Disease expression in juvenile polyposis syndrome: a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers.

PURPOSE: Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. METHODS: We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature. RESULTS: We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%). CONCLUSION: This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.

No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies.

BACKGROUND & AIMS: Patients 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci.

Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.

Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease.

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2 = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.

Human population dynamics in Europe over the Last Glacial Maximum.

The severe cooling and the expansion of the ice sheets during the Last Glacial Maximum (LGM), 27,000-19,000 y ago (27-19 ky ago) had a major impact on plant and animal populations, including humans. Changes in human population size and range have affected our genetic evolution, and recent modeling efforts have reaffirmed the importance of population dynamics in cultural and linguistic evolution, as well. However, in the absence of historical records, estimating past population levels has remained difficult. Here we show that it is possible to model spatially explicit human population dynamics from the pre-LGM at 30 ky ago through the LGM to the Late Glacial in Europe by using climate envelope modeling tools and modern ethnographic datasets to construct a population calibration model. The simulated range and size of the human population correspond significantly with spatiotemporal patterns in the archaeological data, suggesting that climate was a major driver of population dynamics 30-13 ky ago. The simulated population size declined from about 330,000 people at 30 ky ago to a minimum of 130,000 people at 23 ky ago. The Late Glacial population growth was fastest during Greenland interstadial 1, and by 13 ky ago, there were almost 410,000 people in Europe. Even during the coldest part of the LGM, the climatically suitable area for human habitation remained unfragmented and covered 36% of Europe.

Subtotal Colectomy for Colon Cancer Reduces the Need for Subsequent Surgery in Lynch Syndrome.

BACKGROUND: The risk of metachronous colorectal cancer is high after surgical resection for first colon cancer in Lynch syndrome. OBJECTIVE: This study aimed to examine whether extended surgery decreases the risk of subsequent colorectal cancer and improves long-term survival. DESIGN: This was a retrospective study. SETTING: Data were collected from a nationwide registry. PATIENTS: Two hundred forty-two Lynch syndrome pathogenic variant carriers who underwent surgery for a first colon cancer from 1984 to 2009 were included. INTERVENTIONS: Patients underwent standard segmental colectomy (n = 144) or extended colectomy (n = 98) for colon cancer. Patients were followed a median of 14.6 up to 25 years. MAIN OUTCOME MEASURES: Risk of subsequent colorectal cancer in either group, overall and disease-specific survival, and operative mortality were the primary outcomes measured. RESULTS: Subtotal colectomy decreased the risk of subsequent colorectal cancer (HR, 0.20; 95% CI, 0.08-0.52; p = 0.001), compared with segmental resection. Subsequent colorectal cancer decreased in MLH1 carriers. The MSH2 carriers showed no statistical difference, possibly because of their small number. Disease-specific and overall survival within 25 years did not differ between the standard and extended surgeries (82.7% vs 87.2%, p = 0.76 and 47.2% vs 41.4%, p = 0.83). The cumulative risk of subsequent colorectal cancer was 20% in 10 years and 47% within 25 years after standard resection and 4% and 9% after extended surgery. The cumulative risk of metachronous colorectal cancer was 7% within 25 years after subtotal colectomy with ileosigmoidal anastomosis. One patient died of postoperative septicemia within 30 days after segmental colectomy. LIMITATIONS: Data on surgical procedures were primarily collected retrospectively. CONCLUSIONS: Lynch syndrome pathogenic variant carriers may undergo subtotal colectomy to manage first colon cancer and avoid repetitive abdominal surgery and to reduce the remaining bowel to facilitate easier endoscopic surveillance. It provides no survival benefit, compared with segmental colon resection. See Video Abstract at http://links.lww.com/DCR/A319.

Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report.

BACKGROUND: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. METHODS: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. RESULTS: Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). CONCLUSIONS: The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.

Somatic MED12 mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms.

BACKGROUND: Mediator is a multiprotein interface between eukaryotic gene-specific transcription factors and RNA polymerase II. Mutations in exon 2 of the gene encoding MED12, a key subunit of the regulatory kinase module in Mediator, are extremely frequent in uterine leiomyomas, breast fibroadenomas, and phyllodes tumors. These mutations disrupt kinase module interactions and lead to diminished Mediator-associated kinase activity. MED12 mutations in exon 26, resulting in a substitution of leucine 1224 to phenylalanine (L1224F), have been recurrently observed in prostate cancer. METHODS: To elucidate the molecular mechanisms leading to tumorigenesis in prostate cancer, we analyzed global interaction profiles of wild-type and L1224F mutant MED12 with quantitative affinity purification-mass spectrometry (AP-MS). Immunoprecipitation and kinase activity assay were used to further assess the interactions between Mediator complex subunits and kinase activity. The presence of L1224F mutation was analyzed in altogether 877 samples representing prostate hyperplasia, prostate cancer, and various tumor types in which somatic MED12 mutations have previously been observed. RESULTS: In contrast to N-terminal MED12 mutations observed in uterine leiomyomas, the L1224F mutation compromises neither the interaction of MED12 with kinase module subunits Cyclin C and CDK8/19 nor Mediator-associated CDK activity. Instead, the L1224F mutation was shown to affect interactions between MED12 and other Mediator components (MED1, MED13, MED13L, MED14, MED15, MED17, and MED24). Mutation screening revealed one mutation in a Finnish (Caucasian) prostate cancer patient, whereas no mutations in any other tumor type were observed. CONCLUSIONS: Specific somatic MED12 mutations in prostate cancer and uterine leiomyomas accumulate in two separate regions of the gene and promote tumorigenesis through clearly distinct mechanisms.

Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer.

BACKGROUND: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. METHODS: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls. RESULTS: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively. CONCLUSIONS: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.

Eleven candidate susceptibility genes for common familial colorectal cancer.

Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes.

[Diagnosis and treatment of Lynch syndrome]. / Lynchin oireyhtymän diagnostiikka ja hoito.

Lynch syndrome (LS) refers to an autosomal dominant genetic predisposition to develop colon cancer or cancers or the uterine corpus, stomach, urinary tract, ovaries, small intestine, mammary gland or bile ducts at a young age. The predisposition to cancer is caused by a germline mutation in one of the genes of the mismatch repair (MMR) system. International recommendations suggest immunohistochemical analysis of tumor tissue from at least those having developed colorectal cancer or endometrial cancer at an age of less than 70 years. This would allow the selection of patients to be referred for gene testing as well as identification of mutation carriers, for whom a regular colonoscopy follow-up is arranged at an interval of 2 to 3 years.

Genomic profile of pseudomyxoma peritonei analyzed using next-generation sequencing and immunohistochemistry.

Pseudomyxoma peritonei (PMP) is a relatively rare clinical syndrome characterized by neoplastic epithelial cells growing in the peritoneal cavity and secreting mucinous ascites. Our aim was to explore the molecular events behind this fatal but under-investigated disease. We extracted DNA from 19 appendix-derived PMP tumors and nine corresponding normal tissues, and analyzed the mutational hotspot areas of 48 cancer-related genes by amplicon-based next-generation sequencing (NGS). Further, we analyzed the protein expression of V600E mutated BRAF, MLH1, MSH2, MSH6 and p53 from a larger set of PMP tumors (n = 74) using immunohistochemistry. With NGS, we detected activating somatic KRAS mutations in all of the tumors studied. GNAS was mutated in 63% of the tumors with no marked difference between low-grade and high-grade tumors. Only one (5.3%) tumor showed oncogenic PIK3CA mutation, one showed oncogenic AKT1 mutation, three (15.8%) showed SMAD4 mutations and none showed an APC mutation. P53 protein was aberrantly expressed in higher proportion of high-grade tumors as compared with low-grade ones (31.3 vs. 7.1%, respectively; p = 0.012) and aberrant expression was an independent factor for reduced overall survival (p = 0.002). BRAF V600E mutation was only found in one (1.4%) high-grade tumor by immunohistochemistry (n = 74). All the studied tumors expressed mismatch repair proteins MLH1, MSH2 and MSH6. Our results indicate that KRAS mutations are evident in all and GNAS mutations in most of the PMPs, but BRAF V600E, PIK3CA and APC mutations are rare. Aberrantly expressed p53 is associated with high-grade histology and reduced survival.

Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency.

Little is known about the genetic factors that contribute to familial colorectal cancer type X (FCCX), characterized by hereditary nonpolyposis colorectal carcinoma with no mismatch repair defects. Genetic linkage analysis, exome sequencing, tumor studies, and functional investigations of 4 generations of a FCCX family led to the identification of a truncating germline mutation in RPS20, which encodes a component (S20) of the small ribosomal subunit and is a new colon cancer predisposition gene. The mutation was associated with a defect in pre-ribosomal RNA maturation. Our findings show that mutations in a gene encoding a ribosomal protein can predispose individuals to microsatellite-stable colon cancer. Evaluation of additional FCCX families for mutations in RPS20 and other ribosome-associated genes is warranted.

Costs of colorectal cancer in different states of the disease.

OBJECTIVES: This cross-sectional study estimates the resource use and costs among prevalent colorectal cancer (CRC) patients in different states of the disease. METHODS: Altogether 508 Finnish CRC patients (aged 26-96; colon cancer 56%; female 47%) answered a questionnaire enquiring about informal care, work capacity, and demographic factors. Furthermore, data on direct medical resource use and productivity costs were obtained from registries. Patients were divided into five mutually exclusive groups based on the disease state and the time from diagnosis: primary treatments (the first six months after the diagnosis), rehabilitation, remission, metastatic disease, and palliative care. The costs were calculated for a six-month period. Multivariate modeling was performed to find the cost drivers. RESULTS: The costs were highest during the primary treatment state and the advanced disease states. The total costs for the cross-sectional six-month period were €22 200 in the primary treatment state, €2106 in the rehabilitation state, €2812 in the remission state, €20 540 in the metastatic state, and €21 146 in the palliative state. Most of the costs were direct medical costs. The informal care cost was highest per patient in the palliative care state, amounting to 33% of the total costs. The productivity costs varied between disease states, constituting 19-40% of the total costs, and were highest in the primary treatment state. CONCLUSIONS: The first six months after the diagnosis of CRC are resource intensive, but compared with the metastatic disease state, which lasts on average for 2-3 years, the costs are rather modest. Informal care constitutes a remarkable share of the total costs, especially in the palliative state. These results form a basis for the evaluation of the cost effectiveness of new treatments when allocating resources in CRC treatment.

Promoter-specific alterations of APC are a rare cause for mutation-negative familial adenomatous polyposis.

n familial adenomatous polyposis (FAP), 20% of classical and 70% of attenuated/atypical (AFAP) cases remain mutation-negative after routine testing; yet, allelic expression imbalance may suggest an APC alteration. Our aim was to determine the proportion of families attributable to genetic or epigenetic changes in the APC promoter region. We studied 51 unrelated families/cases (26 with classical FAP and 25 with AFAP) with no point mutations in the exons and exon/intron borders and no rearrangements by multiplex ligation-dependent probe amplification (MLPA, P043-B1). Promoter-specific events of APC were addressed by targeted resequencing, MLPA (P043-C1), methylation-specific MLPA, and Sanger sequencing of promoter regions. A novel 132-kb deletion encompassing the APC promoter 1B and upstream sequence occurred in a classical FAP family with allele-specific APC expression. No promoter-specific point mutations or hypermethylation were present in any family. In conclusion, promoter-specific alterations are a rare cause for mutation-negative FAP (1/51, 2%). The frequency and clinical correlations of promoter 1B deletions are poorly defined. This investigation provides frequencies of 1/26 (4%) for classical FAP, 0/25 (0%) for AFAP, and 1/7 (14%) for families with allele-specific expression of APC. Clinically, promoter 1B deletions may associate with classical FAP without extracolonic manifestations.

Mutations in Exon 1 highlight the role of MED12 in uterine leiomyomas.

Mediator regulates transcription by connecting gene-specific transcription factors to the RNA polymerase II initiation complex. We recently discovered by exome sequencing that specific exon 2 mutations in mediator complex subunit 12 (MED12) are extremely common in uterine leiomyomas. Subsequent screening studies have focused on this mutational hot spot, and mutations have been detected in uterine leiomyosarcomas, extrauterine leiomyomas and leiomyosarcomas, endometrial polyps, and colorectal cancers. All mutations have been missense changes or in-frame insertions/deletions. Here, we have analyzed 611 samples representing all above-mentioned tumor types for possible exon 1 mutations. Five mutations were observed, all of which were in-frame insertion/deletions in uterine leiomyomas. Transcriptome-wide expression data revealed that MED12 exon 1 and exon 2 mutations lead to the same unique global gene expression pattern with RAD51B being the most upregulated gene. Immunoprecipitation and kinase activity assays showed that both exon 1 and exon 2 mutations disrupt the interaction between MED12 and Cyclin C and CDK8/19 and abolish the mediator-associated CDK kinase activity. These results further emphasize the role of MED12 in uterine leiomyomas, show that exon 1 and exon 2 exert their tumorigenic effect in similar manner, and stress that exon 1 should be included in subsequent MED12 screenings.

Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer.

ARID1A has been identified as a novel tumor suppressor gene in ovarian cancer and subsequently in various other tumor types. ARID1A belongs to the ARID domain containing gene family, which comprises of 15 genes involved, for example, in transcriptional regulation, proliferation and chromatin remodeling. In this study, we used exome sequencing data to analyze the mutation frequency of all the ARID domain containing genes in 25 microsatellite unstable (MSI) colorectal cancers (CRCs) as a first systematic effort to characterize the mutation pattern of the whole ARID gene family. Genes which fulfilled the selection criteria in this discovery set (mutations in at least 4/25 [16%] samples, including at least one nonsense or splice site mutation) were chosen for further analysis in an independent validation set of 21 MSI CRCs. We found that in addition to ARID1A, which was mutated in 39% of the tumors (18/46), also ARID1B (13%, 6/46), ARID2 (13%, 6/46) and ARID4A (20%, 9/46) were frequently mutated. In all these genes, the mutations were distributed along the entire length of the gene, thus distinguishing them from typical MSI target genes previously described. Our results indicate that in addition to ARID1A, other members of the ARID gene family may play a role in MSI CRC.

Identification of candidate oncogenes in human colorectal cancers with microsatellite instability.

Microsatellite instability can be found in approximately 15% of all colorectal cancers. To detect new oncogenes we sequenced the exomes of 25 colorectal tumors and respective healthy colon tissue. Potential mutation hot spots were confirmed in 15 genes; ADAR, DCAF12L2, GLT1D1, ITGA7, MAP1B, MRGPRX4, PSRC1, RANBP2, RPS6KL1, SNCAIP, TCEAL6, TUBB6, WBP5, VEGFB, and ZBTB2; these were validated in 86 tumors with microsatellite instability. ZBTB2, RANBP2, and PSRC1 also were found to contain hot spot mutations in the validation set. The form of ZBTB2 associated with colorectal cancer increased cell proliferation. The mutation hot spots might be used to develop personalized tumor profiling and therapy.

Comparison of serial debulking and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in pseudomyxoma peritonei of appendiceal origin.

PURPOSE: Patients with pseudomyxoma peritonei (PMP) benefit from cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Reports on this modality usually have included only patients with successful HIPEC treatment, which can potentially cause biased results. We report the survival of a PMP population treated by CRS and HIPEC, including patients who were not eligible for HIPEC. METHODS: The outcome of the whole population of 87 patients with PMP treated by CRS and HIPEC in Helsinki University Central Hospital between 2008 and 2011 was evaluated. The results of treatment were compared with 33 patients treated by serial debulking in our unit between 1984 and 2008. RESULTS: Of the 87 patients in the HIPEC-era group, 56 received HIPEC, 12 were treated non-radically in an attempt at HIPEC, 9 were debulked and 10 were referred back or transferred to palliative care without surgery. The 5-year overall survival for the debulking-era group and the HIPEC-era group were 67 and 69 %, respectively. The number of patients with no evidence of disease was higher in the HIPEC-era group (47/87) than that in the debulking-era group (8/33) at the end of the follow-up. Overall survival for patients who underwent successful CRS and HIPEC at 2 and 5 years was 95 and 93 %, respectively. CONCLUSIONS: The improved survival from using the CRS and HIPEC was not apparent after 5-year follow-up, when the whole patient population was included in the analysis. Even so, patients successfully treated by CRS and HIPEC manage well.

Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts.

Lynch syndrome (LS) 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. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.