Molecular basis of human pathologies

Genetic predisposition to gastrointestinal cancers

Principal Investigator: Prof. Guglielmina Nadia Ranzani

Collaborators: Raefa Abou Khouzam (PhD student), Gianluca Tedaldi (PhD student), Monica Marabelli (postdoctoral fellow)

The main aim of our research activity is the detection and functional characterization of genetic lesions associated with the development of gastrointestinal tumors in families with hereditary syndromes. These syndromes include HNPCC (hereditary non-polyposis colorectal cancer), FAP/MAP (familial adenomatous polyposis/MUTYH-associated polyposis) and HDGC (hereditary diffuse gastric cancer).

Genetic testing of predisposition genes can establish the presence of cancer predisposing alterations or the absence of any specific changes. However, the finding of variants of uncertain significance (often called VUSs), is another possible result that can complicate rather than improve the risk assessment process. The functional significance of VUSs is investigated by different approaches, including in silico analyses, functional assays, gene expression analysis and characterization of splicing products.

Since genes known to be associated with the above syndromes do not explain all selected families, our research group is part of a collaborative study aimed at searching for new disease-genes by NGS approach (cancer-gene-panel and exome sequencing).

Findings from numerous studies have shown that the genetic component plays a crucial role not only in syndromic and familial cases, but also in the development of the so-called sporadic cancers. Indeed, Genome Wide Association Studies (GWAS) have recently detected genetic variants at different loci that can modulate the risk of colorectal cancer. We are interested in investigating if some low-penetrance alleles that have been associated with colorectal cancer can increase the risk of both pre-neoplastic lesions and cancer also in the Italian population.


Collaborators: Tiziana Venesio (Istituto Oncologico-IRCCS, Candiolo-Torino), Costanza Alvisi (Fondazione IRCCS-Policlinico San Matteo, Pavia); Daniele Calistri e Chiara Molinari (Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-IRCCS, Meldola-FC); Bernardo Bonanni (IEO-Istituto Europeo di Oncologia, Milano); Natalia Pellegata (Institute for Diabetes and Cancer IDC Helmholtz Center Munich, Germania)


Somatic genetic lesions associated with progression of gastric and colorectal cancers

Principal Investigator: Prof. Guglielmina Nadia Ranzani

Collaborators: Raefa Abou Khouzam (PhD student), Gianluca Tedaldi (PhD student), Monica Marabelli (postdoctoral fellow)


Beside genetic factors predisposing to gastrointestinal cancers, we are analyzing somatic lesions involved in cancer progression.

In particular, we are interested in analyzing: somatic lesions at different loci in sporadic colorectal cancers (with/without epatic metastases) with the aim of identifying prognostic markers that can be used in clinical practice; somatic lesions in cancer samples of patients with MAP syndrome (MUTYH-associated polyposis), in order to characterize the carcinogenic process associated with Base Excision Repair system defects; somatic lesions of CDH1 (E-cadherin) gene in sporadic gastric tumors, with focus on canonical and non-canonical transcripts that can contribute to cancer development.


Collaborators: Tiziana Venesio (Istituto Oncologico-IRCCS, Candiolo-Torino), Costanza Alvisi (Fondazione IRCCS-Policlinico San Matteo, Pavia); Daniele Calistri e Chiara Molinari (Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-IRCCS, Meldola-FC); Bernardo Bonanni (IEO-Istituto Europeo di Oncologia, Milano); Natalia Pellegata (Institute for Diabetes and Cancer IDC Helmholtz Center Munich, Germania)


Genetics of taste perception

See topic 7 under “Genomics of human and animal populations


Identification of diagnostic markers and therapeutic preclinical studies in celiac disease

(Group leader: Prof. Sergio Comincini)

The celiac disease is a chronic inflammation of the small intestine, triggered by the ingestion of gluten in genetically predisposed individuals. It is characterized by a clinical picture very variable, ranging from profuse diarrhea with marked weight loss, extra-intestinal symptoms, the association with other autoimmune diseases. Untreated celiac disease can lead to complications too dramatic, such as intestinal lymphoma. Celiac disease can be identified with absolute safety through the serological test and biopsy of the duodenal mucosa during endoscopy. The gluten-free diet is the only currently available therapy and should be carried out rigorously for life.

The theme is divided into two distinct phases: the first, is expected to identify molecular markers isolated from the blood of patients with celiac disease and related pediatric controls that will be collected at the S.C. of Pediatric Surgery of the Fondazione IRCCS Policlinico San Matteo. Among the molecular markers of interest, they will be isolated and quantitatively measured the circulating microRNAs, the particular those able to modulate positively/negatively the degradative processes of the cell functionality, including that autophagic one.

Cellular models are also used for studies in celiac disease, with whom develop preclinical therapeutic protocols based on the possibility of modular molecularly or a pharmacologically degradative right of the cell process, autophagy, can potentially degrade the gluten, in particular by reducing the tendency to form larger molecular aggregates.


External collaborations: Prof. Mauro Bozzola, Dr. Cristina Meazza, Dr. Sara Pagani (Maternal and Child Department, IRCCS San Matteo Pavia); Prof. Gloria Pelizzo (Department of Clinical Surgical, Fondazione IRCCS San Matteo Pavia)



Group Leader: Prof. Cuccia Mariaclara

Coworkers: Dott. Chiara Boiocchi (biologist, postdoctoral researcher, PhD in Genetics and Molecular Biology, Clinical Pathology Specialization at Post-Graduate Specialization School), Dott. Cristiana Pistono (PhD student in Genetics, Molecular and Cellular Biology).

Our research encompasses the complexity of the field of human Immunogenetics and in particular the genomic regions involved in diseases with immune component. HLA gene polymorphisms that control self recognition, autoimmune mechanisms and four serum complement proteins are studied as well as proteins involved in inflammation. Research extended to the complete HLA region in order to define supratypes has also demonstrated to be of great interest both for defining markers in different human populations and for its applications in the study of associations between immune genes and human diseases. The mechanisms of gene regulation, especially in immunoglobulin isotype deficiencies, in antibody involvement in organ transplantation, in immunobiology of human reproduction and in human neuroinflammation are studied. Experiments involve the use of in vitro cell cultures, serum, protein analysis, lymphocytes subgrupping, and include work on proteins, RNA and DNA.




Neuroinflammation and Multiple Sclerosis (MS)

Multiple Sclerosis is an autoimmune and complex neurological disease, and its precise etiology is not yet known. Our specific object is to analyse the inflammatory component.

The principal objective will be to study HLA class III gene polymorphisms (RAGE, HSP70, TNF) and other genes (BDNF) polymorphisms involved in the pathological processes and subsequently to establish, by using statistical analysis, possible functional correlations. With this method we think it is possible to identify molecular markers capable of signalling a predisposition or resistance to the inflammatory process in MS patients.

Also the VDR (Vitamin D Receptor) gene is considered, that is important since low levels of vitamin D are considered a risk factor for the development of MS. The study of polymorphisms located in this gene and the analysis of the expression levels are important to verify how genetic and environmental factors could interact.

Secondly, we propose to analyze protein expression of genes that we possibly found involved, at the genetic level, in the various forms of disease. This work will be useful to verify the extent transcription and translation and to associate them with serum differences found in MS patients.

Finally we will study microRNA (miRNA) in sera of MS patients under drug treatment, in order to assess if a drug can influence positively the expression of a particular miRNA.

This research is made in collaboration with Dott. Roberto Bergamaschi, Dott. Diego Franciotta and Dott. Giulia Mallucci, Department of Neurological Sciences, IRCCS National Neurologic Institute “C. Mondino”.


Immunogenetics study of Alzhemier’s Disease (AD)

Alzheimer  Disease (AD) is a neurodegenerative pathology characterized by a progressive accumulation of cerebral proteins, loses of neurons and synapses, and alteration of reactive process with a multifactorial etiology. Immune genes are involved and neuronal inflammation contribute to progression of disease. We study numerous polymorphic genes in order to identify markers of disease onset and progression:  RAGE (Receptor for Advanced Glycation Endproducts), TNF-α (Tumor Necrosis Factor-alpha), HLA-G, TRL4 (Toll-like receptor 4), C4A and C4B (Complement Component 4 A and B) and BDNF (Brain-derived Neurotrophic Factor).

This research is made with Dott C. Cereda, IRCCS National Neurological Institute “C. Mondino” and Prof G. Ricevuti, Department of Internal Medicine and Therapeutics, Section of Geriatrics, University of Pavia.


Chronic Fatigue Syndrome

Chronic Fatigue Syndrome is characterized by debilitating fatigue of an unknown nature associated with normal laboratory findings. It is a relatively unstudied disease, which however is assuming greater relevance. Our group is the first in Italy to have developed a biological bank of DNA, RNA, serum and red blood cells of Italian patients with CFS. On these samples we are studying MHC class III polymorphisms (TNF, RAGE, HSP-70, C4, LTA), cytokine promoter polymorphisms and we are undertaking gene expression studies. Our group is available to exchange material from the bank in collaboration with other research groups. In order to investigate  autoantibodies in CFS we collaborated with Prof. Y. Shonfeld, Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.


Gender studies

We evaluate in three differing models the mother-fetus relation and this genetic selection. The three lines are the following:

  • Maternal/fetal haepatitis virus transmission (in collaboration with Prof. A. Maccabruni, Department of Internal Medicine and Therapeutics, Medical School, University of Pavia); in particular we are analysing KIR polymorphic genes expressed on NK ( Natural Killer lymphocytes) and HLA-C and HLA-G alleles
  • NIMA (Noninherited Maternal Antiges) haplotypes: HLA alleles of mother and cord blood (fetal alleles) are studied, because involved in tolerance of organ transplantation. Microchimerism induced during pregnancy seems extremely important for the future use of cord blood hemopoietic cells in transplantation (in collaboration with Dr. M. Martinetti, IRCCS Policlinico San Matteo)
  • HLA haplotypes in segregation distortion: we are analyzing normal families in order to demonstrated HLA segregation distortion of mendelian inheritance, in relation to newborn genotype and weight (in collaboration with Dr. P Bergamaschi and Dr. C. Capittini, Cord Blood Bank IRCCS Foundation Policlinico San Matteo, Pavia).



Gene polymorphisms that code for inflammatory molecules in CAD (coronary artery disease) patients

Gene polymorphisms that code for important molecules involved in the inflammatory processes occurring at the beginning and during the progression of the atherosclerotic plaque are considered. More specifically, SNPs of the following genes are studied: RAGE (Receptor for Advanced Glycation End products), involved in the progression of the inflammatory response; TNF (Tumor Necrosis Factor) that codifies for one of the most important pro-inflammatory cytokines, and the TNFR1 and TNFR2 genes which code for receptors through which TNF mediated its biological effects. Gene polymorphisms, belonging to HLA class III, that codify for the stress protein HSP-70, and CR1 (complement receptor 1) are also investigated.

This research is made in collaboration with Prof. C. Falcone, Interdepartmental Center for Research in Molecular Medicine, Faculty of Medicine and Surgery, University of Pavia).




External collaborators: at the Biochemistry and Genetics laboratory of Respiratory Diseases, IRCCS Foundation Policlinico S. Matteo, Pavia: Dr. Michele Fidel Zorzetto (biologist, specialized in Clinical Biochemistry), Dr. Ilaria Campo (biologist, PhD in Genetics and Molecular Biology).

At CIRMC (Interdepartmental Center for Research in Molecular Medicine): Prof C. Falcone (Professor in Cardiology, Faculty of Medicine and Surgery, University of Pavia), Dr S. Bozzini (biologist, PhD in Internal Medicine).

At Department of Internal Medicine and Therapeutics, Section of Geriatrics and Gerontology, IDR “S. Margherita”, University of Pavia: Prof. Giovanni Ricevuti (Director of the Section of Geriatrics, University of Pavia).

At the Immunogenetics Laboratory, IRCCS Foundation Policlinico S. Matteo, Pavia: Dott. Annamaria Pasi (Director of the Immunogentics Laboratoty).

At IRCCS National Neurological Institute “C. Mondino”: Dr. Roberto Bergamaschi (Neurologist), Dr. Diego (Neurologist) Franciotta, Dr. Giulia Mallucci (Neurologist), Dr. Cristina Cereda (biologist, director of Laboratory of Experimental Neurobiology).


The laboratory of Immunogenetics of the Department of Biology and Biotechnology “L. Spallanzani”, and the HLA laboratory of the S. Matteo Hospital together form the 2nd Unit and 1st Unit of the “Immunogenetics Group” in Pavia that participate in the collective studies of the “International Histocompatibility Workshop” from 1984.