Incidence and management of patients with colorectal cancer and synchronous and metachronous colorectal metastases: a population-based study.

BACKGROUND: This population-based study aimed to examine the incidence, patterns and results of multimodal management of metastatic colorectal cancer. METHODS: A retrospective population-based study was conducted on patients with metastatic colorectal cancer in Central Finland in 2000-2015. Clinical and histopathological data were retrieved and descriptive analysis was conducted to determine the pattern of metastatic disease, defined as synchronous, early metachronous (within 12 months of diagnosis of primary disease) and late metachronous (more than 12 months after diagnosis). Subgroups were compared for resection and overall survival (OS) rates. RESULTS: Of 1671 patients, 296 (17·7 per cent) had synchronous metastases, and 255 (19·6 per cent) of 1302 patients with resected stage I-III tumours developed metachronous metastases (94 early and 161 late metastases). Liver, pulmonary and intraperitoneal metastases were the most common sites. The commonest metastatic patterns were a combination of liver and lung metastases. The overall metastasectomy rate for patients with synchronous metastases was 16·2 per cent; in this subgroup, 3- and 5-year OS rates after any resection were 63 and 44 per cent respectively, compared with 7·1 and 3·3 per cent following no resection (P < 0·001). The resection rate was higher for late than for early metachronous disease (28·0 versus 17 per cent respectively; P = 0·048). Three- and 5-year OS rates after any resection of metachronous metastases were 78 and 62 per cent respectively versus 42·1 and 18·2 per cent with no metastasectomy (P < 0·001). Similarly, 3- and 5-year OS rates after any metastasectomy for early metachronous metastases were 57 and 50 per cent versus 84 and 66 per cent for late metachronous metastases (P = 0·293). CONCLUSION: The proportion of patients with metastatic colorectal cancer was consistent with that in earlier population-based studies, as were resection rates for liver and lung metastases and survival after resection. Differentiation between synchronous, early and late metachronous metastases can improve assessment of resectability and survival.

ANTECEDENTES: El objetivo de este estudio de base poblacional fue analizar la incidencia, la forma de presentación y los resultados del tratamiento multimodal del cáncer colorrectal metastásico (metastatic colorectal cancer, mCRC). MÉTODOS: Se realizó un estudio retrospectivo de base poblacional en pacientes con mCRC en la región central de Finlandia entre 2000 a 2015. Se recuperaron los datos clínicos e histopatológicos y se realizó un análisis descriptivo con el objetivo de analizar la forma de presentación de la enfermedad metastásica. La enfermedad metastásica se definió como sincrónica, metacrónica precoz (< 12 meses) y metacrónica tardía (> 12 meses después del diagnóstico de la enfermedad primaria) y se compararon las tasas de resección y de supervivencia global (overall survival, OS) en estos subgrupos. RESULTADOS: De los 1.671 pacientes revisados, 296 (17,7%) presentaron metástasis sincrónicas, mientras que de los 1.302 pacientes resecados en estadios I-III, 255 (19,6%) tuvieron metástasis metacrónicas: 94 precoces y 161 tardías. La localización metastásica más frecuente fue el hígado, los pulmones y el peritoneo. La combinación más frecuente fue la de metástasis hepáticas y pulmonares. La tasa de resección para pacientes con metástasis sincrónicas fue del 16,2%; en este subgrupo, la OS a 3 y 5 años después de cualquier tipo de resección fue del 62,6% y 44,2% versus 7,1% y 3,3% en los pacientes sin resección, respectivamente (P < 0,001). La tasa de resección fue mayor en la enfermedad metacrónica tardía que en la enfermedad metacrónica precoz (28% versus 17%, P = 0,048). Las tasas de OS a 3 y 5 años después de cualquier resección en los casos de metástasis metacrónicas fueron del 77,8% y 61,9% versus 42,1% y 18,2% en los pacientes sin metastasectomía, P < 0,001. Las tasas de OS a 3 y 5 años después de cualquier metastasectomía en los casos de metástasis metacrónicas precoces fueron del 57,4% y 50,3%, versus 84,3% y 65,6% en las tardías (P = 0,29) CONCLUSIÓN: La proporción de pacientes con mCRC fue similar a la de estudios anteriores de base poblacional, así como las tasas de resección para metástasis hepáticas y pulmonares y la supervivencia después de la resección. Diferenciar entre metástasis sincrónicas, metacrónicas precoces y tardías puede mejorar la posibilidad de resecabilidad y la supervivencia.

Factors associated with decision-making on prophylactic hysterectomy and attitudes towards gynecological surveillance among women with Lynch syndrome (LS): a descriptive study.

To prevent endometrial carcinoma in Lynch syndrome (LS), regular gynecological surveillance visits and prophylactic surgery are recommended. Previous data have shown that prophylactic hysterectomy is an effective means of cancer prevention, while the advantages and disadvantages of surveillance are somewhat unclear. We aimed to evaluate female LS carriers' attitudes towards regular gynecological surveillance and factors influencing their decision-making on prophylactic surgery that have not been well documented. Pain experienced during endometrial biopsies was also evaluated. Postal questionnaires were sent to LS carriers undergoing regular gynecological surveillance. Questionnaires were sent to 112 women with LS, of whom 76 responded (68%). Forty-two (55%) had undergone prophylactic hysterectomy by the time of the study. The majority of responders (64/76; 84.2%) considered surveillance appointments beneficial. Pain level during endometrial biopsy was not associated with the decision to undergo prophylactic surgery. The level of satisfaction the women had with the information and advice provided during surveillance was significantly associated with the history of prophylactic hysterectomy (satisfaction rate of 73.2% versus 31.8% of nonoperated women, p = 0.003). The women who had undergone prophylactic surgery were older than the nonoperated women both at mutation testing (median of 42.3 years versus 31.6 years, p < 0.001) and at the time of the study (median of 56.9 years versus 46.0 years, respectively, p < 0.001). Women with LS pathogenic variants have positive experiences with gynecological surveillance visits, and their perception of the quality of the information and advice obtained plays an important role in their decision-making concerning prophylactic surgery.

Recurrent groin hernia surgery after primary open inguinal procedures: a reappraisal of the open preperitoneal (Ugahary) technique.

PURPOSE: There are several methods for repairing recurrent inguinal hernia, depending on the type of initial repair. Our aim was to analyze our long follow-up results on the open preperitoneal repair for patients with recurrent inguinal hernia. METHODS: Our retrospective survey included 135 consecutive recurrent inguinal hernia patients, operated on during 1999-2010, with a mean follow-up time of 8.7 years. RESULTS: During the mean follow-up time of 8.7 years, only four (3%) patients developed a re-recurrence. Two of these patients were asymptomatic, and the two other were operated on. Early postoperative complications occurred in four (3%) patients. The complications comprised one hematoma, one seroma, and two infections. Chronic pain was diagnosed in five (3.7%) patients, but their symptoms disappeared spontaneously within a few years. CONCLUSIONS: We conclude that in competent hands, the open preperitoneal repair (Ugahary) is a good surgical option in operating recurrent inguinal hernias.

The Accuracy of the Computed Tomography Diagnosis of Acute Appendicitis: Does the Experience of the Radiologist Matter?

BACKGROUND AND AIMS: To assess the accuracy of computed tomography in diagnosing acute appendicitis with a special reference to radiologist experience. MATERIAL AND METHODS: Data were collected prospectively in our randomized controlled trial comparing surgery and antibiotic treatment for uncomplicated acute appendicitis (APPAC trial, NCT01022567). We evaluated 1065 patients who underwent computed tomography for suspected appendicitis. The on-call radiologist preoperatively analyzed these computed tomography images. In this study, the radiologists were divided into experienced (consultants) and inexperienced (residents) ones, and the comparison of interpretations was made between these two radiologist groups. RESULTS: Out of the 1065 patients, 714 had acute appendicitis and 351 had other or no diagnosis on computed tomography. There were 700 true-positive, 327 true-negative, 14 false-positive, and 24 false-negative cases. The sensitivity and the specificity of computed tomography were 96.7% (95% confidence interval, 95.1-97.8) and 95.9% (95% confidence interval, 93.2-97.5), respectively. The rate of false computed tomography diagnosis was 4.2% for experienced consultant radiologists and 2.2% for inexperienced resident radiologists (p = 0.071). Thus, the experience of the radiologist had no effect on the accuracy of computed tomography diagnosis. CONCLUSION: The accuracy of computed tomography in diagnosing acute appendicitis was high. The experience of the radiologist did not improve the diagnostic accuracy. The results emphasize the role of computed tomography as an accurate modality in daily routine diagnostics for acute appendicitis in all clinical emergency settings.

Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer.

BACKGROUND: The objective of the study was to examine the role of microsatellite instability (MSI) and BRAF(V600E)mutation in colorectal cancer (CRC) by categorising patients into more detailed subtypes based on tumour characteristics. METHODS: Tumour samples from 762 population-based patients with sporadic CRC were analysed for MSI and BRAF(V600E) by immunohistochemistry. Patient survival was followed-up for a median of 5.2 years. RESULTS: Compared with microsatellite stable (MSS) CRC, MSI was prognostic for better disease-free survival (DFS; 5 years: 85.8% vs 75.3%, 10 years: 85.8% vs 72.9%, P=0.027; HR 0.49, CI 0.30-0.80, P=0.005) and disease-specific survival (DSS; 5 years: 83.2% vs 70.5%; 10 years: 83.2 vs 65.0%, P=0.004). Compared with BRAF wild type, BRAF(V600E) was a risk for poor survival (overall survival; 5 years: 62.3% vs 51.6%, P=0.014; HR 1.43, CI 1.07-1.90, P=0.009), especially in rectal cancer (for DSS, HR: 10.60, CI: 3.04-36.92, P<0.001). The MSS/BRAF(V600E) subtype was a risk for poor DSS (HR: 1.88, CI: 1.06-3.31, P=0.030), but MSI/BRAF(V600E) was a prognostic factor for DFS (HR: 0.42, CI: 0.18-0.96, P=0.039). Among stage I-II patients, the MSS/BRAF(V600E) subtype was independently associated with poor DSS (HR: 5.32, CI: 1.74-16.31, P=0.003). CONCLUSIONS: Microsatellite instable tumours were associated with better prognosis compared with MSS. BRAF(V600E) was associated with poor prognosis unless it occurred together with MSI. The MSI/BRAF(V600E) subtype was a favourable prognostic factor compared with the MSS/BRAF wild-type subtype. BRAF(V600E) rectal tumours showed particularly poor prognosis. The MSS/BRAF(V600E) subtype was associated with increased disease-specific mortality even in stage I-II CRC.

Identification of 33 candidate oncogenes by screening for base-specific mutations.

BACKGROUND: Genes with recurrent codon-specific somatic mutations are likely drivers of tumorigenesis and potential therapeutic targets. Hypermutable cancers may represent a sensitive system for generation and selection of oncogenic mutations. METHODS: We utilised exome-sequencing data on 25 sporadic microsatellite-instable (MSI) colorectal cancers (CRCs) and searched for base-specific somatic mutation hotspots. RESULTS: We identified novel mutation hotspots in 33 genes. Fourteen genes displayed mutations in the validation set of 254 MSI CRCs: ANTXR1, MORC2, CEP135, CRYBB1, GALNT9, KRT82, PI15, SLC36A1, CNTF, GLDC, MBTPS1, OR9Q2, R3HDM1 and TTPAL. A database search found examples of the hotspot mutations in multiple cancer types. CONCLUSIONS: This work reveals a variety of new recurrent candidate oncogene mutations to be further scrutinised as potential therapeutic targets.

Evaluation of a fast-track protocol for patients undergoing colorectal surgery.

BACKGROUND AND AIMS: Fast-track protocols have been used to optimize the perioperative care and to enhance postoperative recovery. This study examined short-term clinical outcomes and determinants affecting the length of postoperative hospital stay. MATERIAL AND METHODS: From 2007 to 2009, 180 patients underwent laparoscopic or open bowel resection (N = 138) or sacrocolporectopexy (N = 42) in the Central Hospital of Central Finland for various colorectal diseases in the fast-track setting. The main measures of outcome were time to functional recovery, 30-day morbidity, and readmission rates, with hospital stay and patient satisfaction as secondary outcomes. RESULTS: There were no deaths. Time to functional recovery was median 2 (interquartile range 2-3) days. The overall 30-day postoperative morbidity was 14.5% after bowel resection and 0% after sacrocolporectopexy. Relaparotomy rate was 3.6% and 30-day readmission rate 7.2%. Postoperative hospital stay was median 3 days after small bowel and ileo-colic resection, 4 days after segmental colectomy, and 6 days after rectal resection and subtotal colectomy. Patient's body mass index > 30 kg/m2, malignant disease, complexity of surgery, recovery of bowel function later than 2 days after surgery, time to functional recovery > 2 days and postoperative morbidity were patient- and treatment-related determinants increasing postoperative hospital stay. Protocol compliance-related determinants increasing postoperative hospital stay were intake of normal food and mobilization ≥ 6 h/day later than 2 days after surgery and removal of urinary catheter later than 1 day after surgery. CONCLUSION: Postoperative functional recovery was fast, morbidity and readmission rates were low, and postoperative hospital stay short indicating that fast-track care should form the mainstay of elective colorectal surgery.

Somatic MED12 mutations in uterine leiomyosarcoma and colorectal cancer.

BACKGROUND: Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. Recently, we discovered through exome sequencing that as many as 70% of uterine leiomyomas harbour specific mutations in exon 2 of mediator complex subunit 12 (MED12). In this work, we examined the role of MED12 exon 2 mutations in other tumour types. METHODS: The frequency of MED12 exon 2 mutations was analysed in altogether 1158 tumours by direct sequencing. The tumour spectrum included mesenchymal tumours (extrauterine leiomyomas, endometrial polyps, lipomas, uterine leiomyosarcomas, other sarcomas, gastro-intestinal stromal tumours), hormone-dependent tumours (breast and ovarian cancers), haematological malignancies (acute myeloid leukaemias, acute lymphoid leukaemias, myeloproliferative neoplasms), and tumours associated with abnormal Wnt-signalling (colorectal cancers (CRC)). RESULTS: Five somatic alterations were observed: three in uterine leiomyosarcomas (3/41, 7%; Gly44Ser, Ala38_Leu39ins7, Glu35_Leu36delinsVal), and two in CRC (2/392, 0.5%; Gly44Cys, Ala67Val). CONCLUSION: Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas, suggesting that a subgroup of these malignant tumours may develop from a leiomyoma precursor. Mutations in CRC samples indicate that MED12 may, albeit rarely, contribute to CRC tumorigenesis.

The role of surgery in Crohn's disease: a retrospective analysis from a single hospital.

BACKGROUND: Traditionally, in Crohn's disease (CD), surgery has played an essential role in the treatment of complications. TNF-α-blockers have significantly improved results of conservative treatment but they do not definitely cure Crohn's disease. AIM: Our aim was to examine the prevalence of and indications for surgical procedures in CD in our hospital. MATERIAL AND METHODS: A retrospective survey included all CD patients diagnosed in our hospital referral area during a 10-year period in 1996-2005. RESULTS: Altogether 114 new patients with CD were diagnosed, 56 (49%) males, 58 (51%) fe-males. The median follow-up time was 5.0 years. In all, 31 (27%) patients underwent some sur-gical procedure, and of these, 12 (39%) underwent an emergency operation. The most common indication for surgery was bowel obstruction. The most frequent procedures were ileocolic re-section in 12 (39%) patients and small bowel resection in 10 (32%). CONCLUSIONS: Almost one-third of CD patients needed surgical therapy in an early phase of their disease, and more than one-third of these underwent an emergency procedure. Obstructive symptoms were the most common indication for surgery in the early phase of CD.

Peutz-Jeghers syndrome: a systematic review and recommendations for management.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

Recommendations to improve identification of hereditary and familial colorectal cancer in Europe.

Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment.

Expertise and skill in minimally invasive surgery.

New attitudes to medical ethics and demands for efficiency have brought increased attention to surgical skills and training. It is important to characterize the expertise and skill involved in the multidimensional surgical profession. At a time of change, there is a need to discuss the nature of surgical expertise, and also the prospects for resident training, with special reference to new minimally invasive techniques (MIS). In this paper, we selectively review knowledge on surgical expertise and the specific demands placed on a skilled MIS surgeon. In addition, the review contains a selection of studies from those areas that have been seen as important for the future of training in surgery.

Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors.

Hereditary non-polyposis colorectal carcinoma (Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). Lynch syndrome patients are predisposed to different cancers in a non-random fashion, the basis of which is poorly understood. We addressed this issue by determining the molecular profiles for different tumors from a nationwide cohort of Lynch syndrome families (approximately 150 tumors in total). We focused on some less prevalent cancers, affecting the brain (n = 7) and urinary tract (five bladder and five ureter uroepithelial cancers and four kidney adenocarcinomas), and compared their molecular characteristics to those of the most common cancers, colorectal, gastric and endometrial adenocarcinomas, from the same families. Despite origin from verified MMR gene mutation carriers, the frequency of high-level microsatellite instability in tumors varied between high (100-96% for ureter, stomach and colon), intermediate (63-60% for endometrium and bladder) and low (25-0% for kidney and brain). In contrast to gastrointestinal and endometrial carcinomas, active (nuclear) beta-catenin was rare and KRAS mutations were absent in brain and urological tumors. Compared with other tumors, frequent stabilization of p53 protein characterized urinary tract cancers. Promoter methylation of tumor suppressor genes discriminated the tumors in an organ-specific manner. Our findings suggest that different Lynch syndrome tumors develop along different routes. Uroepithelial cancers of the ureter (and bladder to lesser extent) share many characteristics of MMR deficiency-driven tumorigenesis, whereas brain tumors and kidney adenocarcinomas follow separate pathways.

Guidelines for the clinical management of familial adenomatous polyposis (FAP).

BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.

Direct contact in inviting high-risk members of hereditary colon cancer families to genetic counselling and DNA testing.

BACKGROUND: Identification of hereditary predisposition to cancer has limited significance if not followed by efficient cancer prevention in the family. Probands are traditionally left to inform their relatives about the increased risk, but distant relatives may remain uninformed. An approach to contacting directly at-risk persons assumed to be unaware of their increased cancer risk was taken. With cancer prevention as the ultimate goal, the study was aimed at investigating attitudes towards and psychosocial consequences of this novel strategy. METHODS: In families with hereditary non-polyposis colorectal cancer (Lynch syndrome), 286 healthy adult relatives with a 50% risk of a predisposing mutation were contacted by letter. Of these, 112 participated in counselling and predictive testing. Baseline information and information obtained 1 month after the test for 73 respondents were compared with 299 corresponding subjects, approached via the proband (family-mediated approach in our previous study) in these families. RESULTS: After the contact letter, 51% consented to the study. Of these, 92% approved of the direct contact and 33% had tried to seek information. In 34% of the mutation carriers, neoplasia was identified in the first post-test colonoscopy. Although post-test fear of cancer increased among the mutation carriers and decreased among noncarriers, almost all participants were satisfied with their decision to participate, independently of their test results, parallel to the family-mediated approach. CONCLUSION: In this large-scale study, relatives in cancer families were actively contacted to inform them of the condition and genetic counselling. Their attitudes were encouraging, and the psychosocial consequences were similar to the family-mediated approach. Our results suggest the appropriateness of direct contact as an alternative method of contact in cases of life-threatening treatable disease.

Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer).

Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.

Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study.

BACKGROUND: Gastric cancer is the second most common extracolonic malignancy in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome. As gastric cancer is relatively common in the general population as well, it is not clear whether or not gastric cancer is a true HNPCC spectrum malignancy. AIM: To determine whether or not gastric cancer is a true HNPCC spectrum malignancy. SUBJECTS AND METHODS: The molecular and clinicopathological profiles of gastric cancers (n = 13) from HNPCC mutation carriers were evaluated and compared with the profiles of sporadic gastric cancers (n = 46) stratified by histology and microsatellite instability (MSI) status. RESULTS: This study on sporadic and HNPCC gastric cancers revealed several important universal associations. Loss of heterozygosity in the adenomatous polyposis coli (APC) region was associated with intestinal histology regardless of the MSI (p = 0.007). KRAS-mutations (p = 0.019) and frameshift mutations in repeat tracts of growth-regulatory genes (p<0.001) were associated with MSI tumours being absent in microsatellite stable (MSS) tumours. The average number of methylated tumour suppressor gene loci among the 24 genes studied (methylation index) was higher in MSI than in MSS tumours regardless of histology (p<0.001). Gastric cancers from HNPCC mutation carriers resembled sporadic intestinal MSI gastric cancers, except that MLH1 promoter methylation was absent (p<0.001) and the general methylation index was lower (p = 0.038), suggesting similar, but not identical, developmental pathways. All these lacked the mismatch repair protein corresponding to the germline mutation and displayed high MSI. CONCLUSION: The present molecular evidence, combined with the previous demonstration of an increased incidence relative to the general population, justify considering gastric cancers as true HNPCC spectrum malignancies.

Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis.

Serrated colorectal carcinomas (CRCs) are morphologically different from conventional CRCs and have been proposed to follow a distinct pathway of CRC formation. Despite studies of single molecular events in this tumor type, the diagnosis of serrated CRC relies on morphology and the putative unique biological character of these tumors has not been established. Here we show that the gene expression profiling of 37 CRCs separated serrated and conventional CRCs into two distinct branches in unsupervised hierarchical clustering (P-value 7.8 x 10(-7)), and revealed 201 differentially expressed genes representing potential biomarkers for serrated CRC. Immunohistochemistry was utilized to verify the key findings in the 37 CRCs examined by expression profiling, and a separate validation set of 37 serrated and 86 conventional CRCs was examined to evaluate the candidate biomarkers in an extended sample material. Ephrin receptor B2, hypoxia-inducible factor 1-alpha and patched appeared as proteins important for genesis of serrated CRC. This study establishes serrated CRCs as a biologically distinct subclass of CRC and represents a step forward in the molecular classification of these cancers. The study also provides a platform to understand the molecular basis of serrated CRC and in long term may contribute to the development of specific treatment options for this tumor type.

No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P=0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.