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Introduction In a retrospective analysis of two randomized phase III trials in mCRC patients treated first line with oxaliplatin, fluoropyrimidine with and without Bevacizumab (the AIO KRK 0207 and R091 trials) we evaluated the association of high microsatellite instability (MSI-H), immunoscore (IS) and PD-L1 expression in relation to overall survival (OS). Methods In total, 550 samples were analysed. Immunohistochemical analysis of the MMR proteins and additionally fragment length analysis was performed, molecular examinations via allele-discriminating PCR in combination with DNA sequencing. Furthermore PD-L1 and IS were assessed. Results MSI-H tumors were more frequent in right sided tumors (13.66% vs. 4.14%) and were correlated with mutant BRAF (p = 0.0032), but not with KRAS nor NRAS mutations (MT). 3.1% samples were found to be PD-L1 positive, there was no correlation of PDL1 expression with MSI-H status, but in a subgroup analysis of MSI-H tumors the percentage of PD-L1 positive tumors was higher than in MSS tumors (9.75% vs. 2.55%). 8.5% of samples showed a positive IS, MSI-H was associated with a high IS. The mean IS of the pooled population was 0.57 (SD 0.97), while the IS of MSI-H tumors was significantly higher (mean of 2.4; SD 1.4; p = Discussion Regarding OS in correlation with MSI-H, PD-L1 and IS status we did not find a significant difference. However, PD-L1 positive mCRC tended to exhibit a longer OS compared to PD-L1 negative cancers (28.9 vs. 22.1 months).

Das autosomal-dominant vererbte Lynch-Syndrom (auch: hereditares kolorektales Karzinom ohne Polyposis – HNPCC) ist das haufigste familiare Darmkrebsdispositionssyndrom und betrifft bis zu 3 % aller Patienten mit kolorektalem Karzinom. Erstgradige Verwandte von Patienten mit Lynch-Syndrom haben ein Risiko von 50 %, Anlagetrager zu sein. Bei betroffenen Familien kommt es in vergleichsweise jungem Alter zu einem familiar gehauften Auftreten von mitunter syn- oder metachronen kolorektalen Karzinomen, aber auch bestimmten extrakolonischen Tumoren, wodurch ihre Lebenserwartung ohne Vorsorge gegenuber der Allgemeinbevolkerung reduziert ist. Risikopersonen sollten daher in ein spezielles und lebenslanges Vorsorgeprogramm aufgenommen werden. Das Verbundprojekt der Deutschen Krebshilfe „Familiarer Darmkrebs“ ( http://www.hnpcc.de ) ist ein Zusammenschluss von 6 universitaren klinischen Zentren, einer Referenzpathologie, -gastroenterologie, -onkologie und zentralen Biometrie. Diese befassen sich seit 1999 mit der interdisziplinaren Betreuung von Lynch-Risikopersonen sowie mit der Erarbeitung und Optimierung der Standards fur die Identifizierung, Diagnostik und Fruherkennung des Lynch-Syndroms.

Das kolorektale Karzinom (KRK) stellt mit mehr als 70.000 Neuerkrankungen pro Jahr die zweithaufigste Tumorentitat in Deutschland dar. In 15–25% der Falle liegt eine positive Familienanamnese vor. Etwa 2–5% aller KRK entstehen auf dem Boden einer im engeren Sinne erblichen Krebsdisposition. Die haufigste Form des hereditaren KRK ist das HNPCC-Syndrom („heriditary nonpolyposis colorectal cancer“, auch Lynch-Syndrom genannt). Das kumulative Lebenszeitrisiko fur die Entwicklung von Tumoren liegt bei etwa 80%. Neben dem erhohten Risiko fur ein KRK besteht ein erhohtes Risiko extrakolonischer Neoplasien. Durch die Aufdeckung der genetischen Grundlagen kann heute in den betroffenen Familien mit molekulargenetischen Methoden festgestellt werden, ob Angehorige die Tumordisposition geerbt haben – noch bevor sich Krankheitssymptome entwickeln. Klinisches Bild, Molekulargenetik, Diagnosekriterien, Differenzialdiagnose, Tumorrisiko, Fruherkennungsmasnahmen und Therapiebesonderheiten werden dargestellt.

Das kolorektale Karzinom (KRK) ist mit 70.000 Neuerkrankungen/Jahr der zweithaufigste Tumor in Deutschland. In 20–30% der Falle liegt eine positive Familienanamnese vor und in 2–5% eine erbliche Krebsdisposition. Durch die Aufdeckung der genetischen Grundlagen kann heute festgestellt werden, ob Angehorige betroffener Familien die Tumordisposition geerbt haben, noch bevor sich Krankheitssymptome entwickeln. Die Fruherkennung kolorektaler Neoplasien erfolgt durch die Koloskopie. Videoendoskope mit hoherer Auflosung und Vergroserung bei Bedarf erleichtern das Erkennen von Schleimhautlasionen. Durch den Einsatz einer Schleimhautfarbung (Chromoendoskopie) oder auch des „narrow band imaging“ (NBI) konnen neoplastische von nichtneoplastischen Lasionen relativ sicher voneinander unterschieden werden. Die Koloskopie ist zzt. der Goldstandard fur die Darmkrebsvorsorge in Deutschland. Die Invasivitat der Untersuchung und eine niedrige Teilnahmerate machen alternative Methoden wunschenswert.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant polyposis syndrome caused by STK11 germline mutations. PJS is associated with an increased risk of cancer. In our cohort, clinical and phenotypic parameters were correlated with genotypic findings and patients were prospectively followed by surveillance. Thirty-one patients treated between 2000 and 2006, were evaluated. STK11 genotyping was performed and phenotypes of patients with truncating (TM) and nontruncating mutations (NTM) were compared. Median age at first symptoms was 11 years and complications occurred before the age of ten in 42% of patients. STK11 mutations were detected in 16 of 22 families (12 TM; four NTM). Patients with TM had more surgical gastrointestinal (GI) interventions (p = 0.021), and female patients in the TM group had an increased risk of undergoing gynecological surgery (p = 0.016). Also, there was a trend towards a higher polyp count (p = 0.11) and earlier age at first polypectomy (p = 0.13) in the TM group. Ten carcinomas were detected in six patients resulting in a cancer risk of 65% up to the age of 65 years. Patients with TM tended to develop more cancers (p = 0.10). Importantly, our surveillance strategy used detected 50% of cancers (n = 5) at an early potentially curable stage. Our study shows that almost half of PJ patients have complications early in life independent of mutational status. Patients with TM require more surgical GI interventions and tend to develop more polyps and cancers. Furthermore, close surveillance detects early stage cancers in patients. We propose that surveillance should be started as early as 8 years in all patients to avoid complications. Moreover, patients with TM may benefit from surveillance at shorter intervals.

The monoclonal antibody pertuzumab represents the first HER2 dimerization inhibitor with unknown activity in colon cancer treatment. We examined the antitumor activity of pertuzumab as a single agent or in combination with erlotinib or irinotecan in human colon cancer cells in vitro and in vivo. Colon cancer cell lines were tested for HER1/HER2 expression by western blot analysis. The effect of pertuzumab on cell cycle distribution was analyzed by FACS. Nude mice bearing xenograft tumors were treated with pertuzumab alone, or in combination either with irinotecan or with erlotinib. Tumor volume was measured repeatedly. Tumor histology was analyzed for necrosis. Six of nine cell lines showed high expression of HER1/HER2. Pertuzumab inhibited cell cycle progression in various cell lines. Pertuzumab showed minor antitumor activity in xenograft tumors, but significantly inhibited tumor growth when combined with erlotinib (P

Polyposis-Syndrome bedurfen aufgrund der benignen und malignen Komplikationen besonderer diagnostischer und therapeutischer Aufmerksamkeit. Sie liegen in einer Haufigkeit von weniger als 1% allen kolorektalen Karzinomen zugrunde. Es werden adenomatose und nichtadenomatose Formen unterschieden: Zu den adenomatosen Polyposis-Syndromen gehoren die familiare adenomatose Polyposis, die attenuierte und die MYH-assoziierte Polyposis. Zu den selteneren hamartomatosen Polyposis-Syndromen zahlen das Peutz-Jeghers-Syndrom sowie die familiare juvenile Polyposis. Mit der Ausnahme der MYH-assoziierten Polyposis handelt es sich um autosomal-dominant vererbbare Erkrankungen. Dies bedeutet, dass erstgradig Verwandte (Kinder, Geschwister, Eltern) mit einer Wahrscheinlichkeit von 50% ebenfalls Anlagetrager fur diese Tumordisposition sind. Die genetische Diagnostik und Vorsorgeuntersuchungen sollten in Zusammenarbeit mit erfahrenen Zentren durchgefuhrt werden. Die Polyposis-Syndrome stellen einen wichtigen Risikofaktor fur Dunndarmkarzinome dar. Daher wird in diesem Zusammenhang auch diese seltene, aber differenzialdiagnostisch bedeutsame Tumorerkrankung dargestellt.

Patients with Barrett's esophagus (BE) are at increased risk of developing esophageal adenocarcinoma (EAC). Clinical neoplastic progression risk factors, such as age and the length of the esophageal BE segment, have been identified. However, improved molecular biomarkers predicting increased progression risk are needed for improved risk assessment and stratification. Using real-time quantitative methylation-specific PCR, we screened 10 genes (HPP1, RUNX3, RIZ1, CRBP1, 3-OST-2, APC, TIMP3, p16, MGMT, p14) for promoter hypermethylation in 77 EAC, 93 BE, and 64 normal esophagus (NE) specimens. A subset of genes manifesting significant differences in methylation frequencies between BE and EAC was then analysed in 20 dysplastic specimens. All 10 genes except p14 were frequently methylated in EACs, with RUNX3, HPP1, CRBP1, RIZ1, and OST-2 representing novel methylation targets in EAC and/or BE. p16, RUNX3, and HPP1 displayed increasing methylation frequencies in BE vs EAC. Furthermore, these increases in methylation occurred early, at the interface between BE and low-grade dysplasia (LGD). To demonstrate the silencing effect of hypermethylation, we selected the EAC cells BIC1, in which the HPP1 promoter is natively methylated, and subjected them to 5-aza-2'-deoxycytidine (Aza-C) treatment. Real-time RT-PCR indicated increased HPP1 mRNA levels after 3 days of Aza-C treatment, as well as decreased levels of methylated HPP1 DNA. Hypermethylation of a subset of six genes (APC, TIMP3, CRBP1, p16, RUNX3, and HPP1) was then tested in a retrospective longitudinal study of 99 BE and nine LGD specimens obtained from 53 BE patients undergoing surveillance endoscopy. Only high-grade dysplasia (HGD) or EAC were defined as progression end points. Two patient groups were compared: eight progressors (P) and 45 nonprogressors (NP), using Cox proportional hazards models to determine the relative progression risks of age, BE segment length, and methylation events. Multivariate analyses revealed that only hypermethylation of p16 (odds ratio (OR) 1.74, 95% confidence interval (CI) 1.33-2.20), RUNX3 (OR 1.80, 95% CI 1.08-2.81), and HPP1 (OR 1.77, 95% CI 1.06-2.81) were independently associated with an increased risk of progression, whereas age, BE segment length, and hypermethylation of TIMP3, APC, or CRBP1 were not independent risk factors. In combined analyses, risk was detectable up to, but not earlier than, 2 years preceding neoplastic progression. Hypermethylation of p16, RUNX3, and HPP1 in BE or LGD may represent independent risk factors for the progression of BE to HGD or EAC. These findings have implications regarding risk stratification, early EAC detection, and the appropriate endoscopic surveillance interval for patients with BE.

Der fakale okkulte Bluttest gehort seit Ende der 1970er Jahre zum Programm der gesetzlichen Krebsfruherkennung in Deutschland. Der Nutzen des fakalen Bluttests in der Fruherkennung kolorektaler Karzinome konnte in mehreren grosen, randomisierten Studien nachgewiesen werden. Er ist in seiner Wertigkeit aufgrund einer masigen Sensitivitat jedoch begrenzt. Endoskopische Screeningmethoden sind zur Detektion von Adenomen und Karzinomen zwar deutlich sensitiver, jedoch auch invasiver. Genetische Stuhltests konnten zukunftig eine alternative Screeningstrategie mit hoher Spezifitat und Sensitivitat bei geringer Invasivitat darstellen.

Juvenile polyposis syndrome (JPS) is an autosomal dominant predisposition to multiple juvenile polyps in the gastrointestinal tract. Germline mutations in the MADH4 or BMPR1A genes have been found to be causative of the disease in a subset of JPS patients. So far, no genotype-phenotype correlation has been reported. We examined 29 patients with the clinical diagnosis of JPS for germline mutations in the MADH4 or BMPR1A genes and identified MADH4 mutations in seven (24%) and BMPR1A mutations in five patients (17%). A remarkable prevalence of massive gastric polyposis was observed in patients with MADH4 mutations when compared with patients with BMPR1A mutations or without identified mutations. This is the first genotype-phenotype correlation observed in JPS.

Background To evaluate the value of KRAS codon 13 mutations in patients with advanced colorectal cancer (advanced CRC) treated with oxaliplatin and fluoropyrimidines. Methods Tumor specimens from 201 patients with advanced CRC from a randomized, phase III trial comparing oxaliplatin/5-FU vs. oxaliplatin/capecitabine were retrospectively analyzed for KRAS mutations. Mutation data were correlated to response data (Overall response rate, ORR), progression-free survival (PFS) and overall survival (OS). Results 201 patients were analysed for KRAS mutation (61.2% males; mean age 64.2 ± 8.6 years). KRAS mutations were identified in 36.3% of tumors (28.8% in codon 12, 7.4% in codon 13). The ORR in codon 13 patients compared to codon 12 and wild type patients was significantly lower (p = 0.008). There was a tendency for a better overall survival in KRAS wild type patients compared to mutants (p = 0.085). PFS in all patients was not different in the three KRAS genetic groups (p = 0.72). However, we found a marked difference in PFS between patients with codon 12 and 13 mutant tumors treated with infusional 5-FU versus capecitabine based regimens. Conclusions Our data suggest that the type of KRAS mutation may be of clinical relevance under oxaliplatin combination chemotherapies without the addition of monoclonal antibodies in particular when overall response rates are important. Trial registration number 2002-04-017