Biomarkers of DNA damage in clinical practice: the example of frailty status in elderly

International Scientific Conference on Medicine at the University of Latvia

Riga, 28 Feb 2019

Stefano BONASSI, PhD, ERT

Department of Human Sciences and Quality of Life PromotionSan Raffaele University, Rome, Italy

Unit of Clinical and Molecular EpidemiologyIRCCS San Raffaele Pisana, Rome, Italy

Personalized Medicine Systems Medicine Precision Medicine

All of them look at the systems of the human body as part of an integrated whole, incorporating biochemical, physiological, and environment interactions.

This new approach draws on systems science and systems biology, and considers complex interactions within the human body in light of a patient's genomics, behavior and environment.

www.sanraffaele.it

SM/Personalized medicine- Primary prevention- Secondary prevention- Tertiary prevention- Treatment

Systems biology on precise phenotypes

Health promotionPrimary prevention

Genes

Age

Biological expression of chronic diseasesTranscripts, proteins, metabolitesTarget organ local inflammation

Systemic inflammationCell and tissue remodelling

Clinical expression of chronic diseasesCo-morbidities

Severity of co-morbiditiesPersistence, remissionLong-term morbidity

Responsiveness - side effects to treatment

Life style - environmentRisk and protective factors

Tobacco smoking, PollutantsAllergens, Nutrition, Infections

Physical exercise, Others

Sex

Socioeconomic

determinants

Gender

3

Exposure

Disease

Black Box

Exposome

Genomics, Epigenomics,

et al

Simple/Complex clinical phenotype 4

Prevention(Susceptibility/Early

stages) Diagnosis

Prognosis Therapeutic

target

Endpoint (outcome) in RCT

Mechanism sensor

Applications in Rehabilitation/Primare care

Quality of life

Cognitive functions

Adverse Events in RCT

Marker of Inappropriate prescribing

Genetic profiling in

personalized medicine

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Micronuclei (MN) are a strong cytogenetic indicator of a catastrophic change in the genetic structure and stability of a cell because they originate from either chromosome breaks or whole chromosomes that have been lost from the main nucleus during cell division.

The resulting genetic abnormalities can to lead to cellular malfunction, altered gene expression and impaired regenerative capacity.

6(Bonassi and Fenech, 2018)

Bonassi et al., Carcinogenesis, 2007

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Conclusions

The great majority of published studies show a significant association of increased MN in lymphocytes and/or buccal cells with infertility, pregnancy complications, developmental defects, anaemias, inflammation, diabetes, obesity, cardiovascular disease, kidney disease, neurodegenerative diseases and cancer.

(Micronuclei and their association with infertility, pregnancy complications,developmental defects, anaemias, inflammation, diabetes, kidney disease, obesity, cardiovascular disease, neurodegenerative diseases and cancer. Bonassi and Fenech, 2018)

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• Most of the data is from case-control studies with substantial heterogeneity in number of subjects, study design and/or MN assay protocol.

• Nevertheless, the few prospective cohort studies which have been published relating to the capacity of the MN assay to predict the risk of pregnancy complications, cardiovascular disease mortality and cancer have all proven the capacity of the MN assay as a prognostic biomarker of developmental and degenerative diseases.

• It is necessary, to consolidate these promising outcomes with more prospective studies to verify reproducibility and to test predictive capacity such as infertility, developmental defects, anaemias, diabetes, kidney disease, Alzheimer’s disease, Parkinson’s disease and specific cancers (e.gcervical cancer, prostate cancer, haematopoietic cancers).9

The use of biomarkers in clinical research impliesthe use of clinical Epi/Statmethods.

Clinical application of micronucleus test in exfoliated buccal cells: A

systematic review and metanalysis Bolognesi et al., Mutat Res Review, 2015

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Bolognesi et al., Mutat Res Review, 2015

Oral, Head and Neck cancer: Forest plot of buccal MN. Mean Ratios (MR) and meta-MR estimated from meta-analysis

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Our systematic review indicates a potential usefulness of the buccal micronucleus assay in the

prescreening and follow up of patients at risk for oral and head and neck cancer.

A main limitation of the assay, which needs to be addressed in the perspective of a practical application, is the large variability in the MN

frequency observed across the laboratories in patients as well as in control groups. The main

source for this variability is related to the different experimental protocols and scoring criteria applied

Bolognesi et al., Mutat Res Review, 201513

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Patel et al., 201715

Fried frailty phenotype

assessment components

*

*

Valdiglesias et al., Mutat Res, 2015

A population of 180 elder adults (age >65) was selected among individuals referred to the geriatric outpatient clinic at the Centro di Medicina

dell’Invecchiamento (Ce.M.I.), Policlinico AgostinoGemelli hospital (Rome, Italy) between October 2012 and January2013. All individuals included in the study were classified as ‘frail’(93 subjects) or ‘non frail’ (87 subjects)

according to Fried’s frailty criteria. Patients positive for three or more Fried’s criteria were classified as ‘frail’.

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Fried’s criteria0 (n = 43) 26.2 (9.1) 1.00 – –

1 (n = 37) 24.5 (8.7) 0.93 [0.80; 1.09] n.s.

2 (n = 7) 25.6 (10.8) 1.04 [0.78; 1.37] n.s.

3 (n = 26) 27.1 (8.0) 1.05 [0.89; 1.24] n.s.

4 (n = 52) 26.9 (10.8) 1.03 [0.89; 1.18] n.s.

5 (n = 15) 27.3 (7.8) 1.06 [0.86; 1.30] n.s.

Group Non frail (n = 87) 25.5 (9.0) 1.00 – –

Frail (n = 93) 27.0 (9.6) 1.06 [0.96; 1.18] n.s.

Age

Frailty syndrome and genomic instability in older adults. Sánchez-Flores et al. J Gerontol A Biol Sci Med Sci , 2018

A total of 257 volunteer donors (84 males and 173 females), aged 65 years or more (79.4±8.8, range 65-102), were recruited from associations of retired older people and nursery homes located in Galicia (NW of Spain).

Valdiglesias et al., Mutat Res, 2015

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Total Non-frail Pre-frail FrailTotal N (%) 257 (100) 39 (15.4) 131 (50.6) 87 (34.0)Gender N (%)Males 84 (32.7) 26 (66.7) 36 (27.5) 22 (25.3)Females 173 (67.3) 13 (33.3) 95 (72.5) 65 (74.7)Age (years-old)a

79.4±8.8(65-102)

73.3±5.6(65-85)

77.1±7.7(65-100)

85.6±7.8(65-102)

Sánchez-Flores et al. J Gerontol A Biol Sci Med Sci , 2018

care of frail elderly

Effect of frailty status on MN tests parameters in lymphocytes and buccal cells; models

adjusted by age, sex, BMI, and smoking habit.

Sánchez-Flores et al. J Gerontol A Biol Sci Med Sci , 2018

223 195 159 134 4219 46 83 108 200

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UWL E LPA SWT LGS

Negative PositiveM

N fr

eque

ncy

(‰)

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MN-L frequency in the older adults population, according to each frailty criterion (Fried et al., 2001). The number of individuals included in each group is indicated inside each rod. *P

Fit Frail Total P87 (48.3%) 93 (55.6%) 180 (100%)

Mean SD Mean SD Mean SD

Tryptophan (µM) 59.41 13.60 51.31 13.43 55.42 14.03 P

The Wall Street Journal, Sept, 2004

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