The Prevalence and Molecular Landscape of Lynch Syndrome in the Affected and General Population.

BACKGROUND: Lynch syndrome (LS) is the most frequent genetically pre-disposed colorectal cancer (CRC) syndrome, accounting for 2-3% of all CRC cases. In Estonia, ~1000 new cases are diagnosed each year. This retroactive and prospective study aimed to estimate the prevalence of LS and describe disease-causing variants in mismatch repair (MMR) genes in a diagnostic setting and in the Estonian general population. METHODS: LS data for the diagnostic cohort were gathered from 2012 to 2022 and data for the general population were acquired from the Estonian Biobank (EstBB). Furthermore, we conducted a pilot study to estimate the improvement of LS diagnostic yield by raising the age limit to >50 years for immunohistochemistry analysis of MMR genes. RESULTS: We estimated LS live birth prevalence between 1930 and 2003 in Estonia at 1:8638 (95% CI: 1: 9859-7588). During the study period, we gathered 181 LS individuals. We saw almost a six-fold increase in case prevalence, probably deriving from better health awareness, improved diagnostic possibilities and the implementation of MMR IHC testing in a broader age group. CONCLUSION: The most common genes affected in the diagnostic and EstBB cohorts were MLH1 and PMS2 genes, respectively. The LS diagnosis mean age was 44.8 years for index cases and 36.8 years (p = 0.003) for family members. In the MMR IHC pilot study, 29% had LS.

Time-gated luminescence assay using nonmetal probes for determination of protein kinase activity-based disease markers.

A novel nonmetal optical probe ARC-1063 whose long-lifetime luminescence is induced by association with the target protein kinase is used for the measurement of the concentration of catalytic subunit of protein kinase A (PKAc) in complicated biological solutions. High affinity (K(D) = 10 pM toward PKAc) and unique optical properties of the probe enable its application for the measurement of picomolar concentrations of PKAc in the presence of high concentrations of other proteins. The described assay is applicable in the high-throughput format with the instrument setups designed for lanthanide-based time-gated (time-resolved) luminescence methods. The assay is used for demonstration that extracellular PKAc (ECPKA) is present in plasma samples of all healthy persons and cancer patients but great care must be taken for procedures of treatment of blood samples to avoid disruption, damage, or activation of platelets in the course of plasma (or serum) preparation and conservation.

Deficiency of the complex I of the mitochondrial respiratory chain but improved adenylate control over succinate-dependent respiration are human gastric cancer-specific phenomena.

The purpose of study was to comparatively characterize the oxidative phosphorylation (OXPHOS) and function of respiratory chain in mitochondria in human gastric corpus mucosa undergoing transition from normal to cancer states and in human gastric cancer cell lines, MKN28 and MKN45. The tissue samples taken by endobiopsy and the cells were permeabilized by saponin treatment to assess mitochondrial function in situ by high-resolution oxygraphy. Compared to the control group of endobiopsy samples, the maximal capacity of OXPHOS in the cancer group was almost twice lower. The respiratory chain complex I-dependent respiration, normalized to complex II-dependent respiration, was reduced that suggests deficiency of complex I, but the respiratory control by ADP in the presence of succinate was increased. Similar changes were observed also in mucosa adjacent to cancer tissue. The respiratory capacity of MKN45 cells was higher than that of MKN28 cells, but both types of cells exhibited a deficiency of complex I of the respiratory chain which appears to be an intrinsic property of the cancer cells. In conclusion, human gastric cancer is associated with decreased respiratory capacity, deficiency of the respiratory complex I of mitochondria, and improved coupling of succinate oxidation to phosphorylation in tumor tissue and adjacent atrophic mucosa. Detection of these changes in endobiopsy samples may be of diagnostic value.

Survival for colon and rectal cancer in Estonia: role of staging and treatment.

BACKGROUND: International comparisons have indicated low colorectal cancer (CRC) survival in Estonia, compared to other European countries. The objective of this paper is to analyse long-term survival as well as staging and treatment patterns of CRC in Estonia. MATERIAL AND METHODS: The analysis included all incident cases of CRC diagnosed in Estonia in 1997 (n = 546), identified through the Estonian Cancer Registry and followed up for 10 years after diagnosis. Staging and treatment data were retrospectively collected from medical records. Relative survival rate (RSR) was used to estimate the outcome. RESULTS AND CONCLUSION: The 5-year RSR was 51% for colon cancer and 38% for rectal cancer; the corresponding 10-year RSR was 50% and 39%. We observed no excess mortality for early disease. For stages II and III, the survival was markedly higher in colon cancer (5-year RSR 79% and 66%, respectively) compared to rectal cancer (66% and 30%, respectively). Around 30% of cases were diagnosed with distant disease. Among radically operated colon and rectal cancer patients, the 10-year RSR was 90% and 70%, respectively. Most patients with available pathological information had one to four lymph nodes examined. Survival has notably improved for colon cancer, but not for rectal cancer in Estonia. High proportion of cases with distant metastasis at first diagnosis along with inadequate staging and low proportion of patients treated with curatively intended surgery and appropriate chemotherapy and radiotherapy may have contributed to this outcome. Progress could be achieved by earlier diagnosis and implementing higher standards for staging and treatment. These conclusions are likely to be relevant also for other Eastern European countries.

Changes in the quality of care of colorectal cancer in Estonia: a population-based high-resolution study.

OBJECTIVES: Large disparities in colorectal cancer (CRC) management and survival have been observed across Europe. Despite recent increases, the survival deficit of Estonian patients with CRC persists, particularly for rectal cancer. The aim of this study was to examine diagnostic, staging and treatment patterns of CRC in Estonia, comparing clinical data from 1997 and 2011. DESIGN: Nationwide population-based retrospective study. SETTING: Estonia. PARTICIPANTS: All incident cases of colon and rectal cancer diagnosed in 1997 and 2011 identified from the Estonian Cancer Registry. Clinical data gathered from medical records. OUTCOME MEASURES: Differences in diagnostic, staging and treatment patterns; 5-year relative survival ratios. RESULTS: The number of colon cancer cases was 337 in 1997 and 498 in 2011; for rectal cancer, the respective numbers were 209 and 349. From 1997 to 2011, large increases were seen in the use of colonoscopy and lung and liver imaging. Radical resection rate increased from 48% to 59%, but emergency surgeries showed a rise from 18% to 26% in colon and from 7% to 14% in rectal cancer. The proportion of radically operated patients with ≥12 lymph nodes examined pathologically increased from 2% to 58% in colon cancer and from 2% to 50% in rectal cancer. The use of neoadjuvant radiotherapy increased from 6% to 39% among stage II and from 20% to 50% among patients with stage III rectal cancer. The use of adjuvant chemotherapy in stage III colon cancer increased from 42% to 63%. The 5-year RSR increased from 50% to 58% in colon cancer and from 37% to 64% in patients with rectal cancer. CONCLUSIONS: Major improvements were seen in the diagnostics, staging and treatment of CRC in Estonia contributing to better outcomes. Increase in emergency surgeries highlights possible shortcomings in timely diagnosis and treatment.

Subsite- and stage-specific colorectal cancer trends in Estonia prior to implementation of screening.

BACKGROUND: The occurrence of colorectal cancer (CRC) in Estonia has been characterised by increasing incidence, low survival and no screening. The study aimed to examine long-term incidence and survival trends of CRC in Estonia with specific focus on subsite and stage. METHODS: We analysed CRC incidence and relative survival using Estonian Cancer Registry data on all cases of colorectal cancer (ICD-10 C18-21) diagnosed in 1995-2014. TNM classification was used to categorise stage. RESULTS: Age-standardized incidence of colon cancer increased both in men and women at a rate of approximately 1% per year. Significant increase was seen for right-sided tumours, but not for left-sided tumours. Rectal cancer incidence increased significantly only in men and anal cancer incidence only in women. Age-standardized five-year relative survival for colon cancer increased from 50% in 1995-1999 to 59% in 2010-2014; for rectal cancer, from 38% to 56%. Colon cancer survival improved significantly for left-sided tumours (from 51% to 62%) and stage IV disease (from 6% to 15%). For rectal cancer, significant survival gain was seen for stage II (from 58% to 75%), stage III (from 34% to 70%) and stage IV (from 1% to 12%). CONCLUSION: In the pre-screening era in Estonia, increase in colon cancer incidence was limited to right-sided tumours. Large stage-specific survival gain, particularly for rectal cancer, was probably due to better staging and advances in multimodality treatment. Nonetheless, more than one quarter of new CRC cases are diagnosed at stage IV, emphasising the need for an efficient screening program.

Oxidative phosphorylation and its coupling to mitochondrial creatine and adenylate kinases in human gastric mucosa.

Energy metabolism in gastrobiopsy specimens of the antral and corpus mucosa, treated with saponin to permeabilize the cells, was studied in patients with gastric diseases. The results show twice lower oxidative capacity in the antral mucosa than in the corpus mucosa and the relative deficiency of antral mitochondria in complex I. The mucosal cells expressed mitochondrial and cytosolic isoforms of creatine kinase and adenylate kinase (AK). Creatine (20 mM) and AMP (2 mM) markedly stimulated mitochondrial respiration in the presence of submaximal ADP or ATP concentrations, and creatine reduced apparent Km for ADP in stimulation of respiration, which indicates the functional coupling of mitochondrial kinases to oxidative phosphorylation. Addition of exogenous cytochrome c increased ADP-dependent respiration, and the large-scale cytochrome c effect (>or=20%) was associated with suppressed stimulation of respiration by creatine and AMP in the mucosal preparations. These results point to the impaired mitochondrial outer membrane, probably attributed to the pathogenic effects of Helicobacter pylori. Compared with the corpus mucosa, the antral mucosa exhibited greater sensitivity to such type of injury as the prevalence of the large-scale cytochrome c effect was twice higher among the latter specimens. Active chronic gastritis was associated with decreased respiratory capacity of the corpus mucosa but with its increase in the antral mucosa. In conclusion, human gastric mucosal cells express the mitochondrial and cytosolic isoforms of CK and AK participating in intracellular energy transfer systems. Gastric mucosa disease is associated with the altered functions of these systems and oxidative phosphorylation.