Better survival rates in patients with MLH1-associated hereditary colorectal cancer
Abstract
BACKGROUND & AIMS: Patients with hereditary nonpolyposis colorectal can cer (HNPCC) have been suggested to have a better prognosis than patients with common sporadic colorectal cancer. However, the evidence has not been convincing. The aim of this population-based study was to compare the survival rates of 175 patients with HNPCC with those of 14,000 patients with sporadic colorectal cancer diagnosed at <65 years of age in Finland from 1953 to 1993. METHODS: The recent progress in molecular genetics of hereditary colorectal cancer was utilized for the first time. One hundred twenty of the patients with HNPCC came from families segregating a germline mutation in the MLH1 cancer predisposition gene. RESULTS: The overall 5-year cumulative relative survival rate was 65% for patients with HNPCC and 44% for patients with sporadic colorectal cancer. The relative survival rates of patients with HNPCC were better in every strata analyzed. CONCLUSIONS: MLH1- associated colorectal cancer has a natural history different from that of common sporadic colorectal cancer. The better survival rates may be caused by the heavy mutation burden affecting mismatch repair deficient tumor cells. (Gastroenterology 1996 Mar;110(3):682-7)
References (0)
Cited by (310)
HFE variants in colorectal cancer and their clinicopathological correlations
2021, Human PathologyThe study aimed to screen mutation of human homeostatic iron regulator (HFE) in colorectal carcinoma (CRC) and detect their associations with clinicopathological parameters. Expression of HFE was determined by quantitative polymerase chain reaction in matched CRC and non neoplastic colorectal mucosal tissue of 76 patients. Genomic DNA extracted were subjected to high high-resolution melt curve analysis and Sanger sequencing to detect mutations in HFE. The associations of the identified mutations with a variety of clinical features were determined. Approximately 60% of CRC showed low HFE expression. Of the ten 10 mutations identified in exons 2 and 4, c.187C>G (H63D), c845G>A (C282Y), c.193A>T (S65C), g.3828T>C, g.5795T>C, and g.5728G>A were known mutations. Four novel mutations were discovered; : c.184G>A, c.220T>G, c.322A>C, and c.324T>C. Heterozygous H63D and C282Y mutations were seen in 71% and 49% of cancer tissue, respectively. Tumour site (p = 0.048) and gender (p = 0.039) were significantly associated with H63D and C282Y mutation status, respectively. Local spread of cancer was significantly associated with C282Y mutations in CRC cancer and adjacent non-neoplastic tissue (p = 0.029 & and p = 0.004, respectively). There was a statistically significant association between H63D and C282Y negativity in matched non-neoplastic colorectal mucosa tissue and pathological staging of cancer (p = 0.047 & and p = 0.001, respectively). Patients with H63D and C282Y mutations in cancer tissue tend to have higher survival rates. Hence HFE mutations are common in CRC and are associated with clinicopathological parameters, implying the potential clinical significance of HFE mutations in colorectal carcinogenesis.
Molecular Approach to Colorectal Carcinoma: Current Evidence and Clinical Application
2021, Surgical Pathology ClinicsCitation Excerpt :The advantage of these methods is they can be integrated into existing NGS pipelines for routine clinical testing. MSI-H CRCs have an improved prognosis in comparison with MSS tumors, particularly in the stage II setting.32–34 However, a number of studies have shown discordant results with regard to its role as a predictive biomarker for overall survival in stage III and stage IV CRC.35–39
Hereditary nonpolyposis CRC
2021, Foundations of Colorectal CancerHereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is the most common CRC hereditary syndrome. Clinically, there is a genetic predisposition to the onset of colon cancer at a young age, but it is also associated with other, noncolorectal cancers.
It has an autosomal dominant pattern of inheritance due to the germline mutation of genes involved in the repair of unpaired DNA bases (mismatch repair or MMR genes MLH1, MSH2, MSH6, PMS2, or EPCAM). For subjects who carry a mutation, the risk of developing CRC in the course of their lives ranges from 10% to 75%.
In general, the tumors of HNPCC patients are similar to sporadic CRCs but are more frequent in the right colon, and pathological anatomy studies show more frequent lymphocytic infiltrates, Crohn-like reaction, and a greater presence of peritumoral lymphocytes.
Monitoring of subjects belonging to families with HNPCC should include a complete colonoscopy, together with additional examinations depending on the associated spectrum of noncolorectal tumors present in their family.
Genetic testing for epithelial ovarian cancer
2020, Best Practice and Research: Clinical Obstetrics and GynaecologyAs the treatment of epithelial ovarian cancer (OC) moves further into personalised medicine, the importance of determining the presence or absence of inherited mutations in cancer susceptibility genes has grown. It is now becoming routine to test for germline mutations in the BRCA1 and BRCA2 genes, which are responsible for a significant proportion of hereditary epithelial OC and are established predictive biomarkers of potential benefit from poly ADP ribose polymerase (PARP) inhibitors. The identification of patients with hereditary OC allows the patient to benefit from personalised treatment, while allowing family members to undergo cascade testing, where identification of unaffected carriers can allow early detection, risk-reduction or prevention for both breast and OC, and ultimately improve long-term outcomes. Other susceptibility genes, include the Lynch Syndrome (mismatch repair) genes and several other genes involved in the homologous recombination pathway (HRD genes), are implicated in OC genesis, and are also becoming of increasing interest as therapeutic options grow for these patients. This review will highlight the importance of the early detection of a germline gene pathogenic variant, which informs on the clinical course of disease in a particular patient, and therefore, guides therapeutic management including risk reducing and personalised treatment.
No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies
2018, GastroenterologyPatients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1–2-year intervals), and Finland (patients evaluated at 2–3-year intervals).
We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy).
The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low- and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and time since last colonoscopy.
We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance intervals (the Netherlands, with 1–2-year intervals, and Finland, with 2–3-year intervals). Overall, we did not find a significant association of the interval with CRC risk, although age, sex, mutation, and prior neoplasia were used to individually modify colonoscopy intervals. Studies are needed to develop and validate risk-adapted surveillance strategies and to identify patients who benefit from shorter surveillance intervals.
Inherited mutations in DNA repair genes and cancer risk
2017, Current Problems in CancerAlthough most cancer cases are due to somatic mutations, up to 10% of cases are attributable to germline mutations. This inherited cancer predisposition is mostly due to the loss of function of suppressor genes rather than the activation of oncogenes. Defects in DNA repair genes are the genetic events most commonly involved in hereditary cancers. The implementation of high-throughput sequencing in diagnostic testing has uncovered new predisposition genes. Furthermore, for some tumor types these sequencing techniques have also unveiled a prevalence of germline mutations significantly higher than previous estimations. The clinical implications of many of these repair defects are yet to be defined. Further studies will need to be conducted to establish the most appropriated management of unaffected carriers that are likely to grow in numbers. On the contrary, the presence of DNA repair defects provides a unique opportunity for the development of treatments that take advantage of a tumor feature.
In this review article, we summarize not only the most common syndromes linked to DNA repair defects but also less known entities. We address the underlying genetics and the clinical implications of each DNA repair defect as well as the current recommendations for cancer surveillance.