Molecular Genetics of Cancer

Research project

Background

Cancer control is increasingly focusing on prevention and early diagnosis, where genetic profiling leads to risk factors identification and early stage detection, to allow preliminary treatment and prevent the disease from progressing. Cancer, therefore, is a genetic disease. The identification of aberrations in genes involved in cancer and the creation of "maps of individual risk" are the goals of modern "predictive medicine". Genetic tests and nanotechnology are at the heart of a research program that forms the "interface between basic research and clinical application" for tumour prevention, early diagnosis and treatment. These approaches provide information that is of immediate relevance to the health of the patients, and they also generate a wealth of knowledge essential to open new avenues of research. Our group is composed of two units working on genetic markers of cancer risk and cancer genomics.

Genetic markers of cancer risk

It is well established that constitutional genetic variants exist that may predispose to cancer. The development of molecular tests that identify such at-risk alleles represents one of the most promising approaches for the control of this disease. In fact, carriers of cancer predisposing alleles could be selectively addressed to the adequate programs of prevention and/or surveillance, where available, to reduce the morbidity and mortality related to their conditions.

Basically, cancer predisposing alleles can be distinguished into two groups, at high or low penetrance. High-penetrance alleles confer, by themselves, a risk of cancer much higher (up to 40 times) than that observed in the general population. Conversely, low-penetrance alleles confer a modest increase in cancer risk and are thought to act synergistically in cancer families unexplained by high-penetrance alleles.

Presently ongoing research programs are summarised as follows:

Optimisation of genetic testing in cancer predisposing genes
In collaboration with the DNA sequencing facility of IFOM, this unit is involved in the development of rapid and cost-effective assays for the identification of point mutations and small deletions/insertions in the coding exons and intron-exon boundaries of the main cancer predisposing genes. At present, the laboratory has a database including more that 750 families tested positive for mutations in either of the genes responsible for 'Hereditary Breast and Ovarian Cancer' (BRCA1 and BRCA2), 'Lynch Syndrome' (MLH1, MSH2 and MSH6), and Familial Adenomatous Polyposis (APC and MHY). In addition, to improve the informativeness of genetic analyses in at-risk individuals, this unit is defining the spectra of alterations that may affect genes associated with cancer predispositions. The frequency of molecular defects, such as genomic rearrangements and allele-specific silencing, present within the Italian population is currently under investigation. Moreover, we are also interested in the assessment of the clinical relevance of genetic variants identified in cancer predisposing genes, whose significance in relation to cancer risk is at present undefined. These include mainly missense and intronic mutations in the proximity of splice sites. Such variants are being examined both at the transcript level, to evaluate their effect on the integrity and stability of mRNA, and at the protein level, through the employment of functional assays. Finally, research projects are active focused on the identification of phenotypic - mainly tumour associated - markers that may be used as predictors of germline mutations in cancer predisposing genes, in order to orientate the selection of individuals eligible to genetic tests.

Validation of new genetic markers of cancer risk
A research task is ongoing to validate 'candidate' cancer-related low-penetrance alleles in at-risk individuals from families tested negative for mutations in major cancer predisposing genes, such as BRCA1 and BRCA2. Association studies are performed and the frequencies of these alleles in familial cases are compared with those observed in sporadic cases and in healthy controls from the population. Moreover, the unit is participating in a large collaborative international network, the "Consortium of Investigators of Modifiers of BRCA1/2" (CIMBA), aimed to the assessment of the effect of low-penetrance alleles as modifiers of cancer risk in carriers of mutations in BRCA genes.

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Cancer Genomics

[This project is supervised by Dr. Manuela Gariboldi - tel 02574303284, fax 02574302231]

The focus of our group is the molecular characterization of tumor samples from the IRCCS Foundation Istituto Nazionale dei Tumori (Milano) by means of high-throughput genomic technologies such as DNA microarrays. These technologies allow us to profile different cohorts of samples for coding and non-coding transcripts (miRNA) expression levels, gene and chromosome copy number alterations and gene methylation status on a genome-wide scale.

This information and the integration thereof can then be associated with different clinical end-points to gather a better understanding of disease progression. The outcome of our research is two-fold, on one hand we aim to validate and develop clinically relevant molecular prognostic and predictive models, and on the other hand we aim to perform functional validation of potential therapeutic targets identified in our first line of research.

Our main ongoing projects are briefly summarized below:

1. Identification and characterization of molecular markers associated to hereditary breast cancer
   The aim of the present project is the identification of expression profiles of coding and non-coding transcripts able to distinguish among the different hereditary breast cancers, those with alterations in BRCA1 or BRCA2 genes or defined as BRCAx. We will also try to dissect the BRCAx group and find specific sub-groups with particular gene profiles, putatively referable to common molecular pathways, in which new cancer predisposing genes should be found.
2. Integrated expression profiles in PBL and LCL to define genes associated with patients' response to therapy
   The objective of this project is the identification of gene expression profiles potentially predictive of response to given therapeutic treatment by using an accessible source such as blood, to establish the basis for a practical assay working directly on peripheral blood and will be used to predict response to treatment, therefore enabling to match the appropriate cure to the appropriate patient.
3. Integrative analysis of genetic alterations, mRNA/miRNA expression patterns, copy number alterations and methylated genes in colon and breast cancer
   This project aims to study the relationship between genetic alterations in key player genes and transcriptome data. The integration of gene and miRNA expression together with DNA copy number and methylation analysis could highlight relevant genetic elements not yet associated to these cancer types that could be used to develop more accurate tools for prognosis and therapy.
4. Critical assessment and development of analytical methods for high-throughput genomic studies
   We evaluate the robustness and correctness of previously published results and methods where the goal of the studies is to develop a multivariate classifier to predict patient disease outcome from a gene-expression profile. In addition, we develop new methods applied to the problems of class discovery (clustering), class comparison and class prediction using microarray data and to the problems of meta-analysis and the integration of different genomic data.

The group is part of a special program of the Scientific Direction of IRCCS Foundation Istituto Nazionale dei Tumori (Milano), under the supervision of the Scientific Director Marco A. Pierotti.

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