Perheittäin esiintyvän paksusuolisyövän ja kohdun runko-osan syövän molekyyligeneettinen luokittelu

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common known clearly hereditary cause of colorectal and endometrial cancer (CRC and EC). Dominantly inherited mutations in one of the known mismatch repair (MMR) genes predispose to HNPCC. Defective MMR leads to an accumulation of mutations especially in repeat tracts, presenting microsatellite instability. HNPCC is clinically a very heterogeneous disease. The age at onset varies and the target tissue may vary. In addition, families that fulfill the diagnostic criteria for HNPCC but fail to show any predisposing mutation in MMR genes exist. Our aim was to evaluate the genetic background of familial CRC and EC. We performed comprehensive molecular and DNA copy number analyses of CRCs fulfilling the diagnostic criteria for HNPCC. We studied the role of five pathways (MMR, Wnt, p53, CIN, PI3K/AKT) and divided the tumors into two groups, one with MMR gene germline mutations and the other without. We observed that MMR proficient familial CRC consist of two molecularly distinct groups that differ from MMR deficient tumors. Group A shows paucity of common molecular and chromosomal alterations characteristic of colorectal carcinogenesis. Group B shows molecular features similar to classical microsatellite stable tumors with gross chromosomal alterations. Our finding of a unique tumor profile in group A suggests the involvement of novel predisposing genes and pathways in colorectal cancer cohorts not linked to MMR gene defects. We investigated the genetic background of familial ECs. Among 22 families with clustering of EC, two (9%) were due to MMR gene germline mutations. The remaining familial site-specific ECs are largely comparable with HNPCC associated ECs, the main difference between these groups being MMR proficiency vs. deficiency. We studied the role of PI3K/AKT pathway in familial ECs as well and observed that PIK3CA amplifications are characteristic of familial site-specific EC without MMR gene germline mutations. Most of the high-level amplifications occurred in tumors with stable microsatellites, suggesting that these tumors are more likely associated with chromosomal rather than microsatellite instability and MMR defect. The existence of site-specific endometrial carcinoma as a separate entity remains equivocal until predisposing genes are identified. It is possible that no single highly penetrant gene for this proposed syndrome exists, it may, for example be due to a combination of multiple low penetrance genes. Despite advances in deciphering the molecular genetic background of HNPCC, it is poorly understood why certain organs are more susceptible than others to cancer development. We found that important determinants of the HNPCC tumor spectrum are, in addition to different predisposing germline mutations, organ specific target genes and different instability profiles, loss of heterozygosity at MLH1 locus, and MLH1 promoter methylation. This study provided more precise molecular classification of families with CRC and EC. Our observations on familial CRC and EC are likely to have broader significance that extends to sporadic CRC and EC as well.Kohdun runko-osan syöpä ja paksusuolisyöpä kuuluvat kolmen yleisimmän syöpätaudin joukkoon länsimaissa. Selvästi periytyvistä muodoista yleisin on periytyvä ei-polypoottinen paksusuolisyöpäsyndrooma (hereditary nonpolyposis colorectal cancer, HNPCC), joka aiheuttaa noin 1-5 % kaikista paksusuolen ja kohdun runko-osan syövistä. HNPCC periytyy vallitsevasti ja sille altistavat DNA:ta korjaavien mismatch repair (MMR) geenien (MLH1, MSH2, MSH3, MSH6 ja PMS2) mutaatiot. MMR geenien mutaatiot aiheuttavat korjausmekanismin puutteellisen toiminnan ja virheiden kertymisen solun DNA:han. Tämän tutkimuksen tarkoituksena oli selvittää suvuittain esiintyvän paksusuolisyövän ja kohdun runko-osan syövän geneettistä taustaa. Teimme kattavat molekyyligeneettiset ja kopiolukuihin perustuvat analyysit tutkimalla HNPCC -kriteerit täyttäviä paksusuolisyöpiä. Merkittävin löydöksemme oli niiden syöpien, joiden taustalta ei löytynyt MMR geenien ituratamutaatiota, jakautuminen kahteen ryhmään. Ryhmä A koostuu syövistä, joista ei löydy paksusuolisyövälle tunnusomaisia molekyyli- eikä kromosomitason muutoksia. Ryhmä B puolestaan edustaa klassista paksusuolisyöpäpopulaatiota, jolle stabiilit mikrosatelliitit sekä runsaat kromosomitason muutokset ovat tyypillisiä. Tutkimustemme mukaan ryhmä A on ainutlaatuinen joukko paksusuolisyöpiä, joiden taustalla on todennäköisesti vielä tuntemattomia sairaudelle altistavia geenejä ja signaalireittejä. Selvitimme suvuittain esiintyvän kohdun runko-osan syövän geneettistä taustaa tutkimalla MMR geenien ja PI3K/AKT signaalireitin osuutta näiden syöpien kehittymisessä. Yhteensä 9 %:ssa perheistä, joissa esiintyy sattumaa useammin kohdun runko-osan syöpää, löytyi ituratamutaatio MMR geenistä. Nämä perheet edustavat epätyypillistä HNPCC syndroomaa, joka ilmentyy kohdun runko-osan syöpänä ilman syndroomalle tyypillisiä paksusuolen syöpäkasvaimia. Suurimmassa osassa (91%) perheitä ei löytynyt periytyvää MMR geenin mutaatiota. Näissä perheissä kromosomaaliset muutokset, pikemmin kuin MMR mekanismin toimimattomuus, ovat osallisena kohdun runko-osan syöpien kehittymiseen. Tutkimuksemme jälkeen jäi vielä epäselväksi muodostavatko kyseiset perheet itsenäisen kokonaisuuden, jonka taustalla on yhden geenin virhe, vai ovatko sattumaa useammin esiintyvät kohdun runko-osan syövät näissä perheissä usean eri geenin sekä ympäristön yhteisvaikutuksen tulos. HNPCC -syndrooman geneettinen tausta tunnetaan hyvin, mutta on yhä epäselvää miksi juuri tietyt kudokset ovat erityisen alttiita kasvainten kehittymiselle. Erilaisilla ituratamutaatioilla ja kudosspesifeillä kohdegeeneillä on vaikutuksensa eri kudosten syöpäalttiuteen. Havaitsimme, että HNPCC syöpäkirjon määräytymiseen vaikuttavat lisäksi MLH1 -geenipaikan häviäminen sekä MLH1 -geenin hypermetylaatio. Tässä tutkimuksessa suvuittain esiintyvät paksusuolen syövät ja kohdun runko-osan syövät luokiteltiin tarkemmin molekyyligenetiikan keinoin. Havainnoistamme on todennäköisesti hyötyä myös satunnaisesti esiintyvien syöpien luokittelulle ja sitä kautta mahdollisesti tulevaisuudessa myös potilaiden yksilöidyn hoidon suunnittelulle

The potential of DNA methylation as a biomarker for obesity and smoking

Peer reviewe

Mendelian randomization in (epi)genetic epidemiology : an effective tool to be handled with care

A study examining blood lipid traits takes epigenomics approaches to the next level by using carefully performed Mendelian randomization to assess causality rather than simply reporting associations.Non peer reviewe

Making Sense of the Epigenome Using Data Integration Approaches

Epigenetic research involves examining the mitotically heritable processes that regulate gene expression, independent of changes in the DNA sequence. Recent technical advances such as whole-genome bisulfite sequencing and affordable epigenomic array-based technologies, allow researchers to measure epigenetic profiles of large cohorts at a genome-wide level, generating comprehensive high-dimensional datasets that may contain important information for disease development and treatment opportunities. The epigenomic profile for a certain disease is often a result of the complex interplay between multiple genetic and environmental factors, which poses an enormous challenge to visualize and interpret these data. Furthermore, due to the dynamic nature of the epigenome, it is critical to determine causal relationships from the many correlated associations. In this review we provide an overview of recent data analysis approaches to integrate various omics layers to understand epigenetic mechanisms of complex diseases, such as obesity and cancer. We discuss the following topics: (i) advantages and limitations of major epigenetic profiling techniques, (ii) resources for standardization, annotation and harmonization of epigenetic data, and (iii) statistical methods and machine learning methods for establishing data-driven hypotheses of key regulatory mechanisms. Finally, we discuss the future directions for data integration that shall facilitate the discovery of epigenetic-based biomarkers and therapies

Differences in DNA Methylation-Based Age Prediction Within Twin Pairs Discordant for Cancer

DNA methylation-based age acceleration (DNAmAA) is associated with cancer, with both cancer tissue and blood showing increased DNAmAA. We aimed to investigate whether DNAmAA is associated with cancer risk within twin pairs discordant for cancer, and whether DNAmAA has the potential to serve as a biomarker for such. The study included 47 monozygotic and 48 same-sex-dizygotic cancer-discordant twin pairs from the Finnish Twin Cohort study with blood samples available between 17 and 31 years after the cancer diagnosis. We studied all cancers (95 pairs), then separately breast cancer (24 pairs) and all sites other than breast cancer (71 pairs). DNAmAA was calculated for seven models: Horvath, Horvath intrinsic epigenetic age acceleration, Hannum, Hannum intrinsic epigenetic age acceleration, Hannum extrinsic epigenetic age acceleration, PhenoAge and GrimAge. Within-pair differences in DNAmAA were analyzed by paired t tests and linear regression. Twin pairs sampled before cancer diagnosis did not differ significantly in DNAmAA. However, the within-pair differences in DNAmAA before cancer diagnosis increased significantly the closer the cancer diagnosis was, and this acceleration extended for years after the diagnosis. Pairs sampled after the diagnosis differed for DNAmAA with the Horvath models capturing cancer diagnosis-associated DNAmAA across all three cancer groupings. The results suggest that DNAmAA in blood is associated with cancer diagnosis. This may be due to epigenetic alterations in relation to cancer, its treatment or associated lifestyle changes. Based on the current study, the biomarker potential of DNAmAA in blood appears to be limited.Peer reviewe

Making Sense of the Epigenome Using Data Integration Approaches

Epigenetic research involves examining the mitotically heritable processes that regulate gene expression, independent of changes in the DNA sequence. Recent technical advances such as whole-genome bisulfite sequencing and affordable epigenomic array-based technologies, allow researchers to measure epigenetic profiles of large cohorts at a genome-wide level, generating comprehensive high-dimensional datasets that may contain important information for disease development and treatment opportunities. The epigenomic profile for a certain disease is often a result of the complex interplay between multiple genetic and environmental factors, which poses an enormous challenge to visualize and interpret these data. Furthermore, due to the dynamic nature of the epigenome, it is critical to determine causal relationships from the many correlated associations. In this review we provide an overview of recent data analysis approaches to integrate various omics layers to understand epigenetic mechanisms of complex diseases, such as obesity and cancer. We discuss the following topics: (i) advantages and limitations of major epigenetic profiling techniques, (ii) resources for standardization, annotation and harmonization of epigenetic data, and (iii) statistical methods and machine learning methods for establishing data-driven hypotheses of key regulatory mechanisms. Finally, we discuss the future directions for data integration that shall facilitate the discovery of epigenetic-based biomarkers and therapies.Peer reviewe

The role of adolescent lifestyle habits in biological aging : A prospective twin study

Background: Adolescence is a stage of fast growth and development. Exposures during puberty can have long -term effects on health in later life. This study aims to investigate the role of adolescent lifestyle in biological aging. Methods: The study participants originated from the longitudinal FinnTwin12 study (n = 5114). Adolescent lifestyle-related factors, including body mass index (BMI), leisure -time physical activity, smoking, and alcohol use, were based on self-reports and measured at ages 12, 14, and 17 years. For a subsample, blood -based DNA methylation (DNAm) was used to assess biological aging with six epigenetic aging measures in young adulthood (21-25 years, n = 824). A latent class analysis was conducted to identify patterns of lifestyle behaviors in adolescence, and differences between the subgroups in later biological aging were studied. Genetic and environmental influences on biological aging shared with lifestyle behavior patterns were estimated using quantitative genetic modeling. Results: We identified five subgroups of participants with different adolescent lifestyle behavior patterns. When DNAm GrimAge, DunedinPoAm, and DunedinPACE estimators were used, the class with the unhealthiest lifestyle and the class of participants with high BMI were biologically older than the classes with healthier lifestyle habits. The differences in lifestyle-related factors were maintained into young adulthood. Most of the variation in biological aging shared with adolescent lifestyle was explained by common genetic factors. Conclusions: These findings suggest that an unhealthy lifestyle during pubertal years is associated with accelerated biological aging in young adulthood. Genetic pleiotropy may largely explain the observed associations.Peer reviewe

Leisure-time physical activity and DNA methylation agea twin study

BackgroundEpigenetic clocks may increase our understanding on human aging and how genetic and environmental factors regulate an individual aging process. One of the most promising clocks is Horvath's DNA methylation (DNAm) age. Age acceleration, i.e., discrepancy between DNAm age and chronological age, tells us whether the person is biologically young or old compared to his/her chronological age. Several environmental and lifestyle factors have been shown to affect life span. We investigated genetic and environmental predictors of DNAm age in young and older monozygotic (MZ) and dizygotic (DZ) twins with a focus on leisure time physical activity.ResultsQuantitative genetic modeling revealed that the relative contribution of non-shared environmental factors was larger among older compared with younger twin pairs [47% (95% CI 35, 63) vs. 26% (95% CI: 19, 35), pPeer reviewe

The Association Between Epigenetic Clocks and Physical Functioning in Older Women: A 3-Year Follow-up

Epigenetic clocks are composite markers developed to predict chronological age or mortality risk from DNA methylation (DNAm) data. The present study investigated the associations between 4 epigenetic clocks (Horvath’s and Hannum’s DNAmAge and DNAm GrimAge and PhenoAge) and physical functioning during a 3-year follow-up.We studied 63- to 76-year-old women (N = 413) from the Finnish Twin Study on Aging. DNAm was measured from blood samples at baseline. Age acceleration (AgeAccel), that is, discrepancy between chronological age and DNAm age, was determined as residuals from linear model. Physical functioning was assessed under standardized laboratory conditions at baseline and at follow-up. A cross-sectional analysis was performed with path models, and a longitudinal analysis was conducted with repeated measures linear models. A nonrandom missing data analysis was performed.In comparison to the other clocks, GrimAgeAccel was more strongly associated with physical functioning. At baseline, GrimAgeAccel was associated with lower performance in the Timed Up and Go (TUG) test and the 6-minute walk test. At follow-up, significant associations were observed between GrimAgeAccel and lowered performance in the TUG, 6-minute and 10-m walk tests, and knee extension and ankle plantar flexion strength tests.The DNAm GrimAge, a novel estimate of biological aging, associated with decline in physical functioning over the 3-year follow-up in older women. However, associations between chronological age and physical function phenotypes followed similar pattern. Current epigenetic clocks do not provide strong benefits in predicting the decline of physical functioning at least during a rather short follow-up period and restricted age range.Peer reviewe

Do Epigenetic Clocks Provide Explanations for Sex Differences in Life Span? A Cross-Sectional Twin Study

The sex gap in life expectancy has been narrowing in Finland over the past 4–5 decades; however, on average, women still live longer than men. Epigenetic clocks are markers for biological aging which predict life span. In this study, we examined the mediating role of lifestyle factors on the association between sex and biological aging in younger and older adults.Our sample consists of younger and older twins (21‒42 years, n = 1 477; 50‒76 years, n = 763) including 151 complete younger opposite-sex twin pairs (21‒30 years). Blood-based DNA methylation was used to compute epigenetic age acceleration by 4 epigenetic clocks as a measure of biological aging. Path modeling was used to study whether the association between sex and biological aging is mediated through lifestyle-related factors, that is, education, body mass index, smoking, alcohol use, and physical activity.In comparison to women, men were biologically older and, in general, they had unhealthier life habits. The effect of sex on biological aging was partly mediated by body mass index and, in older twins, by smoking. Sex was directly associated with biological aging and the association was stronger in older twins.Previously reported sex differences in life span are also evident in biological aging. Declining smoking prevalence among men is a plausible explanation for the narrowing of the difference in life expectancy between the sexes. Data generated by the epigenetic clocks may help in estimating the effects of lifestyle and environmental factors on aging and in predicting aging in future generations.Peer reviewe