Publikationen unter Beteiligung des Zentrums für erbliche Tumorerkrankungen

Im Rahmen der Forschung publizieren unsere Mitarbeiter ihre Ergebnisse. Im Folgenden finden Sie eine Liste an ausgewählten Publikationen von unseren Mitarbeitern im Zentrum für erbliche Tumorerkrankungen.

 

Aktuelle Publikationen

Früherkennung, Risikoreduktion, Überwachung und Therapie bei Patienten mit Lynch-Syndrom

"Das Lynch-Syndrom(LS) ist die häufigste Form des erblichen Darmkrebses und verursacht ca. 3 % aller kolorektalen
Karzinome (KRK). Ursächlich ist eine pathogene Sequenzvariante in einem Mismatch-Reparaturgen (MLH1, MSH2,
MSH6, PMS2, EPCAM). Nach aktueller Schätzung ist ca. eine von 300 Personen Anlageträger für LS (ca. 300 000 Mutationsträger/Deutschland). Anlageträger haben ein erhöhtes Lebenszeitrisiko für ein KRK mit einer kumulativen Inzidenz von 15 bis 46 % bis zum 75. Lebensjahr. Weiterhin ist auch das Risiko für extrakolonische Tumoren wie Endometrium-, Dünndarm-, Magen-, Urothel- und andere Karzinome erhöht.
Methoden Das Deutsche Konsortium Familiärer Darmkrebs besteht aus 14 universitären Zentren in Deutschland. Das
Ziel des Konsortiums ist es, geeignete Vorsorgeprogramme zu entwickeln und zu evaluieren, damit diese später in die allgemeine Patientenversorgung übernommen werden können.
Wir haben aktuell die Empfehlung zur klinischen Betreuung von LS-Patienten überarbeitet. Ergebnis Eine Koloskopie sollte ab dem 25. Lebensjahr alle 12–24 Monate erfolgen. Bei Diagnose eines KRK ist eine onkologische
Resektion notwendig, eine Kolektomie mit ileorektaler Anastomose sollte individuell mit dem Patienten besprochen
werden. Das Lebenszeitrisiko für ein Magenkarzinom liegt bei 0,2–13 %. Im Rahmen der endoskopischen Überwachung
können signifikant mehr Magenkarzinome in früheren Tumorstadien entdeckt werden im Vergleich zur symptomgetriggerten Endoskopie. Das Lebenszeitrisiko für ein Dünndarmkarzinom iegt bei 4–8 %. Dünndarmkarzinome treten zur Hälfte im Duodenum auf, in 10% der Fälle vor dem 35. Lebensjahr. Eine ÖGD sollte deshalb ab dem 25. Lebensjahr alle 12–36 Monate erfolgen."

Hüneburg R et al. Z Gastroenterol 2019; 57: 1–12. doi.org/10.1055/a-1008-9827

 

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

"Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer."

Dominguez-Valentin M et al. Genet Med. July 2019. doi:10.1038/s41436-019-0596-9

 

Boosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes.

"Approximately 27–36 million patients in Europe have one of the ~ 5.000–8.000 known rare diseases. These patients often do not receive the care they need or they have a substantial delay from diagnosis to treatment. In March 2017, twenty-four European Reference Networks (ERNs) were launched with the aim to improve the care for these patients through cross border healthcare, in a way that the medical knowledge and expertise travels across the borders, rather than the patients. It is expected that through the ERNs, European patients with a rare disease get access to expert care more often and more quickly, and that research and guideline development will be accelerated resulting in improved diagnostics and therapies. The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS) aims to improve the identification, genetic diagnostics, prevention of cancer, and treatment of European patients with a genetic predisposition for cancer. The ERN GENTURIS focuses on syndromes such as hereditary breast cancer, hereditary colorectal cancer and polyposis, neurofibromatosis and more rare syndromes e.g. PTEN Hamartoma Tumour Syndrome, Li Fraumeni Syndrome and hereditary diffuse gastric cancer."

Vos JR et al. Fam Cancer. 2019;18(2):281-284. doi:10.1007/s10689-018-0110-6

 

Colorectal cancer prevention and early detection: what is the best strategy?

"Der gemeinsame Bundesausschuss (G-BA) hat eine Neuregelung der Darmkrebsvorsorge beschlossen. Ab voraussichtlich Juli 2019 werden anspruchsberechtige Personen schriftlich auf die Möglichkeit der Vorsorgeuntersuchungen hingewiesen. Darüber hinaus sollten Sie als Hausarzt Personen mit erhöhtem Risiko identifizieren können."

Gross M & Holinski-Feder E. MMW Fortschr Med. 2019;161(7):43-48. doi:10.1007/s15006-019-0407-x

 

Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report.

"Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal."

Seppala TT et al. Hered Cancer Clin Pract. 2019;17:8. doi:10.1186/s13053-019-0106-8

 

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

"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)."

Engel C et al. Gastroenterology. 2018;155(5):1400-1409.e2. doi:10.1053/j.gastro.2018.07.030

 

Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility.

"In familial or early-onset gastric cancer (GC) cases, a heritable germline aberration may underlie the development of GC. Elucidation of these germline defects is crucial to improve the clinical management of these patients and their relatives at risk. Pathogenic germline mutations in the CDH1 gene predispose to the development of hereditary diffuse gastric cancer (HDGC) with high GC risk of up to 70%, although the penetrance of CDH1 mutations identified in incident cases through gene panel testing for other reasons is not known. In more than 75% of the families that fulfil the CDH1 testing criteria, a causative germline mutation in CDH1 cannot be identified. In addition to these unexplained HDGC families, no heritable germline defects predisposing to the development of familial mixed-type and intestinal-type GC have been identified yet. Consequently, the putative causative germline aberration remains unknown for the majority of patients with GC."

Weren R et al. J Med Genet. 2018;55(10):669-674. doi:10.1136/jmedgenet-2017-104962

 

Haplotype analysis suggest that the MLH1 c.2059C > T mutation is a Swedish founder mutation.

"Lynch syndrome (LS) predisposes to a spectrum of cancers and increases the lifetime risk of developing colorectal- or endometrial cancer to over 50%. Lynch syndrome is dominantly inherited and is caused by defects in DNA mismatch-repair genes MLH1, MSH2, MSH6 or PMS2, with the vast majority detected in MLH1 and MSH2. Recurrent LS-associated variants observed in apparently unrelated individuals, have either arisen de novo in different families due to mutation hotspots, or are inherited from a founder (a common ancestor) that lived several generations back. There are variants that recur in some populations while also acting as founders in other ethnic groups. Testing for founder mutations can facilitate molecular diagnosis of Lynch Syndrome more efficiently and more cost effective than screening for all possible mutations. Here we report a study of the missense mutation MLH1 c.2059C > T (p.Arg687Trp), a potential founder mutation identified in eight Swedish families and one Finnish family with Swedish ancestors. Haplotype analysis confirmed that the Finnish and Swedish families shared a haplotype of between 0.9 and 2.8 Mb. While MLH1 c.2059C > T exists worldwide, the Swedish haplotype was not found among mutation carriers from Germany or France, which indicates a common founder in the Swedish population. The geographic distribution of MLH1 c.2059C > T in Sweden suggests a single, ancient mutational event in the northern part of Sweden."

von Salome J et al. Fam Cancer. 2018;17(4):531-537. doi:10.1007/s10689-017-0067-x

 

Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database.

"Lynch syndrome (LS) is associated with a high probability of gastrointestinal, gynaecological and other cancers. It is caused by germline pathogenic variants in any of four DNA MMR genes referred to here as path_MSH2, path_MLH1, path_PMS2 or path_MSH6 and collectively as path_MMR. Deletions in the EPCAM gene, which lead to inherited methylation of the adjacent MSH2 promoter, are also referred to as path_MSH2. To date, most patients with LS have been identified following investigation because of their family or personal history of multiple and/or early onset cancers."

Pål Mølle et. al. Gut. 2018;67(7):1306-1316. doi:10.1136/gutjnl-2017-314057

 

Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation.

"We report the second promoter variant stably inducing a hereditary CEM. Concerning the classification of promoter variants, we discuss contradictory results from the literature for two variants, describe classification discrepancies between existing rules for five variants, suggest the (re-)classification of five promoter variants to (likely) benign and regard four variants as functionally unclear."

Morak M et al. J Med Genet. 2018 Feb 22. pii: jmedgenet-2017-104744. doi: 10.1136/jmedgenet-2017-104744.

 

Identification of genetic variants for clinical management of familial colorectal tumors.

"Among high-risk CRC patients that fulfill the AMS criteria or revised Bethesda guidelines, targeted gene sequencing identified likely pathogenic variant and VUS in other genes than the MMR genes (CHEK2, NOTCH3 and MAP3K1). Our study suggests that the analysis of genes currently excluded from routine molecular diagnostic screens may confer cancer susceptibility."

Dominguez-Valentin M et al. BMC Med Genet. 2018 Feb 20;19(1):26. doi: 10.1186/s12881-018-0533-9.

 

Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds.

"We identified 48 women who were tested negative for their family's path_BRCA1 (n = 13) or path_BRCA2 (n = 35) variants. Pathogenic variants in the ATM, BRCA2, MSH6 and MUTYH genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from path_BRCA1 and 9% (3/35) from path_BRCA2 families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing (APC c.721G > A, MAP3K1 c.764A > G and MSH2 c.815C > T). However, by using a minigene, assay we here show that APC c.721G > A does not cause a splicing defect, similarly to what has been recently reported for the MAP3K1 c.764A > G. The MSH2 c.815C > T was previously described as causing partial exon skipping and it was identified in this work together with the path_BRCA2 c.9382C > T (p.R3128X).

All women in breast or breast/ovarian cancer kindreds would benefit from being offered genetic testing irrespective of which causative genetic variants have been demonstrated in their relatives."

Dominguez-Valentin M et al. Hered Cancer Clin Pract. 2018 Jan 15;16:4. doi: 10.1186/s13053-018-0086-0. eCollection 2018.

 

Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility.

"Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population.

Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified."

Weren RDA et al. J Med Genet. 2018 Jan 12. pii: jmedgenet-2017-104962. doi: 10.1136/jmedgenet-2017-104962.

 

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