散发性大肠癌患者中错配修复基因胚系突变筛查策略

目的探讨在散发性大肠癌患者中筛查错配修复(MMR)基因胚系突变的可行性和策略。方法以150例散发性大肠癌患者为研究对象,以微卫星不稳定性(MSI)检测和免疫组化(IHC)检测作为初筛方法,对MSI-H表型或IHC检测MMR蛋白缺失的患者行hMLH1和hMSH2基因测序,检测MMR基因胚系突变。结果150例散发性大肠癌中MSI-H表型20例,IHC示22例MMR蛋白缺失。共发现3例MMR基因突变。MSI检测和IHC检测结果具有很好的一致性。结论散发性大肠癌患者中分子生物学筛查方法能够有效鉴别出MMR基因胚系突变。     

Consequences of testing for mismatch repair deficiency of colorectal cancer in clinical practice

Introduction: Mismatch repair deficiency (dMMR) can be found in Lynch syndrome (LS)-associated colorectal carcinoma and in 15% of sporadic colorectal cancer (CRC). Outcome of MMR-deficiency testing is important for surgical decisions as extended colectomy is recommended in young LS-patients with CRC. Moreover, the finding of a dMMR tumour has consequences for the choices of adjuvant chemotherapy as MMR-deficient CRC is resistant to 5-fluorouracil (5-FU) monotherapy. Aims of our study are to evaluate whether MMR-deficiency testing leads to (1) identification of LS, (2) change in surgical treatment and (3) adjustment of systemic therapy in patients with dMMR CRC.

Methods: We performed a multicentre, retrospective study, in a community hospital and a University Medical Centre. We included all CRC-patients between 2012 and 2016 who were tested for microsatellite instability. We collected clinical data such as gender, age, referral to clinical geneticist, surgical procedure and choice of chemotherapy.

Results: We analysed 225 CRCs. Twenty-four (10.7%) of 225 CRC were MMR-deficient. Of the 24 patients with dMMR CRC, 18 (75%) were referred to the clinical geneticist and in nine (37%) patients a MMR mutation was identified. In one (4%) of the 24 patients, a subtotal colectomy was performed. In seven (35%) out of 20 MMR deficient patients, the chemotherapy regimen was adjusted.

Conclusions: The finding of a dMMR CRC had consequences for decisions on chemotherapy in a relative high proportion of patients. We recommend testing in all patients with CRC independent of age at diagnosis, as proper treatment decisions and genetic counselling are very important.     

Colonoscopy in patients with a family history of colorectal cancer

Since 1982 it has been the second author's policy to advise all patients who have presented with a positive family history of bowel cancer and who are over the age of 30 years to undergo colonoscopy. In the period to August 1990, 600 such patients had at least one colonoscopy. Colorectal polyps or cancer were detected in 270 patients (45 percent). The incidence was essentially the same for the 171 patients with only second-degree relatives affected (43 percent), for the 194 patients with more than one affected relative (45 percent), and for the 429 patients with an affected first-degree relative (46 percent). Only the 55 patients with more than one affected first-degree relative had a higher incidence (67 percent). The incidence in the 136 totally asymptomatic patients was 36 percent but was 48 percent in the 464 with symptoms. In 37 patients carcinoma was diagnosed. Even in the 30- to 39-year age group there was a 29 percent incidence of polyps or carcinoma. Colonoscopic screening of patients with a family history of bowel cancer compares favorably with mass screening for breast cancer. It is currently advised that all patients over 30 years of age with a family history of colorectal cancer undergo colonoscopy on presentation and, if clear, every four years thereafter unless two first-degree relatives are affected, when it should be every two years.Read in part at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, May 12 to 17, 1991.     

Cholecystectomy and the risk of colorectal cancer by tumor mismatch repair deficiency status

Purpose

Gallbladder diseases and cholecystectomy may play a role in the development of colorectal cancer (CRC). Our aim was to investigate the association between cholecystectomy and CRC risk overall and by sex, family history, anatomical location, and tumor mismatch repair (MMR) status.

Methods

This study comprised 5847 incident CRC cases recruited from population cancer registries in Australia, Canada, and the USA into the Colon Cancer Family Registry between 1997 and 2012 and 4970 controls with no personal history of CRC who were either randomly selected from the general population or were spouses of the cases. The association between cholecystectomy and CRC was estimated using logistic regression, after adjusting for confounding factors.

Results

Overall, there was no evidence for an association between cholecystectomy and CRC (odds ratio [OR] = 0.88, 95 % confidence interval 0.73, 1.08). In the stratified analyses, there was no evidence for a difference in the association between women and men (P = 0.54), between individuals with and without family history of CRC in first-degree relative (P = 0.64), between tumor anatomical locations (P = 0.45), or between MMR-proficient and MMR-deficient cases (P = 0.54).

Conclusion

Cholecystectomy is not a substantial risk factor for CRC, regardless of sex, family history, anatomical location, or tumor MMR status.

     

Accuracy of reporting of family history of colorectal cancer

BACKGROUND AND AIMS: Family history is used extensively to estimate the risk of colorectal cancer but there is considerable potential for recall bias and inaccuracy. Hence we systematically assessed the accuracy of family history reported at interview compared with actual cancer experience in relatives. METHODS: Using face to face interviews, we recorded family history from 199 colorectal cancer cases and 133 community controls, totalling 5637 first and second degree relatives (FDRs/SDRs). We linked computerised cancer registry data to interview information to determine the accuracy of family history reporting. RESULTS: Cases substantially underreported colorectal cancer arising both in FDRs (sensitivity 0.566 (95% confidence interval (CI) 0.433, 0.690); specificity 0.990 (95% CI 0.983, 0.994)) and SDRs (sensitivity 0.271 (95% CI 0.166, 0.410); specificity 0.996 (95% CI 0.992, 0.998)). There was no observable difference in accuracy of reporting family history between case and control interviewees. Control subjects similarly underreported colorectal cancer in FDRs (sensitivity 0.529 (95% CI 0.310, 0.738); specificity 0.995 (95% CI 0.989, 0.998)) and SDRs (sensitivity 0.333 (95% CI 0.192, 0.512); specificity 0.995 (95% CI 0.991, 0.995)). To determine practical implications of inaccurate family history, we applied family history criteria before and after record linkage. Only two of five families reported at interview to meet surveillance criteria did so after validation, whereas only two of six families that actually merited surveillance were identified by interview. CONCLUSIONS: This study has quantified the inaccuracy of interview in identifying people at risk of colorectal cancer due to a family history. Colorectal cancer was substantially underreported and so family history information should be interpreted with caution. These findings have considerable relevance to identifying patients who merit surveillance colonoscopy and to epidemiological studies.     

Screening for defective DNA mismatch repair in stage II and III colorectal cancer patients.

BACKGROUND & AIMS: Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome usually present in younger patients, show loss of mismatch repair (MMR) gene expression, and exhibit microsatellite instability (MSI). About 12% of sporadic colorectal cancers also show MMR loss and MSI. The aims of this study were to evaluate MMR loss and MSI in relation to patient age, sex, tumor stage, and site in the large bowel. METHODS: Tissue microarrays were created from 1020 stage II and III colorectal cancer cases and immunohistochemical staining performed to detect expression of the 2 major MMR proteins, hMLH1 and hMSH2. MSI was determined using the BAT-26 mononucleotide repeat. RESULTS: Ten percent of tumors showed loss of hMLH1 expression and 1.2% showed loss of hMSH2 expression. hMLH1 loss was more frequent in women (P < .001), older patients (P = .004), earlier stage tumors (P = .0001), and proximal colon tumors ( P < .0001). In contrast, tumors showing hMSH2 loss were more frequent in younger (P < .001), male (P = .05) patients and were distributed evenly between the proximal colon and distal colon/rectum. Eleven percent of tumors were MSI+ and these showed similar age, sex, stage, and site characteristics as tumors with hMLH1 loss. Discordance between MMR loss and MSI+ was found in 24 of 983 (2.4%) tumors. Of the 231 patients aged <60 years at diagnosis, 12 (5.2%) showed loss of hMLH1 and 8 (3.5%) showed loss of hMSH2. CONCLUSIONS: Routine immunohistochemical screening for MMR loss in younger colorectal cancer patients may provide a useful, first-step screening tool for the population-based detection of HNPCC.     

The risk of developing a mismatch repair deficient colorectal cancer after undergoing cholecystectomy

Objectives: Mismatch repair deficient (dMMR) colorectal cancer (CRC) is caused by inactivation of the MMR DNA repair system, most commonly via epigenetic inactivation of the MLH1 gene, and these tumors occur most frequently in the right colon. The objective was to determine whether cholecystectomy (CCY) increases the risk of a dMMR CRC by comparing CCY incidence in patients with dMMR CRC and proficient MMR (pMMR) CRC to unaffected controls.

Materials and methods: All patients diagnosed with CRC in Iceland from 2000 to 2009 (n?=?1171) were included. They had previously been screened for dMMR by immunohistochemistry (n?=?129 were dMMR). Unaffected age- and sex-matched controls (n?=?17,460) were obtained from large Icelandic cohort studies. Subjects were cross-referenced with all pathology databases in Iceland to establish who had undergone CCY. Odds ratios were calculated using unconditional logistic regression.

Results: Eighteen (13.7%) dMMR CRC cases and 90 (8.7%) pMMR CRC cases had undergone CCY compared to 1532 (8.8%) controls. CCY-related odds ratios (OR) were 1.06 (95% CI 0.90–1.26, p?=?.577) for all CRC, 1.16 (95% CI 0.66–2.05 p?=?.602) for dMMR CRCand 1.04 (95% CI 0.83–1.29, p?=?.744) for pMMR CRC. Furthermore, OR for dMMR CRC was 0.51 (95% CI 0.16–1.67, p?=?.266), 2.04 (95% CI 0.92–4.50, p?=?.080) and 1.08 (95% CI 0.40–2.89, p?=?.875)?<10 years, 10–20 years and?>20 years after a CCY, respectively.

Conclusions: There was no evidence of increased risk of developing dMMR CRC after CCY although a borderline significantly increased 2-fold risk was observed 10–20 years after CCY. Larger studies are warranted to examine this further.     

Colonoscopy in asymptomatic individuals with a family history of colorectal cancer

A prevalence screening program with colonoscopy was undertaken in four kindreds manifesting the cancer family syndrome. Forty-five percent of counseled patients underwent colonoscopy, providing 42 asymptomatic individuals. Seven patients (17%) were found to have adenomatous or villous polyps; two of these were malignant and one showed epithelial atypia. Three of the seven patients with polyps had multiple lesions. Only two patients had rectosigmoid polyps. From these limited data, colonoscopy is recommended as a useful screening procedure in individuals at high risk for colorectal cancer.     

Deficient mismatch repair phenotype is a prognostic factor for colorectal cancer in elderly patients

ObjectiveAbout 15% of colorectal adenocarcinomas have a deficient DNA mismatch repair phenotype. The frequency of deficient DNA mismatch repair tumours increases with age due to the hypermethylation of hMLH1 promoter. The study aimed to determine the prognostic value of deficient DNA mismatch repair phenotype in elderly patients.DesignMismatch repair phenotype was retrospectively determined by molecular analysis in consecutive resected colorectal adenocarcinoma specimens from patients over 75 years of age from 4 Oncology centres.Results231 patients (median age: 81, range: 75–100) were enrolled from 2005 to 2008. Mean prevalence of deficient DNA mismatch repair phenotype was 22.5%, and 36% for patients over 85 years. Deficient DNA mismatch repair status was significantly associated with older age, female sex, proximal colon primary and high grade tumour. For stage II tumours no deficient DNA mismatch repair tumours had a recurrence at end of follow-up compared to 17% for tumours with proficient phenotype. The proficient phenotype status was significantly associated with worse age-adjusted overall survival [HR 2.60; 95% CI 1.05–6.44; p = 0.039]. For stage III tumours a trend for less recurrence was observed for deficient DNA mismatch repair phenotype (16%) compared to proficient phenotype (36%).Conclusiondeficient DNA mismatch repair phenotype is a prognostic factor in stage II colorectal tumour in elderly patients. Our results suggest that mismatch repair phenotype should be taken in consideration for adjuvant chemotherapy decision in elderly patients.     

DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer

BACKGROUND AND AIM: Hereditary non-polyposis colorectal cancer (HNPCC), as its name implies, is associated with few adenomas, and the early evolution of colorectal neoplasia is poorly understood. In this study our aim was to clarify the genetic profiles of benign polyps in subjects with HNPCC using a combined molecular and immunohistochemical approach. METHODS: Thirty adenomas and 17 hyperplastic polyps were obtained from 24 affected HNPCC subjects. DNA was extracted from paraffin embedded tissue by microdissection and analysed for the presence of microsatellite instability (MSI) and mutations in five genes known to be targets in mismatch repair deficiency (TGFbetaRII, IGF2R, BAX, hMSH3, and hMSH6). Serial sections were stained by immunohistochemistry for hMLH1 and hMSH2. RESULTS: Twenty four (80%) of 30 adenomas showed MSI. Of MSI positive adenomas, 66.7% showed MSI at more than 40% of markers (high level of MSI (MSI-H)). Two of 17 hyperplastic polyps revealed MSI at one marker (low level of MSI (MSI-L)). A significant association was found between MSI-H and high grade dysplasia in adenomas (p=0.004). Eight of nine adenomas with mutations of coding sequences revealed high grade dysplasia and all nine were MSI-H. Four of the nine ranged in size from 2 to 5 mm. The presence of the hMSH6 mutation was significantly correlated with high levels of MSI (80% of markers) (p<0.02). Twenty four adenomas gave evaluable results with immunohistochemistry. One of six (17%) microsatellite stable, six of seven (86%) MSI-L, and 11 of 11 (100%) MSI-H adenomas showed loss of either hMLH1 or hMSH2. CONCLUSIONS: Most adenomas in subjects with a definite diagnosis of HNPCC show MSI (80%). The finding of MSI-L is usually associated with loss of expression of hMLH1 or hMSH2, unlike the situation in MSI-L sporadic colorectal cancer. The transition from MSI-L to MSI-H correlated with the finding of high grade dysplasia and mutation of coding sequences and may be driven by mutation of secondary mutators such as hMSH3 and hMSH6. Advanced genetic changes may be present in adenomas of minute size.