Auteurs: Mioara C. Matei, Valeriu Chirica, Doina Azoicăi

Résumé: Le cancer colorectal (CRC) représente un problème  important  de la santé publique.  De nos jours il y a des différences significatives entre la Roumanie et d’autres pays européens en ce qui concerne la prévention, la détection précoce, le traitement et les taux de survie des sujets avec CRC. L’objectif de cette étude était d’évaluer si notre système et les structures sanitaires  locales et nationales, si nos patients, si les communautés sont préparés ou non  à introduire l’approche oncogénétique dans le management des sujets et des familles avec un risque héréditaire de cancer colorectal. Les aspects suivants ont été évalués : les besoins de mise en place de l’approche oncogénétique dans le management actuel du CRC, les conditions exigées pour une approche oncogénétique des sujets avec CRC ou avec un grand risque de le développer, l’ouverture de la société d’aider ces personnes et le désir des sujets d’être  aidés par la société. L’approche oncogénétique du CRC implique trois dimensions dans l’activité d’un Département d’Oncogénétique: celle clinique pour le monitorage des sujets, celle moléculaire pour les investigations de laboratoire et celle épidémiologique pour l’interprétation des données. Pour ces activités il y a de nombreux besoins  à prendre en considération : l’infrastructure, les ressources humaines,  les spécialistes formant un Groupe de Consultance Multidisciplinaire, le rapport coûts – efficacité, l’éducation et le conseil pour les patients et les stratégies appropriées. Tenant compte que l’Oncogénétique représente une chance pour la prévention du CRC héréditaire parmi les sujets identifiés avec un risque génétique, on pourrait développer un réseau national en vue de mettre en place une approche oncogénétique qui pourrait devenir un instrument de réalisation des objectifs du Système de Santé sur la prévention du cancer colorectal.

Mots clé: cancer héréditaire, oncogénétique, cancer colorectal, risque génétique

Introduction

  1. Colorectal Cancer – public health issue / problem

Globally, with an estimated number of cases around 1.4 million and 694,000 death in 2012, colorectal cancer (CRC) is an important public health problem, being the third most frequent cancer in males (10% from the total) and the second in females (9.2% from all cancers). Worldwide, colorectal cancer represents the fourth oncological pathology as mortality, with the highest rates registered for both sex in developing countries, such as Central and East European countries (20.3 deaths/100,000 in men and 11.7/100,000 in women) [1].

The incidence of CRC is increasing in some countries from Asia and Eastern Europe (34.5 new cases/100,000 in men and 21.7/100,000 in women), probably as a result of an increased prevalence of risk factors for this type of cancer (as unhealthy diet, obesity and tobacco exposure). Worldwide, the mortality rates of CRC are decreasing in a high number of countries, but there are some other countries with limited resources and increasing incidence rates (Brazil and Chile – in South America and Romania and Russia – in Eastern Europe) that still show an increasing in the mortality rates [2].

Primary prevention for CRC includes: promotion of protective factors and the removal of risk. The secondary prevention includes: screening that can detect colorectal polyps (they can be removed in the precancerous stage) and can detect cancer at an early stage (when treatment is  less extensive and more effective). Population-based colorectal screening programs should not be recommended in some less development countries where the incidence of the disease is not high enough to have a cost-efficient screening program [2].

In 2012, in Romania 4,496 new cases of colorectal cancer were diagnosed (12.6% of all cancers) and 2,446 deaths were identified (12.6% of all cancers) in women. For men the values were a little higher [3].

Nowadays, there are important differences between Romania and other European countries regarding prevention, early detection, treatment, and survival rates for subjects with oncological diseases, in general, and with colorectal cancer, in particular.

Many risk factors were involved in the occurrence of CRC. Some of them are modifiable factors, which increase the risk for sporadic cancers, that could be prevented if every individual takes responsibility to avoid environmental and lifestyle risk factors (foods containing red meat or processed meat, foods rich in animal fats, low fruits, vegetables and fibers diet, overweight and obesity, tobacco smoking, alcohol consumption, the association of diabetes mellitus or metabolic syndrome, Helicobacter pylori infections, and HPV infections) [4, 5, 6].

 

  1. Hereditary Colorectal Cancers

Hereditary Colorectal Cancers (HCRC) represent a group with significant risk, which include Hereditary Non-Polyposis Colorectal Cancer – HNPCC (Lynch Syndrome) and Familial Adenomatous Polyposis (FAP). In both cases, the cumulative lifetime risk for CRC is very high, genetic factors having an essential role in the occurrence of colorectal cancer. So, health monitoring with the aim of prevention and surveillance is necessary [7].

Among genetic factors there are some genes which are frequently involved in the occurrence of CRCs: MMR-genes, associated to HNPCC (MSH2, MLH1, and MSH6); APC gene, associated to FAP [8, 9]. Other genes include: BRCA1 (increases the risk with 8%), p53 (Ly Fraumeni Syndrome), LKB1 (in Peutz-Jeghers Syndrome), PTEN (Cowden Syndrome), BMPR1A and MADH/DPC4 (in the Juvenile Polyposis Syndrome) [10].

People with a first-degree relative with colorectal cancer or more than one affected relative have a higher risk to develop the disease (one first-degree relative – RR = 2.2; > 1 relative –   RR

= 4). Also, the risk is increased if the relative was diagnosed at a younger age (< 45 years) (RR = 3.9) [6, 11].

Around 5% of subjects with CRC have a genetic syndrome involved in the occurrence of the disease. 1 in 35 CRC cases has Lynch Syndrome (HNPCC) and they are at risk to develop many types of cancers (ovarian, endometrial, or stomach), but the highest is for CRC [12].

In order to increase the opportunity for cancer prevention there is an important interest in improving methods for identifying HNPCC among CRC patients [13]. For these high-risk groups of subjects there are evidences to support the combination of chemoprevention with screening tests [14, 15].

The second most frequent predisposing genetic syndrome is FAP, which provides a lifetime risk of CRC of 100% by the age of 40, without intervention. This means that an accurate identification of families with a history of CRC and/or predisposing genetic disorders is necessary in order to begin the testing at an early stage, but the epidemiological studies have shown that registration of cancer history in medical records is lacking in 50% of primary care patients [6].

The inherited part of CRC is about 35% and the hereditary syndromes represent 3-5% of all CRC. The carriers of pathogenic mutations responsible for Lynch syndrome and adenomatous polyposis presents a high lifetime risk for colorectal and other types of cancers. In about 25-30% of all cases with CRC, the disease occurs in families without evidences for one of the known inherited syndrome. Familial non-syndromic CRC is a heterogeneous condition that includes patients with unrecognized hereditary syndromes, but with apparently sporadic forms that are grouped in families [11].

The factors that are involved in the occurrence of this type of CRC are: inherited genetic factors (low-penetrance genetic variants) which act along with the environmental ones.  Although, the risk for CRC associated with each of these variants is not very important at the individual level, they have a significant contribution to the overall disease burden because of their frequencies in the population [11].

 

  1. Oncogenetic approach

Oncogenetics is defined as the medical and diagnostic monitoring of patients and their families, who present monogenic hereditary risk (caused by a mutated gene with high penetrance) or a familial risk to develop cancer. In our case, the main objectives of Oncogenetics approach in CRC include a better understanding of genetic risk factors which raise the probability of CRC occurrence and, on the other hand, a better understanding of the population features in cancer genetics in order to decrease the mortality among groups of people with hereditary risk for CRC development.

At the international level, some major genes for cancer predisposition / susceptibility were discovered at the beginning of ‘90s (BRCA genes for breast cancer and MMR genes for CRC) and the oncogenetic activity started to be developed. That way a new opportunity arisen for those with an important burden of cancer risk: the identification and stratification of cancer risk (oncogenetic consultation), possibility of genetic testing (molecular laboratory diagnostic) and personalized solutions for risk reduction (for individuals with mutations/cancers and their families) [16].

Until 2014, in Romania there was no medical care system of Oncogenetics. There were some oncogenetic activities in Iasi, in a context of scientific research as a result of the collaboration with the research team from Jean Perrin Centre, Clermont-Ferrand, France [17, 18, 19, 20, 21,22].

The aim of this study was to evaluate if our local and national medical structure and system, our patients, our community conditions are ready or not to introduce the oncogenetic approach in the management of subjects and families with a HCC risk. This oncogenetic approach in the management of hereditary colorectal cancer requires different issues which have to be addressed: infrastructure, human resources, a Multidisciplinary Consultancy Group, cost-efficiency approach, patient education and counselling and appropriate strategies.

 

Materials and methods

In 2015 it was conducted a situation analysis within the Department of Oncogenetics Iasi. There were evaluated the following aspects: the needs for the implementation of oncogenetic approach in the actual management of colorectal cancer (infrastructure, human resources, patient education and strategies); the conditions required for the oncogenetic approach of the subjects with CRC or with a high risk of developing this type of malignancy in order to be effective (cost- efficiency); the society willingness to help these people and the desire of subjects to be supported by the society. The informed consent used in the Department of Oncogenetics Iasi was approved by the Ethics Committee of “Grigore T. Popa” University of Medicine and Pharmacy – Iasi.  Also, the informed consent was obtained from each subject who meets the criteria for inclusion  in the Department analysis.

 

Results

Needs for the implementation of oncogenetic approach in the management of CRC

The oncogenetic approach of CRC involves 3 dimensions of the activity within an Oncogenetics Department: clinical for subjects monitoring; molecular for laboratory investigation, and epidemiological for statistical analysis and the interpretation of all data.

As we previously mentioned, for these activities there are many important needs that have to be considered: infrastructure, human resources, a Multidisciplinary Consultancy Group of specialists, cost-efficiency approach, patient education and appropriate strategies.

  1. Infrastructure needs. Our Department of Oncogenetics, within “Grigore T. Popa” University of Medicine and Pharmacy from Iasi includes very well divided rooms with well- established circuits, well and appropriate equipped: special room for secretariat activities, for oncogenetic consultations and molecular diagnostic laboratory. The first 100 molecular analyses were financed by the University. Also, a very specialized software, SEM software [23], has a very important role in the management of epidemiological and oncogenetic data (database, genetic tree and statistical analysis), which was implemented in our Department as a result of our collaboration with the research team from Jean-Perrin Centre.
  2. The human resource, another piece with a very strong contribution to the activities within the Department of Oncogenetics. Because of its novelty, for the implementation of oncogenetic approach in our Health Care System there is a need for specialized training courses offered to our doctors and nurses from different specialties to acquire the necessary information and to build the local, interregional and national  network  of oncogenetics. Also,     statisticians/informatician are involved to help a Department with the management of the computer network, software and other IT issues. Since 2012 our staffs was trained in Oncogenetics, the University organizing annual postgraduate courses and Advanced Schools in collaboration with  international specialists from Jean-Perrin Centre, France.
  3. A Multidisciplinary Consultancy Group (MDCG), which is the most important decision making entity within the Department of Oncogenetics. This group is based on the collaboration of doctors from different fields of medicine: epidemiologists, oncologists, geneticists, gastroenterologists, gynecologists, surgical oncologists, family doctors, imaging specialists, psychiatrists, and specialists in bioethics with biologists and psychologists. The role of MDCG is to evaluate the files of eligible patients in order to decide if the molecular investigation is recommended or not, to coordinate and to implement the Personalized Oncogenetic Surveillance Program (POSP) where necessary and to establish the appropriate primary / secondary prevention measures for a specific case.
  4. The cost-efficiency approach. The following costs are taken into account for the evaluation of one individual within the Department of Oncogenetics: the cost clinical and epidemiological investigation for a person which was diagnosed with a genetic risk for CRC; the cost for molecular tests for gene mutation identification for a person which was investigated through; and the cost for the investigation using clinical, epidemiological, and molecular methods of a relative of a person diagnosed with a risk for CRC.

From the point of view of the laboratory activities, the simultaneous analysis of 100 samples means a higher efficiency and a lower cost per patient. In contrast, analysis of a single sample means less efficiency and a higher cost per patient. Taken into consideration on the one hand the UMF Iasi investment, and on the other hand the need for patients to have a diagnostic answer as soon as possible, in the Department was established the following situation as being the most cost-efficient: a simultaneous analysis of 40 samples, with 75% efficiency and a cost of 3000 EUR per patient.

However, if the cost for the oncogenetic management of one individual with hereditary risk of developing CRC is around € 3.000, in order to be highly cost-efficient, the oncogenetic approach have to include very good and sensitive eligibility criteria for an appropriate selection of individual with high hereditary risk and a high susceptibility to have a MMR gene mutation and to develop colorectal cancer.

  1. Patients’/ subjects’ education and counseling is an essential requirement for the implementation of the oncogenetic approach in the management of hereditary CRC. Some of the topics in which patients/subjects are involved includes: the informed consent, the oncogenetic counselling, and the result communication. The informed consent has to be obtained before any other intervention and is recommended to be written. The oncogenetic counseling, which means a specialized help for individuals and their families to deal with intra-familial experiences that involves hard to manage medical decisions, has two steps: pre- and post- molecular testing, and includes psychological counselling, oriented through the development of some adaptation and integration models for an appropriate approach of the genetic risk of developing CRC. Many factors can influence the psychological impact of the oncogenetic testing: the anxiety, the misunderstanding of medical information, familial problems that can appear during the elaboration of genetic tree (family history), the period which follows after molecular testing, the period when the individual waits for the testing result, the moment when the testing result is communicated, the moment when the subject accept to take into consideration the oncological prevention recommended or during the POSP [16].

Another important issue discussed with a patient / subject is the result communication, which involves specialized support for one subject in order to take a very well informed decision along with a psychological support in the adaptation process. Some of the most important issues related to the communication of the testing result are: if the patient wants or not to know the result and if the patient wants or not to communicate the result to his/her relatives. In this respect, we have identified in our Department the following situations:

  • the subjects were diagnosed with genetic mutation and they express their desire to communicate the result to their sons/ daughters and to include them for molecular testing;
  • the subjects were diagnosed with cancer in a final stage of the disease, and also with a genetic mutation, addressed the Department without the knowledge of their families, express their desire not to communicate the results to other family members, but to convinced them to get the molecular testing;
  • in the most common situation, the subjects want to communicate the result to their relatives in order to give them a chance for prevention and they also recommend the molecular testing for their relatives;
  • in some situations the subjects don’t want their families to know they addressed the Department because if they will have a positive result they will be blamed by their families if other members will be identified later with genetic mutations;
  • some subjects declared that they don’t have a good relation with their relatives, they don’t communicate with other members of the family, so they do not inform them about their intention to address the Department or about the molecular testing result.

However, there is an imperious need for patient health education in order to optimize the implementation of oncogenetic approach in the management of HCRC. The patient / subject has to know about their health problem (addressability to the appropriate healthcare providers, information to help the genetic tree elaboration/ family history, risk factors for their disease, sign and symptoms, prevention methods, early detection, the implication of their decision for their families or relatives, and for society).

  1. Local and national strategies

Local strategies refer to the organization strategies for the activities within the Department of Oncogenetics. A first strategy aims the secretariat activity which establishes the schedule for patients/subjects, register the epidemiological information and elaborate the genetic tree. Also, during this step takes place the collection of biological samples by qualified staff, if necessary.

A second strategy refers to the first phase of the oncogenetic consultation, during which takes place the familial evaluation, the risk estimation, the signing of informed consent by the patient, oncogenetic counseling, and the convening of other family members, if necessary.

A third strategy has, as an essential element, the activity of molecular diagnosis, which establish the molecular genetic diagnostic using DNA sequencing technique, identifying the presence/absence of a specific genetic mutation (MMR or APC genes mutations).

The next strategy refers to the second oncogenetic consultation, which has to be delivered when the molecular diagnostic is established and the result has to be communicated. This consultation has to include also the psychological counseling.

The last strategy is targeted to the monitoring step, which means that the Multidisciplinary Consultancy Group establishes the appropriate POSP for both the investigated subject  and his/her family.

At the national level there are five major strategies to be considered in order to implement the oncogenetic approach in the management of HCRC. First, there is a need for the implementation and development of Medical Oncogenetics in Romania, started with the short term objective, which is training and qualification of healthcare specialists in the field of oncogenetic consultations (with the following most important topics: the inclusion criteria for the identification of subjects with hereditary susceptibility to colorectal cancer, patients/subjects recruitment and oncogenetic monitoring). The long term objective of this strategy is to develop a network of specialists in Oncogenetics, able to connect Romania with the similar European structures dedicated to the management of subjects with hereditary risk of CRC.

The next strategy addresses the identification and recruitment of target group of patients/subjects for the monitoring of HNPCC and AFP. The recruitment of patients means   the

 

introduction of epidemiological, clinical, familial, morpho-pathological, molecular, and genetic data into a comprehensive database (representing an important biobank, according to the European and national regulations).

Another strategy is dedicated to biomolecular analysis of the genetic risk factors (including BRCA1, BRCA2, MMR, and APC genes). There is a need for two steps approach: a prescreening test for specific, known mutations (recurrent or frequent among our population) and a complex screening test of mutations using complete sequencing of genes.

Strategies refer to the results interpretation, which is also very important and has to be carefully evaluated using epidemiological analysis of cancer risk factors among Romanian population. This analysis puts into our country specific context the results of molecular and other investigations.

And the last strategy, in this logic reasoning, is the genetic information feedback to oncogenetician and to the investigated subject, with the development of personalized oncogenetic monitoring activities for risk subjects and their families.

 

Discussion

International experts also consider the multidisciplinary approach (different health care professionals and psychologists) as being essential for the management of individuals with hereditary risk for cancers [24].

There is no doubt that the Oncogenetic approach is a patient-centered care which involves the participation of individual in the process of a well-informed decision-making. So, an appropriate patient education is needed targeting all steps of this complex approach (inclusion criteria, the molecular analysis, communication of positive or negative result, and monitoring). In this respect, our Department supports the same ideas as Robays et al. [24].

To introduce and to implement the Oncogenetic approach in the management of HCRC is a very complex issue that requires time, maturity of all factors involved (health care professionals, psychologists, medical authorities as decision factors, patients and their families, and the society, in general) and financial resources. This maturity comes from a very good understanding of the phenomenon. We appreciate,  in agreement  with other professionals  [24, 25]  that education is essential for the implementation of the Oncogenetic approach with a maximum of benefits from this preventive measure. There are different levels of education for health care staff (oncologists, gastroenterologists, general practitioners, geneticists, epidemiologists, radiologists, and psychologists), for patients/subjects and their families, for authorities, and for the society (to understand and support this individuals at high risk for HCRC).

Does the society want to help these people?

There are discussions around the willingness of the society to help these people. If there is  a poor society and the frequency of HCRC isn’t too high, the authorities will direct the funding  to diagnostic and treatment of some frequent diseases, not to prevention and among general population there is a lack of health education. If the society is a rich one, people are educated and the authorities have enough money to support these subjects at a high risk to develop CRC. Usually, these individuals are young and the burden for the society is very important. These developed societies understand and have the resources to prevent the disease, this way both, affected individuals and society, taking the benefits from using the Oncogenetic approach in the management of HCRC. If we talk about countries that are on their way to progress, the Oncogenetic approach could help the subjects with a high genetic risk to cancer, but there is a need for authorities to have very good abilities to manage the resources (all kind of) to educate people and to elaborate Public Health Policies to help the implementation of Oncogenetic strategies to address hereditary cancers. There are agreements that a uniform policy followed by all Oncogenetic Centers/Departments all over the country is very important [24].

Also, we are in agreement with other specialists [24, 25, 26] regarding the patient education and oncogenetic counseling, which have to be provided by experts in cancer genetics (complex teams including geneticists, epidemiologists, psychologists, and a secretarial service). We did not evaluate this, but there are studies showed that there is not necessary a supplementary oncogenetic counseling in order to renewal the information to ensure that patients/subjects followed their personalized preventive measures [26].

It is the role of patient education, oncogenetic counseling and education of the society to help individuals of high genetic risk to develop CRC to accept the support and the help from the society. This could be a hard /tough issue without education and support from health care professionals, family, other patients and society.

Do these subjects want to be helped by the society?

This is a sensitive issue. There are people who consider the identification of a mutation like a punishment and they think that they will be blamed if other people in the family will be diagnosed letter with the same mutation or they will be blamed by the society. So, they don’t want to be supported by the society to discover their risk or to manage the situation, they are afraid to know about their health status. There are other people that consider as their duty to know about their genetic profile in relation with the risk of HCRC and to help their families to prevent the disease. These individuals want and search to be supported by the society for a better management of this genetic risk. A third category of people looks for help and support from society cause they are suffering and they need a strong support to face their problem. Other people consider that the society is responsible for their disease, so “the responsible has to help them”. No matter which is the situation this issue represents also a matter of education.

Regarding the funding for the Oncogenetic approach in other countries is covered by medical insurance [24].

 

Conclusion

There are some points to be covered when we want to implement the oncogenetic approach in the management of HCRC. First of all, the necessity of the identification of a continue financing source for the oncogenetic activities (regents and other costs) to ensure the continuity and the efficiency of the oncogenetic approach for CRC. The next points are the necessity to extend the courses and advanced schools to other regions and at the national level, and the necessity for an interregional and national multidisciplinary group of specialists in order to  ensure qualified human resources. Also, in this discussion we have to consider the necessity of  an appropriate selection of subjects, based on eligibility criteria, to be included for molecular testing which involve a very well conducted epidemiological investigation with a very well documented genetic tree. Another point to be considered is the necessity of the inclusion of very well informed patients / subjects, who understand their responsibility for the rest of the family and who can manage the situation with the specialized help from the Department, in the process of medical decision-making.

Taken into account the fact that the Oncogenetics represents the chance for hereditary colorectal cancer prevention among subjects identified with high genetic risk and the strategies for the Oncogenetic Department organization, the network could be developed at the national level and could be the tool used for the achievement of the objective of the Health Care System related to prevention of colorectal cancer.


Conflict of interest statement

None declared.

Authors’ contributions

MCM and VC conducted the data collection. DA supervised the data collection. MCM contributed to drafting of all sections of the manuscript. DA and VC participated in drafting the paper. MCM, VC and DA were involved in the writing of the final form of this manuscript. All authors read and approved the final manuscript.

Abbreviations: CRC – Colorectal Cancer; HCRC – Hereditary Colorectal Cancer; HNPCC – Hereditary Non- Polyposis Colorectal Cancer; FAP – Familial Adenomatous Polyposis; SEM – Statistics Epidemiology Medicine; HPV – Human Papillomavirus; MDCG – Multidisciplinary Consultancy Group; POSP – Personalized Oncogenetic Surveillance Program; RR – Relative Risk.


References

  1. Ferlay J, Soerjomataram I, Ervik M et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11, 2013 [Internet]. Lyon, France: International Agency for Research on Cancer. (http://globocan.iarc.fr.).

  2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global Cancer Statistics, 2012. CA Cancer J Clin 2015; 65 : 87–108.

  3. *** GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 (http://globocan.iarc.fr/Pages/fact_sheets_population.aspx, accessed at 15 May 2016).

  4. Huxley RR, Ansary-Moghaddam A, Clifton P, et al. The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence. Int J Cancer 2009; 125 (1) : 171-180.

  5. Matei M, Manole A. Epidemiologia cancerelor. In: Prisecari V: Epidemiologie specială. SA

  6. „Tipografia Reclama”, Chisinau, 2015, 369-392.

  7. *** American Cancer Society. Colorectal Cancer Facts & Figures 2014-2016. Atlanta, American Cancer Society, 2014.

  8. Azoicăi D, Matei M, Negura L, Drugus D. Contribuţia Oncogeneticii în depistarea şi monitorizarea cancerului ereditar. În: Teleman S (ed): Al X-lea Simpozion Naţional de Citologie Clinică. Editura STEF, Iasi, 2015.

  9. Bonadona V, Bonaïti B, Olschwang S et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011; 305 (22) : 2304-2310. doi: 10.1001/jama.2011.743.

  10. Suceveanu AI, Suceveanu A, Voinea F, Mazilu L, Mixici F, Adam T. Introduction of Cytogenetic Tests in Colorectal Cancer Screening. J Gastrointestin Liver Dis 2009; 18 (1) : 33-38.

  11. *** PDQ database of National Cancer Institute.

  12. (http://www.cancer.gov/cancertopics/pdq/genetics/colorectal/HealthProfessional/Page2#_7 2 – accessed in April 2015).

  13. Armelao F, de Pretis G. Familial colorectal cancer: A review. WJG 2014; 20 (28) : 9292- 9298.

  14. Stoffel E, Mukherjee B, Raymond VM et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology 2009; 137 (5) : 1621-1627. doi: 10.1053/j.gastro.2009.07.039.

  15. Ward RL, Hicks S, Hawkins NJ. Population-based molecular screening for Lynch syndrome: implications for personalized medicine. J Clin Oncol 2013; 31: 2554-2562.

  16. Burn J, Mathers JC, Bishop DT. Chemoprevention in Lynch syndrome. Fam Cancer 2013; 12 (4) : 707-718. doi: 10.1007/s10689-013-9650-y.

  17. Burn J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2011; 378 (9809) : 2081-2087. doi: 10.1016/S0140-6736(11)61049-0.

  18. Azoicai D. Oncogenetics saves lifes. Rev Med Chir Soc Med Nat Iasi 2014; 118 (1) : 7-10.

  19. Matei MC, Negura L, Liliac L, Negura A, Azoicai D. Validation of PCR-RFLP techniques for the evaluation of codon 72 of p53 and CYP1A1 gene`s polymorphisms in relation with ovarian cancer in a Romanian population. Rom J Morphol Embryol 2012; 53 (1):47–54. (http://www.rjme.ro/RJME/resources/files/530112047054.pdf).

  20. Negură L, Negură A, Coneac A, Neagoe IB, Azoicăi D, Irimie A. Pathogenic intronic and deleterious benign: two extremes in cancer predisposition molecular diagnosis. Rev Rom Med Lab 2012; 20 (4) : 317-326.

  21. (http://www.rrml.ro/articole/2012/2012_4_2.pdf)

  22. Negură L, Azoicăi D, Matei M, Popoiu G, Negură A. Screening of a novel BRCA2 mutation by rapid in-house PCR-RFLP. Rev Rom Med Lab 2011; 19 (4) : 333-339. (http://www.rrml.ro/articole/2012/2012_4_2.pdf).

  23. Negura L, Carasevici E, Negura A, Uhrhammer N, Bignon YJ. Identification of a recurrent BRCA1 mutation in two breast/ovarian cancer predisposition families with distinct phenotypes, by allele-specific multiplex-PCR. Rev Rom Med Lab 2010; 18 (2) : 53-61. (http://www.rrml.ro/articole/2010/2010_2_6.pdf)

  24. Negura L, Uhrhammer N, Negura A, Artenie V, Carasevici E, Bignon YJ. Complete BRCA mutation screening in breast and ovarian cancer predisposition families from a North-Eastern Romanian population. Familial Cancer 2010; 9 (4) : 519-523. (http://link.springer.com.dbproxy.umfiasi.ro/journal/10689/9/4/page/1)

  25. Negura A, Matei M., Negură L et al. Ethical implications in communicating molecular tests results to hereditary cancer predisposition families. Rev Rom Bioet 2010; 8 (4) : 74-83. (http://www.bioetica.ro/index.php/arhiva-bioetica/article/view/185/299).

  26. Kwiatkowski F, Girard M, Hacene K, Berlie J. SEM: a suitable statistical software adapted for research in oncology. Bull Cancer 2000; 87 (10) : 715-721.

  27. Robays J, Stordeur S, Hulstaert F et al. Oncogenetic testing and follow-up for women with familial breast/ovarian cancer, LiFraumeni syndrome and Cowden syndrome. Good Clinical Practice (GCP) Brussels: Belgian Health Care Knowledge Centre (KCE). 2015. KCE Reports 236. D/2015/10.273/09.

  28. Prochniak CF, Martin LJ, Miller EM, Knapke SC. Barriers to and Motivations for Physician Referral of Patients to Cancer Genetics Clinics. J Genet Counsel 2012; 21 (2) : 305–325. DOI 10.1007/s10897-011-9401-x.

  29. Kwiatkowski F, Dessenne P, Laquet C, Petit MF, Bignon YJ. Permanence of the information given during oncogenetic counseling to persons at familial risk of breast/ovarian and/or colon cancer. Eur J Hum Genet 2012; 20 (2) : 141-147. doi: 10.1038/ejhg.2011.169.