutational signature in any individual patient or in the overall set of MCRA cases. These results suggest that hypermutation of APC does not cause our patients' disease and strongly suggests that MAP is not a paradigm for the remaining MCRA patients. Our MCRA patients' colons showed no evidence of microadenomas, unlike in MAP and familial adenomatous polyposis (FAP). However, nuclear beta-catenin expression was significantly greater in MCRA patients' tumours than in sporadic adenomas. We suggest that, at least in some cases, the MCRA phenotype results from germline variation that acts subsequent to tumour initiation, perhaps by causing more rapid or more likely progression from microadenoma to macroadenoma.     

Association between genetic polymorphisms of the base excision repair gene MUTYH and increased colorectal cancer risk in a Japanese population

The MUTYH gene encodes a DNA glycosylase that can initiate the base excision repair pathway and prevent G:C > T:A transversion by excising adenine mispaired with 8-hydroxyguanine. Biallelic germline mutations of MUTYH have been shown to predict familial and sporadic multiple colorectal adenomas and carcinomas, however, whether there is an association between single nucleotide polymorphisms (SNPs) of MUTYH and sporadic colorectal cancer (CRC) risk has remained unclear. In this study we investigated four MUTYH SNPs, IVS1+11C > T, IVS6+35G > A, IVS10–2A > G, and 972G > C (Gln324His), for an association with increased CRC risk in a population-based series of 685 CRC patients and 778 control subjects from Kyushu, Japan. A statistically significant association was demonstrated between IVS1+11T and increased CRC risk (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.012–2.030; P  = 0.042) and one of the five haplotypes based on the four SNPs, the IVS1+11T – IVS6+35G – IVS10–2A – 972C (TGAC) haplotype containing IVS1+11T, was demonstrated to be associated with increased CRC risk (OR, 1.43; 95% CI, 1.005–2.029; P  = 0.046). Subsite-specific analysis showed that the TGAC haplotype was statistically significantly ( P  = 0.013) associated with an increased risk of distal colon, but not proximal colon or rectal cancer. Furthermore, IVS1+11C > T was found to be in complete linkage disequilibrium with –280G > A and 1389G > C (Thr463Thr). The results indicated that Japanese individuals with – 280A/IVS1+11T/1389C genotypes or the TGAC haplotype are susceptible to CRC. ( Cancer Sci 2008; 99: 355–360)     

碱基切除修复基因APE和XRCC1表达与大肠癌发生相关性的探讨

目的:通过检测大肠癌、癌旁黏膜与正常黏膜中APE和XRCC1蛋白的表达,探讨大肠癌的发生机制.方法:选取大肠癌手术切除标本185例,其中32例标本取癌旁黏膜组织;正常黏膜组织36例.通过免疫组化方法检测APE和XRCC1蛋白在癌、癌旁黏膜和正常黏膜的表达.结果:大肠癌、癌旁黏膜组APE阳性表达率分别为78.9％(146/185)和81.2％(26/32),两者均明显高于正常黏膜组的61.1％(22/36),x2值分别为5.23和4.86,P值分别为0.024和0.03,但前两者APE表达差异无统计学意义.大肠癌中APE蛋白表达与患者性别、年龄、肿瘤部位、分化程度、浆膜浸润及淋巴结转移无明显相关关系.大肠癌与癌旁黏膜组XRCC1阳性表达率分别为94.6％(175/185)和87.5％(27/32),两者均明显高于正常黏膜组的27.7％(10/36),x2值分别为4.43和29.69,P值分别为0.036和0.002,但前两者间差异无统计学意义.大肠癌中XRCC1蛋白表达与患者性别、年龄、肿瘤部位、分化程度、浆膜浸润及淋巴结转移无明显相关关系.大肠癌XRCC1阳性组的APE阳性率为95.8％(136/142),显著高于大肠癌XRCC1阴性组的86.0％(37/43),XRCC1与APE两者表达呈明显正相关关系,r=0.354,P=0.02.大肠癌和癌旁黏膜组的APE和XRCC1蛋白同时表达的阳性率分别为75.8％(140/185)和65.6％(21/32),两组均明显高于正常黏膜组的16.7％(6/36),x2值分别为46.8和16.17,P值分别为0.001和0.001 5,但癌组与癌旁组间差异无统计学意义.结论:大肠癌和癌旁黏膜中存在APE和XRCC1表达上调.大肠癌发生可能与DNA复制时位点损伤及烷化剂等有毒物质损伤关系密切,同时检测大肠黏膜不同种类DNA修复基因的表达有助于大肠癌的早期诊断.     

AluYb8 insertion in the MUTYH gene and risk of early-onset breast and gastric cancers in the Chinese population

Background: A common polymorphism of the AluYb8 insertion in the MUTYH gene (AluYb8MUTYH), which led to the increase of oxidative DNA damage and acceleration of chronic diseases, was previously detected. Considering the relationship between carcinogenesis and oxidative stress, an investigation was held on whether the common variant of the MUTYH gene increases the risk for gastric and breast cancers. Methods: The AluYb8MUTYH allele frequencies of 545 breast cancer patients and 762 gastric cancer patients were analyzed and compared with that of the healthy control group using the Chi-square test. The binary logistic regression model was used to examine the association between the polymorphism genotypes and cancer risk. Genomic DNA specimens from the investigated population were tested by polymerase chain reaction in agarose gel electrophoresis. According to the insertion absence or presence of the variant segment, the patterns for the AluYb8MUTYH genotypes were classified as a homozygous of absence/absence (A/A) and presence/presence (P/P) or a heterozygous of absence/presence (A/P). Results: The variant allele frequency (insertion present, P) was inclined to be enhanced in breast cancer patients as compared with the normal female controls (46.8% versus 43.3%), and also, in gastric cancer patients, as compared with the general normal controls (45.1% versus 43.9%). However, a significantly different P allele frequency was only detected between the early-onset breast cancerpatients (<55 years old) and their counterpart female controls (46.6% versus 40.9%, p=0.042; OR=1.26, 95% CI, 1.01–1.56), as well as between the early-onset gastric cancer patients and their respective controls (49.2% versus 41.3%, p=0.042; OR, 1.37; 95% CI, 1.02–1.85). Comparisons on the genotypes of AluYb8MUTYH show that this variation of MUTYH has also a significantly higher prevalence in the early-onset cancer patients, either in breast or gastric cancer patients, than that in their counterpart controls. Conclusions: The AluYb8MUTYH allele frequency can be associated with the early-onset breast and gastric cancer in the Chinese population.Probably, there is importance in screening the carriers with the susceptibility alleles to evaluate their risk of breast and gastric cancer for further research.     

Effects of base excision repair gene polymorphisms on pancreatic cancer survival

To explore the association between single nucleotide polymorphisms of DNA repair genes and overall survival of patients with pancreatic cancer, we conducted a study in 378 cases of pancreatic adenocarcinoma who were treated at The University of Texas M. D. Anderson Cancer Center between February 1999 and October 2004 and were followed up to April 2006. Genotypes were determined using genomic DNA and the MassCode method. Overall survival was analyzed using the Kaplan-Meier plot, log-rank test and Cox regression. We observed a strong effect of the POLB A165G and T2133C genotypes on overall survival. The median survival time (MST) was 35.7 months for patients carrying at least 1 of the 2 homozygous variant POLB GG or CC genotypes, compared with 14.8 months for those carrying the AA/AG or TT/TC genotypes (p = 0.02, log rank test). The homozygous variants of hOGG1 G2657A, APEX1 D148E and XRCC1 R194W polymorphisms all showed a weak but significant effect on overall survival as demonstrated by either log rank test or multivariate COX regression after adjusting for other potential confounders. In combined genotype analysis, a predominant effect of the POLB homozygous variants on survival was observed. When POLB was not included in the model, a slightly better survival was observed among those carrying none of the adverse genotypes than those carrying at least one of the adverse genotypes. These observations suggest that polymorphisms of base excision repair genes significantly affect the clinical outcome of patients with pancreatic cancer. These observations need to be confirmed in a larger study of homogenous patient population.     

The role of microbiota in the development of colorectal cancer

Colorectal cancer is the third largest cancer in worldwide and has been proven to be closely related to the intestinal microbiota. Many reports and clinical studies have shown that intestinal microbial behavior may lead to pathological changes in the host intestines. The changes can be divided into epigenetic changes and carcinogenic changes at the gene level, which ultimately promote the production and development of colorectal cancer. This article reviews the pathways of microbial signaling in the intestinal epithelial barrier, the role of microbiota in inflammatory colorectal tumors, and typical microbial carcinogenesis. Finally, by gaining a deeper understanding of the intestinal microbiota, we hope to achieve the goal of treating colorectal cancer using current microbiota technologies, such as fecal microbiological transplantation.     

Mismatch repair gene defects in sporadic colorectal cancer enhance immune surveillance

Background

There is evidence that colorectal cancers (CRC) with DNA mismatch repair deficiency (MMR-D) are associated with a better prognosis than the generality of large bowel malignancies. Since an active immune surveillance process has been demonstrated to influence CRC outcome, we investigated whether MMR-D can enhance the immune response in CRC.

Patients and Methods

A group of 113 consecutive patients operated for CRC (42 stage I or II and 71 with stage III or IV) was retrospectively analyzed. The expression of MMR genes (MSH2, MLH1, MSH6 and PSM2) and co-stimulatory molecule CD80 was assessed by tissue microarray immunohistochemistry. In addition, tumor infiltrating mononuclear cells (TIMC) and T cell subpopulations (CD4, CD8, T-bet and FoxP-3) were quantified. The effect of specific siRNA (siMSH2, siMLH1, siMSH6 and siPSM2) transfection in HT29 on CD80 expression was quantified by flow cytometry. Non parametric statistics and survival analysis were used.

Results

Patients with MMR-D showed a higher T-bet/CD4 ratio (p = 0.02), a higher rate of CD80 expression and CD8 lymphocyte infiltration compared to those with no MMR-D. Moreover, in the MMR-D group, the Treg marker FoxP-3 was not expressed (p = 0.05). MMR-D patients with stage I or II and T-bet expression had a significant better survival (p = 0.009). Silencing of MSH2, MLH1 and MSH6, but not PSM2, significantly increased the rate of CD80+ HT29 cells (p = 0.007, p = 0.023 and p = 0.015, respectively).

Conclusions

CRC with MMR-D showed a higher CD80 expression, and CD8+ and Th1 T-cell infiltration. In vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate. These results suggest an enhanced immune surveillance mechanism in presence of MMR-D.     

筛查结直肠癌DNA错配修复基因缺失的方法分析

目的:通过对筛查结直肠癌DNA错配修复(mismatch repair,MMR)基因缺失两种最常用的检测方法的分析,寻找更为经济有效的检测策略。方法:分析新疆医科大学第一附属医院2018年9月至2019年9月收治并行手术的结直肠癌患者的肿瘤组织223例,采用免疫组织化学法检测平台检测MLH1、MSH2、PMS2、MSH6的表达缺失情况,PCR-毛细管电泳法检测肿瘤微卫星不稳定(microstatellites instability,MSI)状态。结果:在223例结直肠癌中,27例(12.1%)MMR蛋白表达缺失(MMR deficiency,dMMR),196例(87.9%)MMR蛋白表达完整(MMR proficient,pMMR)。MLH1、MSH2、MSH6和PMS2的缺失率分别为9.0%(20/223)、1.8%(4/223)、2.7%(6/223)和9.4%(21/223)。包含PMS2和MSH6的2种抗体试验筛查dMMR结直肠癌的灵敏度和特异度与4种抗体试验(MLH1、MSH2、PMS2、MSH6)的灵敏度和特异度均相同。微卫星高度不稳定(MSI-high,MSI-H)2...     

Boris knockout eliminates AOM/DSS-induced in situ colorectal cancer by suppressing DNA damage repair and inflammation

The Brother of Regulator of Imprinted Sites (BORIS, gene symbol CTCFL) has previously been shown to promote colorectal cancer cell proliferation, inhibit cancer cell apoptosis, and resist chemotherapy. However, it is unknown whether Boris plays a role in the progression of in situ colorectal cancer. Here Boris knockout (KO) mice were constructed. The function loss of the cloned Boris mutation that was retained in KO mice was verified by testing its activities in colorectal cell lines compared with the Boris wild-type gene. Boris knockout reduced the incidence and severity of azoxymethane/dextran sulfate-sodium (AOM/DSS)-induced colon cancer. The importance of Boris is emphasized in the progression of in situ colorectal cancer. Boris knockout significantly promoted the phosphorylation of γH2AX and the DNA damage in colorectal cancer tissues and suppressed Wnt and MAPK pathways that are responsible for the callback of DNA damage repair. This indicates the strong inhibition of colorectal cancer in Boris KO mice. By considering that the DSS-promoted inflammation contributes to tumorigenesis, Boris KO mice were also studied in DSS-induced colitis. Our data showed that Boris knockout alleviated DSS-induced colitis and that Boris knockdown inhibited the NF-κB signaling pathway in RAW264.7 cells. Therefore Boris knockout eliminates colorectal cancer generation by inhibiting DNA damage repair in cancer cells and relieving inflammation in macrophages. Our findings demonstrate the importance of Boris in the development of in situ colorectal cancer and provide evidence for the feasibility of colorectal cancer therapy on Boris.     

MUTYH c.892-2A>G剪切位点突变在家族性乳腺癌中的意义

背景与目的：MUTYH基因变异与结直肠癌患癌风险升高有关,但其突变与乳腺癌发生的相关性尚不明确,该研究探讨MUTYH c.892-2A>G剪切位点突变在中国家族性乳腺癌中的意义。方法：采用二代测序(next generation sequencing,NGS)方法检测95个家族性乳腺癌患者及亲属MUTYH基因突变情况,并与BRCA1、BRCA2基因突变情况进行比较。结果：95个家系224名受试者中有4个家系共7名受试者检出MUTYHc.892-2A>G突变,突变率为3.1%,其中只有1例先证者检出MUTYH c.892-2A>G突变。95个家系中也只有1例先证者检出携带BRCA1突变;5个家系中共9名受试者检出携带BRCA2突变,突变率为4.0%。MUTYH c.892-2A>G突变人数分别与BRCA2、BRCA1突变人数相比较,不存在基因共突变现象。结论：MUTYH c.892-2A>G突变虽然在有乳腺癌家族史的高危正常人群中突变率较高,但很可能是低外显的乳腺癌发生相关的致病位点。     

饮食在大肠癌发生发展中致病作用的研究进展

大肠癌是常见的恶性肿瘤之一，全世界大肠癌的发病率每年以2％的速度上升，在西欧、北美国家中发病率较高，可达35-50／10万，亚、非、拉国家发病率较低；在美国所有死于癌症的病人中，大肠癌居第二位，其中85％-90％的病人癌发生与环境和饮食因素有关。近年来从我国各地资料显示：随着人民生活水平的提高，饮食结构的改变，结肠癌发病率呈逐年上升趋势，其年平均增长率为4％，现已成为市区第四位常见癌症。据统计，1992年上海市大肠癌的年发病率为28．35／10万，已接近欧美国家水平。遗传学和临床研究认为，大肠癌发病可能是遗传易感性和饮食因素协同作用所致，其中环境、生活习惯、尤其是与饮食方式有密切关系。     

Mutations of the 'minor' mismatch repair gene MSH6 in typical and atypical hereditary nonpolyposis colorectal cancer

Mutations of the mismatch repair (MMR) genes MLH1 and MSH2 are associated with hereditary nonpolyposis colorectal cancer (HNPCC), a highly penetrant autosomal dominant condition characterized by hypermutability of short tandemly repeated sequences in tumor DNA. Mutations of another MMR gene, MSH6, seem to be less common than MLH1 and MSH2 defects, and have been mostly observed in atypical HNPCC families, characterized by a weaker tumor family history, higher age at disease onset, and low degrees of microsatellite instability (MSI), predominantly involving mononucleotide runs. We have investigated the MSH6 gene sequence in the peripheral blood of 4 HNPCC and 20 atypical HNPCC probands. Two frameshift mutations within exon 4 were detected in 2 patients. One mutation was found in a proband from a typical HNPCC family, who had developed a colorectal cancer (CRC), a gastric cancer and a rectal adenoma. The CRC and the adenoma showed mild MSI limited to mononucleotide tracts, while the gastric carcinoma was microsatellite stable. The other mutation was detected in an atypical HNPCC proband, whose CRC showed widespread MSI involving both mono- and dinucleotide repeats. The phenotypic variability associated with MSH6 constitutional mutations represents a complicating factor for the optimization of strategies aimed at identifying candidates to MSH6 genetic testing.     

Three molecular pathways model colorectal carcinogenesis in Lynch syndrome

Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR‐deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR‐deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR‐deficient cells by chemoprevention or vaccines against MMR deficiency‐induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome.