Tumor mutation burden determined by a 645-cancer gene panel and compared with microsatellite instability and mismatch repair genes in colorectal cancer

BackgroundTumor mutation burden (TMB) assessed by tumor-related gene panels (CRGP), microsatellite instability (MSI), and mismatch repair (MMR) has been proven to be associated with prognosis, and these factors are prognostic indicators in predicting the benefits of immune checkpoint blockade (ICB) in solid tumors. However, whether the TMB calculated by CRGPs, MSI, and MMR is associated with overall survival (OS) in patients with colorectal cancer (CRC) remains to be explored.MethodsThe prognostic threshold of the panel-TMB was explored by a panel of 645 genes (GP645) from 41 CRC patients in Jiangsu Cancer Hospital (JCH dataset). The results were further validated using 531 CRC patients from The Cancer Genome Atlas (TCGA) database.ResultsMutations of the GP645 genes were distributed on 21 chromosomes. Spearman correlation analysis showed that the panel-TMB was positively correlated with TMB measured by whole-exome sequencing (WES) (wTMB) in the TCGA dataset (R=0.75, P<0.001). Kaplan-Meier survival analysis demonstrated that higher panel-TMB in CRC patients was significantly associated with a poor OS (P=0.0062). MSI and MMR status were determined using the GP645 by next-generation sequencing (NGS). The proportions of MSI-H and dMMR accounted for less than 10% in CRC, the vast majority of MSI-H/dMMR samples also had high TMB [positive predictive value (PPV) =66.6%], and only 13.3% of samples with high TMB were classified as MSI-high/dMMR. In addition, patients with low-TMB were associated with MSS/pMMR (96.2%), and these results are consistent with earlier studies.ConclusionsGP645 was constructed to evaluate OS in Chinese CRC patients. Panel-TMB and MSI/MMR might be potential prognostic predictors of CRC patients using the GP645.     

Hereditary nonpolyposis colorectal cancer in endometrial cancer patients

Endometrial cancer is the second most common cancer in hereditary nonpolyposis colorectal cancer (HNPCC). It has often been overlooked to explore the possibility of HNPCC in endometrial cancer patients. Our study was to investigate how many HNPCC patients existed among endometrial cancer patients. Among patients who underwent hysterectomy for endometrial cancer at Seoul National University Hospital from 1996 to 2004, 113 patients were included, whose family history and clinical data could be obtained and tumor specimens were available for microsatellite instability (MSI) testing and immunohistochemical (IHC) staining of MLH1, MSH2 and MSH6 proteins. There were 4 (3.5%) clinical HNPCC patients fulfilling the Amsterdam criteria II, and 2 (2/4, 50%) of them carried MSH2 germline mutations. There were also 8 (7.1%) suspected HNPCC (s-HNPCC) patients fulfilling the revised criteria for s-HNPCC, and one (1/8, 12.5%) of them revealed MLH1 germline mutation. In 101 patients, who were not clinical HNPCC or s-HNPCC, 11 patients showed both MSI-high and loss of expression of MLH1, MSH2 or MSH6 proteins, and 2 (2/11, 18.2%) of them showed MSH6 germline mutations. In 113 patients with endometrial cancer, we could find 5 (4.4%) HNPCC patients with MMR germline mutation and 2 (1.8%) clinical HNPCC patients without identified MMR gene mutation. Family history was critical in detecting 3 HNPCC patients with MMR germline mutation, and MSI testing with IHC staining for MLH1, MSH2 and MSH6 proteins was needed in the diagnosis of 2 HNPCC patients who were not clinical HNPCC or s-HNPCC, especially for MSH6 germline mutation.     

Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells

Microsatellite instability (MSI) caused by deficient DNA mismatch-repair functions is a hallmark of cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome but is also found in about 15% of all sporadic tumors. Most affected microsatellites reside in untranslated intergenic or intronic sequences. However, recently few genes with coding microsatellites were also shown to be mutational targets in MSI-positive cancers and might represent important mutation targets in their pathogenesis. The systematic identification of such genes and the analysis of their mutation frequency in MSI-positive cancers might thus reveal major clues to their functional role in MSI-associated carcinogenesis. We therefore initiated a systematic database search in 33,595 distinctly annotated human genes and identified 17,654 potentially coding mononucleotide repeats (cMNRs) and 2,028 coding dinucleotide repeats (cDNRs), which consist of n > or = 6 and n > or = 4 repeat units, respectively. Expression pattern and mutation frequency of 19 of these genes with the longest repeats were compared between DNA mismatch repair-deficient (MSI(+)) and proficient (MSS) cancer cells. Instability frequencies in these coding microsatellite genes ranged from 10% to 100% in MSI-H tumor cells, whereas MSS cancer cells did not show mutations. RT-PCR analysis further showed that most of the affected genes (10/15) were highly expressed in tumor cells. The approach outlined here identified a new set of genes frequently affected by mutations in MSI-positive tumor cells. It will lead to novel and highly specific diagnostic and therapeutic targets for microsatellite unstable cancers.     

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...     

Microsatellite instability indicative of defects in the major mismatch repair genes is rare in patients with B-cell chronic lymphocytic leukemia: Evaluation with disease stage and family history

A possible role for DNA mismatch repair defects and microsatellite instability (MSI) in the pathogenesis of a number of B-cell lymphoproliferative disorders has recently been debated. To gain further insight into the impact of MSI on B-CLL, we evaluated samples from a series of 982 patients using the mono-satellite markers BAT25 and BAT26, which are highly sensitive in demonstrating classical mismatch repair (MMR) deficiency. Only 1% of cases displayed MSI and this was not correlated with stage of disease or family history of B-CLL. A sub-polymorphic germline variant of BAT25 was identified in one familial case, which was also detected in the patient's affected brother. In conclusion, our study demonstrates that MSI does not have a prominent role in the pathogenesis of B-CLL.     

Perineural invasion is a prognostic factor in stage II colorectal cancer but not a treatment indicator for traditional chemotherapy: a retrospective cohort study

BackgroundPerineural invasion (PNI) is considered a risk factor of survival but does not yet inform treatment decisions, and has not been studied separately in stage II colorectal cancer (CRC) patients whose postoperative traditional chemotherapy is controversial. This cohort study aimed to assess the association of PNI with basic clinicopathological features and patient outcomes after curative resection and the effects of PNI on responses to adjuvant chemotherapy in stage II CRC.MethodsThe clinical data of 371 stage II CRC patients who underwent curative-intent surgery at the National Cancer Center/Cancer Hospital in 2014 were retrospectively reviewed. The adjuvant chemotherapy data were acquired from follow-up information. PNI status was examined, and the overall survival (OS) and disease-free survival (DFS) rates were analyzed.ResultsPNI was detected in 82 of the 371 patients (22.1%) and was closely correlated with preoperative serum carcinoembryonic antigen (CEA) levels (P=0.030), gross tumor type (P=0.010), tumor differentiation (P=0.010), p stage (P<0.001), and extramural vascular invasion (EMVI) (P<0.001). The median follow-up time was 71 months. The 5-year OS was 84.1% and 96.5% (P<0.001), and the 5-year DFS was 75.6% and 91.3% (P<0.001) for PNI-positive (+) and PNI-negative (−) patients, respectively. The multivariate regression analyses identified PNI as an independent negative prognostic factor for DFS [hazard ratio (HR): 2.95; 95% confidence interval (CI), 1.546–5.626; P=0.001] and OS (HR: 3.966; 95% CI, 1.642–9.575; P=0.002). Among PNI (+) patients, DFS and OS were positively correlated with CEA levels (P=0.005 and P=0.004, respectively). Postoperative chemotherapy failed to improve DFS (P=0.480 and P=0.267, respectively) and OS (P=0.940 and P=0.077, respectively) regardless of whether the patients were PNI positive or not.ConclusionsIn stage II CRC patients, PNI was a poor independent predictor for DFS and OS. Among PNI (+) patients, CEA levels were positively correlated with DFS and OS. Traditional postoperative adjuvant chemotherapy does not improve outcomes of PNI (+) patients. Therefore, as to the active role of PNI and vacancy for treatment in allusion to PNI, follow-up of PNI (+) patients with elevated CEA level should be strengthened and further research on drug conducted on PNI deserve to be carried on.     

Clinical features of biliary tract cancer in Japanese individuals with Lynch syndrome

BackgroundBiliary tract cancer (BTC) is a Lynch syndrome (LS)-associated cancer with a high mortality rate. This study aimed to clarify the clinical features of BTC in individuals with LS and to discuss its management.MethodsWe obtained data from genetically verified Japanese individuals with LS who were diagnosed at a single institution, between January 2003 and April 2021. Moreover, 21 individuals with sporadic BTC (n=15) and LS associated BTC (n=6) underwent microsatellite instability (MSI) testing.ResultsAmong 92 individuals with LS, 6 individuals with MLH1 variants developed BTCs (10 lesions, male/female, 2:1). The median age at diagnosis of initial BTC was 69 years (range, 34–78 years). Histological examination revealed a predominance of differentiated adenocarcinoma (89%). Then, 2 individuals had multiple BTCs. All available 7 BTC lesions showed high-frequency of microsatellite instability (MSI-H). MLH1 carriers showed a 7.2% cumulative risk of BTC development at an age of 70 years. Five of the six individuals died of BTC.ConclusionsMSI analysis could facilitate LS identification in individuals with BTC. Surveillance for BTC should be considered for MLH1 carriers in Japan.     

Evaluation of a new panel of six mononucleotide repeat markers for the detection of DNA mismatch repair-deficient tumours

Background:

Microsatellite instability (MSI) is a molecular phenotype due to defective DNA mismatch repair (MMR) system. It is used to predict outcome of colorectal tumours and to screen tumours for Lynch syndrome (LS). A pentaplex panel composed of five mononucleotide markers has been largely recommended for determination of the MSI status. However, its sensitivity may be taken in default in occasional situations. The aim of the study was to optimise this panel for the detection of MSI.

Methods:

We developed an assay allowing co-amplification of six mononucleotide repeat markers (BAT25, BAT26, BAT40, NR21, NR22, NR27) and one polymorphic dinucleotide marker (D3S1260) in a single reaction. Performances of the new panel were evaluated on a cohort of patients suspected of LS.

Results:

We demonstrate that our assay is technically as easy to use as the pentaplex assay. The hexaplex panel shows similar performances for the identification of colorectal and non-MSH6-deficient tumours. On the other hand, the hexaplex panel has higher sensitivity for the identification of MSH6-deficient tumours (94.7% vs 84.2%) and MMR-deficient tumours other than colorectal cancer (92.9% vs 85.7%).

Conclusion:

The hexaplex panel could thus be an attractive alternative to the pentaplex panel for the identification of patients with LS.     

Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor.

Hereditary non-polyposis colorectal cancer (HNPCC) is linked to an inherited defect in the DNA mismatch repair system. DNA from HNPCC tumours shows microsatellite instability (MSI). It has been reported that HNPCC patients have a better prognosis than patients with sporadic colorectal cancer. We examined whether the presence of MSI in a series of unselected colorectal tumours carries prognostic information. In a series of 181 unselected colorectal tumours, 22 tumours (12%) showed MSI. Survival analysis at 5-10 years follow-up showed no statistically significant difference in prognosis between MSI-positive and -negative tumours. Our results suggest that the MSI phenotype as such is not an independent prognostic factor.     

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.     

Germline Mutations of the hMLH1 and hMSH2 Mismatch Repair Genes in Belgian Hereditary Nonpolyposis Colon Cancer (HNPCC) Patients

Background: Hereditary nonpolyposis colon cancer (HNPCC-Lynch syndrome) is caused by mutations in genes involved in DNA mismatch repair (MMR), mostly in the hMLH1 and hMSH2 genes. The mutation spectrum in the Belgian population is still poorly documented. Aim: To report our experience on the mutation screening in Belgian familial colorectal cancer (CRC) patients, including the investigation of the pathogenicity of the missense and splice mutations. To increase the mutation detection rate by selecting the target population. Methods: Two hundred and twenty five Belgian patients with familial clustering of CRC were genetically tested. Point mutations in the hMLH1 and hMSH2 genes were screened by denaturing gradient gel electrophoresis (DGGE) followed by direct sequencing. Genomic deletions and duplications were assessed by multiplex ligase dependent probe amplification (MLPA) and multiplex PCR. Missense mutations were examined for pathogenicity by means of cosegregation of the mutation with the disease, microsatellite instability (MSI) in tumors, immunohistochemical staining of tumors and determination of the population frequency of the particular mutation. Results: Twenty five pathogenic mutations were identified from which 16 were novel: 7 frameshifts, one in frame deletion, 5 genomic deletions, 5 splice defects, 4 nonsense (stop) mutations and 3 missense mutations which were classified as pathogenic (out of 10 missense mutations). In retrospect, a mutation detection rate of 71% was obtained if MSI was used as a supplementary selection criterion in addition to familial clustering. Conclusion: Different types of pathogenic mutations in the hMLH1 and hMSH2 genes were identified in a Belgian CRC group with familial clustering. The mutation detection yield drastically increased by preliminar selection of those familial CRC patients with a microsatellite instable tumor. Considerable attention went to the assessment of the pathogenicity of the missense mutations. In practice, the cosegregation with the disease was the most relevant criterion.     

Association of apolipoprotein E polymorphisms and dietary factors in colorectal cancer

ApoE single nucleotide polymorphisms (SNPs) Cys112Arg (Epsilon-4), and Arg158Cys (Epsilon-2) have been implicated in cardiovascular and Alzheimer''s disease, but their role in colorectal cancer (CRC) has not been extensively studied. We investigated whether ApoE polymorphisms alone or in combination with dietary factors selectively contribute to mismatch-repair (MMR) proficient (microsatellite stable/low or MSS/L) vs deficient (microsatellite unstable or MSI-H) CRCs. We carried out a case–control study with 906 CRC cases and 911 unaffected controls to examine the associations between ApoE polymorphisms and dietary factors and assessed their contribution to MSS/L and MSI-H CRCs. We used unconditional logistic regression to evaluate the associations between ApoE SNPs, tumour MSI status, and dietary factors after adjusting for age and sex. All statistical tests were two-sided. No significant differences in ApoE genotype frequencies were observed between CRC cases and unaffected controls. We observed that increased dietary intake of total fat, saturated fat, cholesterol, and red meat was significantly associated with CRC. Among non-ApoE4 carriers, 2–4 and >4 red meat servings/week were associated with developing MSS/L CRC (OR=1.51, 95% CI 1.10–2.07 and OR=1.80, 95% CI 1.30–2.48, respectively), whereas among ApoE4 allele carriers, four or more red meat servings/week were associated with MSI-H CRC (OR=4.62, 95% CI 1.20–17.77) when compared with the controls. ApoE isoforms modulate the risk of MSI-H and MSS/L CRCs among high red meat consumers.     

Assessment of microsatellite instability status for the prediction of metachronous recurrence after initial endoscopic submucosal dissection for early gastric cancer

The technique of endoscopic submucosal dissection (ESD) has been developed for en bloc resection of early gastric cancer (EGC); however, little is known about the risk of metachronous cancer in the remnant stomach after initial ESD. In this study, we investigated the correlation between microsatellite instability (MSI) status and the incidence of metachronous recurrence of gastric cancer. According to the genetic/molecular background determined with MSI status and expression levels of hMLH1 and p53 tumour suppressor, 110 EGCs removed with ESD were subclassified into three groups: the mutator/MSI-type (8%), suppressor/p53-type (45%) and unclassified type (47%). Interestingly, patients with the mutator/MSI-type tumour had a high incidence (67%) of metachronous recurrence of gastric cancer within a 3-year observation after initial ESD, which was significantly higher than those with the suppressor/p53-type and unclassified type tumours (P<0.01). Although we investigated mucin phenotypes, there was no correlation between mucin phenotype and the recurrence of EGC. These findings suggest that subclassification of molecular pathological pathways in EGCs is required for the assessment of patients with a high risk of recurrent gastric cancer. The information delivered from our investigation is expected to be of value for decisions about therapy and surveillance after ESD.     

Incidence and detection of high microsatellite instability in colorectal cancer in a Chinese population: a meta-analysis

BackgroundThe 4 most common types of DNA mutations in tumors are single-nucleotide variations, insertion-deletion, fusion, and copy number variations. This is followed by microsatellite instability (MSI), which is known to trigger the development of MSI-high (MSI-H) cancer and is responsible for 300,000 new cases of cancer per year in China. We aim to conduct a meta-analysis based on a comparison between the positive rates of the National Cancer Institute (NCI) panel (also known as 2B3D NCI panel) and mononucleotide panels for the diagnosis of MSI in the Chinese population.MethodsIn the present meta-analysis, we searched the PubMed, Embase, Web of Science, CNKI, Wanfang, CQVIP, and CBM databases. MSI diagnosis studies by PCR and capillary electrophoresis were included to compare the incidence of MSI-H in colorectal cancer obtained from panels with different microsatellite markers. Egger’s bias test was used to assess risk of bias.ResultsSeventeen articles were included, which used the Newcastle-Ottawa Scale (NOS) scale for quality evaluation. The NOS scores of the included documents were ≥7 points, and the quality of the documents met the requirements. The incidence of MSI-H detected by the 2B3D NCI panel was 13.5% [95% confidence interval (CI): 10.8–16.4, I²=52.321%, P=0.026, n=10 studies including 2,681 participants], the incidence of MSI-H detected by the mononucleotide panels was 10.6% (95% CI: 7.1–14.7, I²=81.147%, P=0.000, n=7 studies including 3,249 participants). This indicates that, in the Chinese population, the 2B3D NCI panel can detect 27.4% more MSI-H cancers than the mononucleotide panels, 54.7% more MSI-H cancers than the panel of 6 mononucleotides, and its sensitivity is comparable to that of Promega.ConclusionsThe findings of the meta-analysis demonstrated that, using the 2B3D NCI panel for MSI detection can avoid the underestimation of the incidence MSI-H in colorectal cancer and can be considered the most suitable panel for MSI detection in the Chinese population. The inclusion of only published data might be a potential source of publication bias.     

Deficient mismatch repair system in patients with sporadic advanced colorectal cancer

A deficient mismatch repair system (dMMR) is present in 10–20% of patients with sporadic colorectal cancer (CRC) and is associated with a favourable prognosis in early stage disease. Data on patients with advanced disease are scarce. Our aim was to investigate the incidence and outcome of sporadic dMMR in advanced CRC. Data were collected from a phase III study in 820 advanced CRC patients. Expression of mismatch repair proteins was examined by immunohistochemistry. In addition microsatellite instability analysis was performed and the methylation status of the MLH1 promoter was assessed. We then correlated MMR status to clinical outcome. Deficient mismatch repair was found in only 18 (3.5%) out of 515 evaluable patients, of which 13 were caused by hypermethylation of the MLH1 promoter. The median overall survival in proficient MMR (pMMR), dMMR caused by hypermethylation of the MLH1 promoter and total dMMR was 17.9 months (95% confidence interval 16.2–18.8), 7.4 months (95% CI 3.7–16.9) and 10.2 months (95% CI 5.9–19.8), respectively. The disease control rate in pMMR and dMMR patients was 83% (95% CI 79–86%) and 56% (30–80%), respectively. We conclude that dMMR is rare in patients with sporadic advanced CRC. This supports the hypothesis that dMMR tumours have a reduced metastatic potential, as is observed in dMMR patients with early stage disease. The low incidence of dMMR does not allow drawing meaningful conclusions about the outcome of treatment in these patients.     

Mismatch repair status in patients with primary operable colorectal cancer: associations with the local and systemic tumour environment

Background:

Mismatch repair-deficient (dMMR) colorectal cancer (CRC) is associated with a conspicuous local immune infiltrate; however, its relationship with systemic inflammatory responses remains to be determined. The present study aims to examine the relationships and prognostic value of assessment of the local and systemic environment in the context of MMR status in patients with CRC.

Methods:

The relationship between MMR status, determined using immunohistochemistry, and the local inflammatory cell infiltrate, differential white cell count, neutrophil : platelet score (NPS), neutrophil : lymphocyte ratio and modified Glasgow Prognostic Score (mGPS), and cancer-specific survival was examined in 228 patients undergoing resection of stage I–III CRC.

Results:

Thirty-five patients (15%) had dMMR CRC. Mismatch repair deficiency was associated with a higher density of CD3⁺, CD8⁺ and CD45R0⁺ T lymphocytes within the cancer cell nests and an elevated mGPS (mGPS2: 23% vs 9%, P=0.007) and NPS (NPS2: 19% vs 3%, P=0.001). CD3⁺ density (P<0.001), mGPS (P=0.01) and NPS (P=0.042) were associated with survival independent of MMR status (P=0.367) and stratified 5-year survival of patients with MMR-competent CRC from 94% to 67%, 83% to 46% and 78% to 60% respectively.

Conclusions:

Mismatch repair deficiency was associated with local and systemic environments, and in comparison with their assessment, dMMR had relatively poor prognostic value in patients with primary operable CRC. In addition to MMR status, local and systemic inflammatory responses should be assessed in these patients.     

错配修复基因变异与中国人散发性大肠癌发病年龄之间的关系

目的 :探讨错配修复基因变异与中国人散发性大肠癌发病年龄之间的关系。方法 :随机选取 1 0 0例临床初诊的散发性大肠癌患者 ,配对提取手术切除的癌组织和同源正常组织的基因组DNA ,检测并分析癌细胞微卫星DNA不稳定性 (MSI)。结果 :46/1 0 0 (46 % )的癌组织MSI阳性 (MSI+ ) ,其中 1 8%为MSI+ H ,2 8%MSI+ L。按年龄分组分析表明 ,发病年龄 <45岁的大肠癌患者中MSI+ 检出率明显高于≥ 65岁的大肠癌患者 (P <0 .0 5) ,且MSI+ 的检出率与患者的发病年龄呈负相关 (r =- 0 .95 ,P <0 .0 5) ,但与癌细胞的分化及患者的临床分期无关。结论 :中国人散发性大肠癌中错配修复基因功能的丧失可能出现在癌症发生的早期 ,可能参与构成部分散发性大肠癌发病的遗传背景因素