Seulontatutkimukset periytyvään paksusuolisyöpäsukuun kuuluvilla

Hereditary nonpolyposis colorectal cancer (HNPCC) is an inherited cancer predisposition syn-drome characterized by early onset colorectal cancer (CRC) and several other extra-colonic cancers, most commonly endometrial cancer (EC) and gastric cancer. Our aim was to evaluate the efficiency and results of the ongoing CRC and EC surveillance programs and to investigate the grounds for future gastric cancer screening by comparing the gastric biopsies of mutation positive and negative siblings in search for premalignant lesions. We also compared a new surveillance method, computerized tomographic colonoscopy (CTC) with optic colonoscopy. The patient material consisted of 579 family members from 111 Finnish HNPCC families al-most all harboring a known mismatch repair gene mutation. The efficacy of CRC and EC surveillance programs on HNPCC patients was evaluated by comparing the stage and survival of cancer cases detected with surveillance versus without. The performance of a new technique, CTC, was explored using a same-day colonoscopy as a reference standard. The use of intrauterine aspiration biopsies for EC surveillance was intro-duced for the first time in a HNPCC setting. Upper GI endoscopies were performed and biop-sies taken from mutation carriers and their mutation-negative siblings. The present surveillance program for CRC proved to be efficient. The CRC cases detected by surveillance were at a significantly more favorable stage than those in the non-surveilled group. This advantage was reflected in a significantly higher CRC-specific survival in the sur-veilled group. The performance of a new technique, CTC was found insufficient for polyp detection in this population in which every polyp, no matter the size, should be detected and removed. Colono-scopy was confirmed as a better surveillance modality than CTC. We could not observe any of the assumed differences in the gastric mucosa from mutation carriers and their mutation-negative siblings and no cases of gastric cancer were detected. The results gave no support for gastric surveillance. The EC surveillance program (transvaginal ultrasound and intra-uterine biopsy every 2-3 years) seemed to be efficient. It yielded several asymptomatic cancer cases and premalignant lesions. The stage distribution of the endometrial cancers in the group under surveillance tended to be more favorable than that of the mutation-positive, symptomatic EC patients who had no surveillance. None of the surveilled EC patients died of EC compared to six in the non-surveilled patients during the follow up. The improvement was, however, not statistically sig-nificant, thus far. Another observation was the good performance of endometrial aspiration biopsies used in this setting for the first time.Seulontatutkimukset periytyvään paksusuolisyöpäsukuun kuuluvilla Periytyvälle, ei-polypoottiselle paksusuolisyöpäsyndroomalle (Hereditary nonpolyposis colorec-tal cancer, HNPCC ) on tyypillistä jo nuorella iällä merkittävästi suurentunut riski eri syöpiin, suurimpana paksu- ja peräsuolisyöpä, kohdun runko-osan syöpä ja mahalaukun syöpä. Väitöskirjatyön tavoitteena oli selvittää suomalaisen HNPCC syöpäseulonnan tehokkuutta paksu- ja peräsuolisyövän sekä kohtusyövän osalta vertaamalla seulonnassa löytyneitä syöpä-tapauksia oireiden takia, ilman seulontaa löytyneisiin. Vertasimme myös kahta eri suoliseulon-tametodia, tavallista paksusuolitähystystä tietokonepohjaiseen virtuaalitähystykseen siten, että toimenpiteet tehtiin sokkoutetusti peräkkäin. Kohtusyöpäseulonnassa käytettiin ensi kerran kohdun limakalvonäytteitä seulontametodina. Lisäksi selvitettiin, löytyykö mutaationkantajien ja heidän geeneiltään terveeksi todettujen sisarusten mahalaukun tähystyksessä otetuista näyt-teistä syövän esiasteita tai muita eroja, jotka antaisivat perusteen mahalaukun tähystysseulon-nan aloittamiselle. Väitöskirjan aineistona olivat soveltuvin osin Suomen HNPCC-rekisterin mutaationkantajat. Kaikenkaikkiaan lähes 600 henkilöä 111 HNPCC-suvusta oli mukana näissä tutkimuksissa. Seulonnan avulla löytyneet paksu- ja peräsuolisyövät olivat merkittävästi varhaisemman vai-heen kasvaimia kuin ilman seulontaa löydetyt ja kuolleisuus paksu- ja peräsuolisyöpään oli myös merkitsevästi vähäisempää seulontaryhmässä viitaten seulonnan tehokkuuteen. Koh-tusyövän suhteen havaittiin vastaava ero diagnoosihetken levinneisyydessä mutta kuolleisuu-dessa ei kuitenkaan nähty tilastollisesti merkitsevää eroa ryhmien välillä. Gynekologisessa seulonnassa löytyi toistakymmentä uutta, oireetonta syöpätapausta ja myös syövän esiasteita viitaten seulonnan hyödyllisyyteen. Kohdun limakalvobiopsia osoittautui lupaavaksi seulonta-metodiksi. Tavallinen optinen paksusuolitähystys osoittautui vertailussa paremmaksi metodiksi polyyppeja etsiessä, koska virtuaalitähystyksen herkkyys pienten polyyppien havaitsemisessa oli huono. Mahalaukun tähystyksissä ja biopsioissa ei havaittu syöpiä, syöpien esiasteita tai mitään eroja limakalvopatologiassa mutaation kantajien ja heidän terveiden sisarustensa välillä joten tällä perusteella mahalaukkutähystysten järjestäminen seulontamielessä ei vaikuta hyö-dylliseltä

Clinical management of 52 consecutive retro-rectal tumours treated at a tertiary referral centre

Abstract Aim The aim of this single institution study was to analyse the diagnostic methods, pre-operative work-up and outcomes of 52 retrorectal tumours. Method All patients treated for retro-rectal tumours from 2012 to 2017 were included. Results Out of 52 patients, 40 (77%) were women. The patients? median age at the time of surgery was 43 (19-76) years, and 30 (58%) of the patients were asymptomatic at the time of diagnosis. All tumours were visible on magnetic resonance imaging (MRI) prior to surgery. The sensitivity and specificity for predicting malignancy on pre-operative imaging for retro-rectal tumours were 25% and 98%, respectively. Forty-four procedures (85%) were performed using the perineal approach. The median hospital stay was three (1-18) days. There was no 30-day post-operative mortality. Eleven (21%) patients developed post-operative complications, mostly surgical site infections. Twenty-nine tumours (56%) were benign tailgut cysts. Four (8%) tumours were malignant and were considered to be removed with a tumour-free resection margin. Local recurrent disease was detected on MRI in 14 (27%) patients at a median of 1.05 (range: 0.78-1.77) years after primary surgery. Only the multi-lobular shape of the tumour was found to be an independent risk factor for recurrence (p=0.030). Conclusion A pre-operative MRI is mandatory in order to plan the surgical strategy for retro-rectal tumours. Symptomatic, solid, large tumours should be removed because of the risk of malignancy. Minor cystic lesions with thin walls as well as asymptomatic recurrences of benign tumours are suitable to be followed conservatively.Peer reviewe

Is there a need for neoadjuvant short-course radiotherapy in T3 rectal cancer with positive lymph node involvement? A single-center retrospective cohort study

Background Neoadjuvant short-course radiotherapy is used to reduce local recurrences in stage III rectal cancer. Radiotherapy is not harmless, and meticulous total mesorectal excision surgery alone has been reported to result in low local recurrence rate in favorable stage III tumors. The aim was to evaluate the effect of short-course (5 x 5 Gy) radiotherapy on the local recurrence risk in patients with pT3N1-2 rectal cancer. Materials and methods This was a retrospective study with 151 consecutive pT3N1-2M0 rectal cancer patients operated on at Helsinki University Hospital, Helsinki, Finland, during January 2005 to June 2014. Short-course radiotherapy was given to 94 patients, and 57 patients were operated on without neoadjuvant radiotherapy. The main outcome measurement was the effect of radiotherapy on local recurrence. Also, the risk factors for local recurrence were analyzed. Results Local recurrence occurred in a total 17 of 151 (11.3%) patients, 8 of 57 (14.0%) in surgery only group compared with 9 of 94 (9.6%) in radiotherapy plus surgery group (p = 0.44). In univariate Cox regression analysis, the risk factors for local recurrence were tumor location under 6 cm from the anal verge (p = 0.01), involved lateral margin (p <0.001), tumor perforation (p <0.001), and mucinous histology (p = 0.006). In multivariate analysis, risk factors were tumor location under 6 cm from anal verge (p = 0.03) and involved lateral margin (p = 0.002). Conclusion Neoadjuvant short-course radiotherapy did not affect the local recurrence risk of pT3N1-2M0 rectal cancer. Further studies with larger patient number are needed to evaluate the role of short-course radiotherapy in different T3 subgroups (3a-c) as well as in N1 and N2 cancers in separate.Peer reviewe

Data-driven comorbidity analysis of 100 common disorders reveals patient subgroups with differing mortality risks and laboratory correlates

The populational heterogeneity of a disease, in part due to comorbidity, poses several complexities. Individual comorbidity profiles, on the other hand, contain useful information to refine phenotyping, prognostication, and risk assessment, and they provide clues to underlying biology. Nevertheless, the spectrum and the implications of the diagnosis profiles remain largely uncharted. Here we mapped comorbidity patterns in 100 common diseases using 4-year retrospective data from 526,779 patients and developed an online tool to visualize the results. Our analysis exposed disease-specific patient subgroups with distinctive diagnosis patterns, survival functions, and laboratory correlates. Computational modeling and real-world data shed light on the structure, variation, and relevance of populational comorbidity patterns, paving the way for improved diagnostics, risk assessment, and individualization of care. Variation in outcomes and biological correlates of a disease emphasizes the importance of evaluating the generalizability of current treatment strategies, as well as considering the limitations that selective inclusion criteria pose on clinical trials.Peer reviewe

Converging endometrial and ovarian tumorigenesis in Lynch syndrome : Shared origin of synchronous carcinomas

AbstractObjective The diagnosis of carcinoma in both the uterus and the ovary simultaneously is not uncommon and raises the question of synchronous primaries vs. metastatic disease. Targeted sequencing of sporadic synchronous endometrial and ovarian carcinomas has shown that such tumors are clonally related and thus represent metastatic disease from one site to the other. Our purpose was to investigate whether or not the same applies to Lynch syndrome (LS), in which synchronous cancers of the gynecological tract are twice as frequent as in sporadic cases, reflecting inherited defects in DNA mismatch repair (MMR). Methods MMR gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nationwide registry. Endometrial (n = 35) and ovarian carcinomas (n = 23), including 13 synchronous carcinoma pairs, were collected as well as endometrial hyperplasias (n = 56) and normal endometria (n = 99) from a surveillance program over two decades. All samples were studied for MMR status, ARID1A and L1CAM protein expression and tumor suppressor gene promoter methylation, and synchronous carcinomas additionally for somatic mutation profiles of 578 cancer-relevant genes. Results Synchronous carcinomas were molecularly concordant in all cases. Prior or concurrent complex (but not simple) endometrial hyperplasias showed a high degree of concordance with endometrial or ovarian carcinoma as the endpoint lesion. Conclusions Our investigation suggests shared origins for synchronous endometrial and ovarian carcinomas in LS, in analogy to sporadic cases. The similar degrees of concordance between complex hyperplasias and endometrial vs. ovarian carcinoma highlight converging pathways for endometrial and ovarian tumorigenesis overall.Peer reviewe

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.Peer reviewe

DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression

Background: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR. Methods: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n 49) and MMR-proficient (MMR-P, n 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing. Findings: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (1612, NEUROGI,CRABP1, and CDKN2A) and TSGs (SERPI and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas. Interpretation: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR. Fund: Jane and Aatos Erkko Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid juselius Foundation, and HiL1FE. (C) 2019 Published by Elsevier B.V.Peer reviewe

Colorectal cancer incidences in Lynch syndrome : a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.Peer reviewe

Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome

BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P <.001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.Peer reviewe