Molecular oncology

‘Tumour’ or ‘neoplasm’ refers to a pathological condition characterised by the uncontrolled proliferation of cells that, due to alterations in their genetic heritage, lose proliferative control and acquire the ability to infiltrate the body’s tissues, altering their structure and functioning.

What are the causes of cancer? Why do we get sick?

The etiopathogenesis, or cause, of neoplasm onset is undoubtedly multifactorial. It involves a combination of constitutional (genetic) risk factors and environmental risk factors. These environmental factors include not only toxic exposures but also agents capable of altering DNA structure (mutagens) and regulators of gene expression (epigenetic factors).

Are they hereditary?

Not always. In 70–80% of cases, tumours are ‘sporadic’, i.e., they occur in the general population without any family history or conditions leading to the suspicion of a clear predisposing factor on a genetic basis. In such cases, the cause of the neoplasm lies in gene variants (mutations) occurring by chance in somatic cells, capable of growing uncontrollably and infiltrating adjacent tissues and extending to the organ, organ system and the entire organism (metastasis). In 15–20% of cases, the tumour is ‘familial’, i.e., found in several persons in the family. Family history is a risk factor mainly due to environmental factors (sharing common environmental risk factors such as lifestyle, diet, pollutants, etc.), without there being a specific genetic alteration predisposing to the disease. Such variants will only be found in neoplastic cells.
The remaining 5–10% of cases are ‘hereditary’ tumours, although this percentage depends on the type of tumour: for example, in breast cancer, 5–10% of cases are hereditary, and in ovarian cancer, almost 23%. Hereditary cancers arise from mutations in the DNA of germ cells (gametes) and can therefore be passed on to offspring. A person who has inherited a germline mutation will be genetically predisposed to becoming ill; they will present this variant in all the cells of their body. Genetic predisposition alone does not determine the onset of neoplasia; further mutations are required, which will add exponentially to the germline mutation.

Is it possible to know one's risk of developing cancer?

Certainly.
Analysis by NGS makes it possible to identify people at risk of developing a specific neoplasm, whether the tests are targeted or extended. In particular, it is possible to search for genetic predisposition for the following types of tumours:

  • Breast tumour: Analysis of ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH, NBN, NF1, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11 and TP53 genes;
  • Gynaecological tumours (Breast/Ovarian/Uterus): Analysis of ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, DICER1, EPCAM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, SMARCA4, STK11 and TP53 genes;
  • Colorectal tumour: analysis of APC, AXIN2, BMPR1A, CDH1, CHEK2, EPCAM, GALNT12, GREM1, MLH1, MSH2, MSH3, MSH6, MUTYH, NTHL1, PMS2, POLD1, PTEN, SMAD4, STK11 and TP53 genes;
  • Gastric tumour: analysis of APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, PMS2, STK11, SMAD4 and TP53 genes;
  • Pancreatic tumour: analysis of APC, ATM, BMPR1A, BRCA1, BRCA2, CDK4, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, SMAD4, STK11 and TP53 genes;
  • Prostate tumour: analysis of ATM, BRCA1, BRCA2, CHEK2, EPCAM, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D and TP53 genes;
  • Skin tumour (Melanoma): analysis of BAP1, BRCA2, CDK4, CDKN2A, MITF, PTEN, RB1 and TP53 genes;
  • Brain/Nervous System tumour: analysis of AIP, ALK, APC, CDKN1B, CDKN2A, DICER1, EPCAM, HRAS, MEN1, MLH1, MSH2, MSH6, NBN, NF1, NF2, PHOX2B, PMS2, PRKAR1A, PTCH1, PTEN, RB1, SMARCA4, SMARCB1, SMARCE1, SUFU, TP53, TSC1, TSC2 and VHL genes;
  • Renal/Urinary Tract tumour: analysis of BAP1, CDC73, CDKN1C, DICER1, DIS3L2, EPCAM, FH, FLCN, GPC3, Met, MITF, MLH1, MSH2, MSH6, PMS2, PTEN, SDHA, SDHB, SDHC, SDHD, SMARCA4, SMARCB1, TP53, TSC1, TSC2, VHL and WT1 genes;
  • Pheochromocytoma/Paraganglioma: analysis of EGLN1, FH, KIF1B, MAX, MEN1, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127 and VHL genes;
    Thyroid: analysis of APC, CHEK2, DICER1, PRKAR1A, PTEN, RET, TP53, MEN1, SDHB and SDHD genes.

Who is the test intended for?

  • Persons with a positive family history (high and specific incidence of neoplastic diseases in previous generations) either for the same type of neoplasm or for related tumours,
  • subjects with multiple tumours;
  • tumours that arose at a young age.

What are the benefits of this test?

  • Identification of subjects at risk of developing a neoplasm;
  • possibility of early diagnosis of the tumour;
  • a better therapeutic approach;
  • reduction of mortality.

Oncological genetic counselling

When is it indicated?
In the case of family-related or hereditary neoplasms. In such cases, ensuring the family history is also examined by geneticists will guarantee that the best possible health precautions are in place.

Health prevention is the set of all measures useful to prevent the appearance, spread and progression of diseases, as well as to limit irreversible damage when the disease is in progress.
Three levels of prevention can be distinguished:

Primary prevention:it consists of the prevention of the development of the disease.
Examples of primary prevention: vaccinations, changing high-risk behaviours (smoking, alcohol, diet, exposure to genotoxic and toxic substances), chemoprevention.

Secondary prevention: consists of early diagnosis and treatment, if possible, before the onset of symptoms, minimising adverse consequences.
Examples include: screening programmes (metabolic diseases, faecal occult blood screening, mammography, dual-energy X-ray absorptiometry or DXA, PAP tests, HPV-DNA tests), contact tracing, isolation and treatment of infectious diseases.

Tertiary prevention: consists of all activities and interventions aimed at containing and controlling the complex outcomes of a disease. It therefore deals with people who are already ill, with chronic or irreversible diseases, with the aim of limiting the occurrence of relapses, complications or disability. Tertiary prevention often overlaps with therapy (e.g., diet for a person with diabetes). Tertiary prevention includes rehabilitation, understood as the recovery of a functional state that is as normal as possible for a patient who, as a consequence of a pathological or dysfunctional state, presents functional deficits and disabilities.
Clinical, haematochemical, molecular and, where possible, periodic instrumental follow-up (careful monitoring of blood glucose, coagulation factors, blood pressure, liver and kidney function) and a personalised therapeutic approach (physical activity, personalised diet, chemotherapy, nutraceuticals, etc.) are concrete examples of this.

The geneticist, using secondary prevention, will be able to ascertain whether the patient is a carrier of a mutation that predisposes them to the development of a specific tumour and, if the test is positive, the investigation can be extended to the patient’s family members, in order to identify those at risk.
The genetic information thus obtained can bring significant benefits, such as

  • the identification of family members who are at a high risk of developing cancer;
  • the organisation of an adequate medical control programme reserved for high-risk subjects, in such a way as to facilitate early diagnosis at the onset of cancer;
  • knowledge of the possibility of transmission of gene mutations to offspring and the identification of children with germline, high-risk gene mutations;
  • the evaluation of any indications for preventive prophylaxis therapies.

How is the test performed?
Genomic DNA is isolated from the biological sample under examination. Subsequently, by means of a technologically advanced DNA sequencing process called Next Generation Sequencing (NGS), the genes listed in table 1 – which are involved in most cases of hereditary predisposition to the development of the tumours described above – were sequenced completely (whole exome sequencing, exons and adjacent intronic regions, ± 5 nucleotides), at a high reading depth.

A positive result does not mean that the patient who has been found to have a mutation will necessarily develop cancer, but only that this patient has a predisposition to do so, i.e., they have a higher risk than a person who does not have the specific mutation. In fact, not all people who carry a mutation develop the neoplastic disease; although these mutations greatly increase the risk of developing cancer, it does not develop until the normal copy of the corresponding gene mutates.

The identification of a predisposing mutation makes it possible to establish a protocol of close clinical follow-up and to assess the appropriateness of preventive interventions. It also allows the test to be extended to other family members at risk. In the latter, the analysis has value as a predictive test because it makes it possible to distinguish, within these families, mutation carriers from non-carriers, identifying individuals who present a high risk of cancer and those whose risk is comparable to that of the general population. In this way, the former can be targeted to specific surveillance programmes for early diagnosis or prophylaxis, while the latter can be directed to the controls envisaged for the general population.

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