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Usefulness of the oncogenetic molecular counselling in adults whith familial cancer

How to cite this article: Valdespino-Gómez VM, Valdespino-Castillo VE. [Usefulness of the oncogenetic molecular counselling in adults whith familial cancer]. Rev Med Inst Mex Seguro Soc. 2016 May-Jun;54(3):364-74.



Received: December 23rd 2014

Judged: February 12th 2015

Usefulness of the oncogenetic molecular counselling in adults whith familial cancer

Víctor M. Valdespino-Gómez,a Víctor E. Valdespino-Castillob

aDepartamento de Atención a la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana Xochimilco, Ciudad de México

bHospital General de Zona 1, Instituto Mexicano del Seguro Social, Campeche, Campeche


Communication with: Víctor Manuel Valdespino-Gómez

Teléfono: (55) 5674 3439


More than 200 cancer susceptibility syndromes (CSS) have been recognized through performing classic epidemiologic studies and genetic linkage analysis. In most CSSs clinical conditions of the patients have been identified as well as their hereditary patterns and the predisponent genes to cancer development. Cancer hereditary identification is a useful condition, since cancer family integrants may benefit of efficient strategies in early screening and in tumor prevention strategies; this consultation is performed by oncogenetic molecular medical consultants who must be scientifically competent for Human Genetics and Cancer molecular biology domains. The oncogenetic molecular consult of patients and family relatives of cancer predisposition families is a medical service in health programs of developed and developing countries; in our country this type of medical service needs to be organized and settled to be part of the integral oncology medical service. The oncogenetic molecular consultation is a structural process of assessment and communication of the associated integral problems of the cancer inherited susceptibility in familial cancer.

Key words: Genetic predisposition to disease; Cancer genes; Cancer; Genetic counseling

The high prevalence of malignancies is a common condition among different populations in different countries. From the point of view of pathogenesis, two types are distinguished globally, sporadic cancers and cancers of high hereditary predisposition. The sporadic type present in a range between 90 and 95% of cases, occur in older ages, and are related to the accumulation of acquired and epigenetic genetic disorders in certain somatic cells. A much lower percentage, from 5 to 10%, are cancers of hereditary predisposition, and between 15 and 20% have familial aggregation, in which several family members have cancer, but a clear pattern of Mendelian inheritance is not identified. The latter two subgroups of cancers develop in early to middle age and constitute hereditary cancer syndromes caused by germline mutations in cancer susceptibility genes that are transmitted across generations. These mutations affect all cells in a person’s body (germlines). Acquiring two mutations in the same gene takes longer than acquiring one, so cancers that develop in cells with a native or inherited mutation tend to occur earlier in life. However, the fact of inheriting a genetic disorder with susceptibility to developing cancer does not directly mean that a tumor will be generated, but the risk or susceptibility to this is significantly higher than in the general population. In recent years about 114 genes involved in different inherited cancer predisposition syndromes have been identified.1 The main challenge in cancer of hereditary predisposition is to apply advances in cancer genomics to clinically benefit families and individuals at risk.  

Over 200 syndromes of human hereditary susceptibility to developing cancer (HHSDC) are described, identified based on classic epidemiological studies and genetic linkage analysis. In these HHSDC, the mutations of some cancer predisposition genes (CPG) confer on carriers a high risk of developing different types of cancer in early stages of life.1-4 The most obvious example of HHSDC in children is hereditary retinoblastoma, in which one allele of the RB1 gene is inherited deleted or mutated and the other allele is blocked by a genetic alteration that causes loss of heterozygosity. The best known HHSDC’s in the adult population are hereditary breast-ovarian cancer syndrome and hereditary colorectal cancer syndrome. In these, more than two decades ago mutations of the BRCA1/BRCA2 and APC, MSH1 and MSH2 genes were identified as conductive molecules involved in the process of carcinogenesis of breast-ovarian and colorectal cancer, respectively, and their family heritability was demonstrated through linkage analysis studies following a Mendelian autosomal dominant pattern. Years later, in the descendants of young patients who developed these cancers, both with germline mutations of these genes, the benefits were demonstrated of screening with periodic colonoscopy with the effect of prophylactic colectomy in individuals affected by familial adenomatous polyposis, along with prophylactic bilateral salpingo-oophorectomy in reducing the risk of breast / ovarian cancer in BRCA1/2 mutation carriers.2,3      

In most of these HHSDC, the alteration of a gene (monogenic model) is inherited in an autosomal dominant fashion, so that there is a 50% chance that an altered allele is transmitted and the disease therefore manifests itself. Some general clinical characteristics have been identified in the frequency and presentation of patients with tumors, which allow seeing them as members of families with susceptibility to developing cancer. These features are as follows: 1) two or more relatives diagnosed with cancer, 2) a family member diagnosed with cancer at an earlier age than the general population, 3) presence of the same cancer in family members 4) bilateralism of the tumor, when this occurs in paired organs 5) multifocal tumors in an organ, 6) development of benign or malignant tumors associated with developmental defects, such as asymmetric body overgrowth, dysmorphia, birth defects, or mental retardation 7) the presentation of a cancer in individuals of the gender that is usually not affected, and 8) the presentation of a rare cancer in one or more members of the family.3,5-7 Occasionally, an HHSDC cannot be easily recognized due to variability in the penetrance (e.g. incomplete), expressiveness, and genomic imprinting, and because a high incidence of cancer in the same family could occur because of its association with epigenetic factors.

For over a decade, the organization and practice of molecular oncogenetic consultation has been done by trained professionals or genetic counseling units in concentration hospitals serving patients with cancer (e.g., in the different autonomous communities of Spain, or in regional centers in the UK). These professionals assess the risk of developing cancer in members of families with familial cancer, in order to inform and suggest primary and secondary prevention measures to prolong time and quality of life for individuals / patients at high risk of developing different cancers;8 particularly in our environment, this type of consultation is practiced outside the context of care given in social security systems.9-11 Professionals who practice this type of consultation aim to improve care for this group of individuals, carry out training and research activities, and are often grouped into academic sections or chapters within different societies of oncology professionals, as in the case of such sections in the American Society of Clinical Oncology US (ASCO), the Instituto Nacional del Cáncer (INC) in Argentina, the Sociedad Española de Oncología Médica (SEOM), and many more oncology societies. These groups have even established collaborative agreements with primary health care associations in the coordination and implementation of clinical care of individuals with hereditary cancer. Identifying families with possible hereditary cancers is important because its members can benefit from effective measures not only in early detection, but in preventing tumors. Clinical evaluation of a particular individual based on the genetic and genomic information of the disease is an important area in the practice of personalized medicine.4,12 The assessment of the origins and molecular profile of tumors has important implications for diagnosis, prognosis, and therapeutic decisions.12

The aim of this article is to describe the main applicative elements used in the practice of a molecular oncogenetics consultation, aimed at providing support and benefits to different members of families with familial cancer.

Genetic alterations associated with the development of cancer

The process of cellular transformation is due to the deregulation of a large amount of oncogene-encoded proteins and tumor suppressor genes, which have undergone mutations, deletions, multiplications, or alterations in their native expression. In the various hereditary tumor syndromes, it has been shown that the predominant alterations correspond to the inactivation of some tumor-suppressor genes (TSG). TSG’s can be classified into two types: 1) the cell cycle guardian genes, which regulate cell division together with the decision of cell apoptosis (gatekeepers), and 2) genome integrity caregiver genes or DNA error repairers (caretakers), whose mutations or deletions can condition carcinogenesis. HHSDC’s in much smaller numbers may be associated with protooncogene mutations (P/O, many of which encode kinases) transmitted in the germline (P-O).1,2  

However, TSG mutations with high penetrance and those of the P/O in HHSDC’s explain only 10% of cases of hereditary cancer, so in most cases a polygenic model should probably be considered.3 In this model, the transmission of several alleles of moderate and low penetrance, each with a small individual effect, can cause much of the risk observed in the population; the detection of such alleles in coding and regulatory regions in different cancers is currently cause for research through association studies and genome sequencing, coupled with the study of epigenetic identification patterns.4,13,14

Detection and identification of major cancer susceptibility syndromes in adults

In most HHSDC’s, genetic perturbations correspond to monogenic mutations and are inherited in relatively easy to identify Mendelian patterns. The data of family history are the most important indicators to suspect the probability that a family has an HHSDC and to refer the patient / individual to molecular oncogenetic consultation. The oncogenetic assessment of the members of affected families will benefit with better prevention measures and early detection of cancer or cancers for those most likely to develop this disease. When a patient or a family shows one or more of the clinical features of increased susceptibility to developing cancer noted in the previous eight points (see Introduction), it is a good idea to refer them to specialized familial cancer consultation for assessment, and eventually specific genetic testing and comprehensive advising. After evaluation and study, family members will know the risks of developing specific cancers, the recommendations to establish appropriate surveillance and monitoring measures, and the scheduling to allow primary tumor prevention in individuals at risk. In the end the implementation of all this will produce an effective reduction of cancer mortality in the high-risk group. Table I shows the most common syndromes of hereditary predisposition to cancer, identifying the gene or genes responsible, the incidence of the syndrome in the population, the penetrance, and the statistical risk of developing cancer.2,6 Clinical signs and family data to establish the susceptibility to different familial cancers are heterogeneous and vary from one syndrome to another; however, in most types of familial cancer particular clinical criteria have been identified to be used as preindicators of suspicion for this condition in order to refer the patient to be evaluated by molecular oncogenetics consultants. The product of many meetings of interdisciplinary health professionals has allowed the development of clinical guidelines or criteria that identify families that present with high or moderate risk for developing different cancers; these criteria and guidelines are used as references for evaluation by specialists who do oncogenetic consultations.15,16

Table I Most common cancer susceptibility syndromes 4,6
Name of
syndrome *
Other genes
identified with NSG
Inheritance model Penetrance
Incidence Cancer
risk (%)
Hereditary breast and
ovarian cancer
BRCA1 and BRCA2 XRCC2, FAN1, PPM1D (mosaic) AD 60 1/500-
Lynch syndrome MLH1, MSH2, MSH6, PMS2 GREM1, POLE POLD1 AD 80-90 1/200-
Neurofibromatosis NF1 AD 100 1/3500 2-5
Tuberous sclerosis TSC1, TSC2 AD 95-100 1/6000-
Familial adenomatous polyposis APC GREM1, POLE
AD 100 1/6000-
Familial malignant melanoma CDKN2A and
MITF, TERT AD 30 [-50] 1/10000 90
Hereditary retinoblastoma RB1 AD 90 1/13500-
Familial Wilms Tumor WT1 AD 10 1/10000 100
Multiple endocrine neoplasia-2 RET AD 70-100 1/25000 70 [to the]
70 years]
AD = autosomal dominant; NSG = next-generation DNA sequencing
*Another 30 cancer susceptibility syndromes have been described, which have an incidence of over 1/25000

Hereditary breast and ovarian cancer syndrome (HBOC)

Clinical criteria for recognizing families with high / moderate breast and ovarian cancer risk are described in Table II.17,18 The presentation of these clinical features is enough to suspect that there is an increased risk of family breast and ovary cancer, and thus to send the patient or family to molecular oncogenetic consultation.   

Table II Clinical criteria of families with hereditary ovarian and breast cancer 14,15
Presentation of cases in families with high risk Presentation of cases in families with moderate risk
A case of breast cancer < 42 years old Two cases of breast cancer between ages 51 and 60, in first-degree relatives
Diagnosis of breast and ovary cancer in the same patient A case of breast cancer and another case in a first or second degree relative, if the sum of ages at diagnosis is > 118 years
Two or more cases of breast or ovary cancer, one of them
bilateral or in age < 50 years
A case of breast cancer at age < 50 years old and one of ovary in a first or second degree relative
Three cases of breast or ovary cancer in first
or second degree relatives
Two cases of ovarian cancer in first or second degree relatives
A case of breast cancer in a male and another breast cancer (male or female) or ovary in a first or second degree relative

20% of all breast cancers correspond to their familial forms, within which inherited genes are involved in the different HBOC’s: with high penetrance (BRCA1/2, TP53, PTEN, CDH1, STK11), moderate (CHEK2, BRIPI, ATM, PALB2), and low (FGFR2 and many other known and candidates for polygenic susceptibility).18,19 Between 5 and 10% of cases of breast cancer are considered hereditary due to mutations of high-penetrance caretaker genes, like the aforementioned BRCA1 (located at 17q21) and BRCA2 (located at 13q12). BRCA1, beyond participating in maintaining genomic integrity, is involved in other basic intracellular signaling pathways. BRCA2 is specifically involved in DNA repair and directly interacts with RAD51.

The HBOC in the molecular testing of BRCA1/2 is currently the only one recommended in clinical application; these genes also increase the risk of developing pancreatic and prostate cancer. The prevalence of BRCA1/2 is moderately different in different populations. Thus in populations of Ashkenazi Jewish descent it is significantly greater, which is associated with a higher incidence of breast cancer; another genetic factor associated with higher incidence are some polymorphisms in the gene RAD51.17,18

Mammary carcinomas associated with mutations in BRCA1 often have baseline phenotype (triple negative for hormone receptors and HER2) and express basal cytokeratins 5/6 and epidermal growth factor. These tumors represent a challenge from a therapeutic point of view, since they cannot be managed with hormonal treatments or anti-HER2 antibodies, so the only option is chemotherapy. However, because polymerase poly-ADP-ribose (PARP) interacts in the recruitment of BRCA1/2 proteins in the process of repairing DNA replication errors, it has been shown that the use of PARP inhibitors as targeted molecular therapy against tumor clones carrying BRCA1/2 mutations has produced a therapeutic effect (because of synthetic lethality) in phase 1 clinical studies; therefore, their combined use with some chemotherapeutic agents is currently being investigated in phase 2 studies.20,21  

Families with high risk of hereditary breast and ovarian cancer require molecular oncogenetic consultation, analysis of the BRCA1 and BRCA2 genes, personalized clinical follow-up measures, and, if gene mutation is positive, a comprehensive survey of susceptible family members with high risk of developing the syndrome.17,18 Women who carry BRCA1/2 have a 50 to 85% risk of developing breast cancer (relative risk 10 to 30 times more than the general population) and a 15 to 20% risk of developing ovarian cancer.18 Generally, members of families with moderate risk require oncogenetics evaluation (without BRCA1/2 testing) and personalized clinical follow-up measures. In particular, in mid-2013 in the UK oncogenetic consultation more than doubled in the population, which was associated with the publication of updated guidelines on familial breast cancer in the United Kingdom.22 This was also related to the decision of the actress Angelina Jolie to undergo prophylactic bilateral mastectomy, because of having high risk of developing breast cancer as calculated by molecular oncogenetic evaluation.23

Hereditary non-polyposis colorectal cancer syndrome (HNPCC)

It has been estimated that approximately 30% of all colorectal cancers (CRC) have a component of family susceptibility of transmission, such as hereditary forms (mutations associated with high germline penetrance level) or familial aggregation. Most families with colorectal cancer susceptibility syndromes are associated with Lynch syndrome and, to a lesser extent, with familial adenomatous polyposis (FAP), classic (presentation of more than 100 polyps), or attenuated (less than 100 polyps), and other syndromes presenting hamartomatous polyps (Table I).15,24,25 HNPCC and FAP syndromes cause respectively 2-4 and 1% of prevalent cases of CRC; the remaining 20-25% of cases are not yet fully known from the point of view of associations with autosomal genes, and are globally known as family CRC, so monitoring strategies for the individual and their family are based predominantly on clinical criteria (Table III).24-26  

Table III Clinical criteria to determine families with hereditary colorectal cancer 21,22
Amsterdam I criteria Amsterdam II criteria Bethesda criteria
At least three relatives with colorectal cancer At least three relatives with
HNPCC-associated* cancer
A case with colorectal cancer at age < 50 years
One case should be first degree relative
of the other two
One of the cases must be first degree relative Presentation of synchronous and metachronous colorectal cancers, or other HNPCC-associated tumors
Presentation of cancer in two
successive generations
Presentation of the different types of
cancer in two successive generations
Presentation of one case of
microsatellite instability-associated colorectal cancer
at age < 60 years
One of the cases at age < 50 years One of the cases occurs at age < 50 years A case of colorectal or HNPCC-associated* cancers at less than age 50
Exclude cases of familial adenomatous polyposis Exclude cases of familial adenomatous polyposis At least two first or second degree relatives with colorectal or HNPCC-associated* cancers, of any age
HNPCC = hereditary non-polyposis colorectal cancer
* The HNPCC-associated cancers: Colorectal, endometrial, stomach, ovary, ureter/renal pelvis, brain, small intestine, hepatobiliary duct, and cutaneous

Individuals with HNPCC have few colonic polyps, and the CRC that appears in this syndrome develops at a younger age (44 years or more), often in the proximal colon, with higher incidence of multiple, synchronous, and metachronous tumors, and with some individual histopathological alterations. Individuals from families with Lynch syndrome have a 25-75% cumulative risk of developing both CCR and endometrial cancer (women), and between 1 and 13% for cancers in other locations. CRC developed in Lynch syndrome shows a high variation or instability of microsatellites (MSI-Hi) in the genomic sequences of the tumor, and low expression of proteins of the DNA repair system, in immunohistochemistry studies (IHC) of histopathologic tumor sections; particularly, the determination of these markers is used as second approach tests (screening) of suspected syndrome, before testing to look for mutations by sequencing. In particular, IHC studies can specify which protein is not expressed or is with less intensity, which is associated with the mutation of the corresponding gene; this gives guidance on which gene to search for mutations.26

HNPCC results from germline mutations of some genes encoding proteins involved in the repair of errors that occur during DNA replication, particularly MLH1, MSH2, MSH6, PMS1, and PMS2;27 the mutations of these genes are inherited with high penetrance. When a repair gene has both its alleles inactivated, this is reflected in the accumulation of errors in DNA structure, predominantly in segments containing multiple and short repeated sequences (dinucleotides), called microsatellites. The instability of high microsatellites (MSI-Hi) is considered a manifestation of genomic instability and is used as an indicator of deficiency in the DNA repair system, which is observed both in the CRC developed in HNPCC, and in the 15% of sporadic CRC (due to hypermethylation of the MLH1 promoter or BRAF gene mutations). Cases of CRC-MSI-Hi have a better prognosis than CRC-MSI-Lo (low level), but show resistance to treatment with 5-fluorouracil.25

Clinical guidelines to determine the conditions of high risk for developing familial colorectal cancer in HNPCC have been established based on the four expert meetings in Amsterdam (2) and Bethesda (2),24,25 hence the name of the guides. Clinical elements of the four guides are complementary to suspect the diagnosis of familial colorectal cancer. The presentation of one of these conditions is sufficient to suspect the existence of familial colorectal cancer and refer the patient or the family to molecular oncogenetics consultation (Table III).

Thus, patients or family members who meet the diagnosis of HNPCC endorsed by the Amsterdam I-II or Bethesda criteria must complete tests looking for high microsatellite instability in the tumor genome and assess the expression of error repair system proteins through IHC genome studies in histopathological sections. If changes are identified in any of these groups of markers, sequencing analysis testing of the MLH1, MSH2, MSH6, PMS1, and PMS2 genes is indicated. In HNPCC, mutations of MLH1 and MSH2 are predominantly associated with developing CRC, whereas those of MSH6 and PMS2 are linked with the development of endometrial and other associated cancers.25,26

Clinical follow-up and prophylaxis in patients or relatives with HNPCC are based on regular medical checkups, as this reduces the incidence and mortality related to CRC and endometrial cancer. It is suggested to do surveillance using colonoscopy at intervals of one to two years starting between 20 and 25 years,24,27 or with gynecological clinical examination, transvaginal ultrasound, and endometrial aspirates at one to two year intervals starting at 30 years. Sub total colectomy should be considered in cases of CRC with HNPCC, or prophylactic sub total colectomy when it is not possible to fulfill clinical monitoring, and prophylactic total abdominal hysterectomy and salpingo-oophorectomy after reproductive years or menopause.25,26

Within the group of other family susceptibility syndromes for colorectal cancer, the aforementioned FAP stands out, corresponding to another dominant autosomal monogenic disease with almost 100% penetrance. FAP is the second most common hereditary CRC syndrome, characterized by the development of hundreds of thousands of adenomas in the colon and rectum; the gene affected in this disease is the APC (adenomatosis polyposis coli), which corresponds to a gatekeeper tumor suppressor gene, which regulates beta-catenin in the WNT intracellular signaling pathway; APC mutations are associated with the development of polyps in the digestive tract (colon-rectum, stomach-duodenum). Patients with FAP syndrome may develop colorectal cancers starting in the second decade of life, so surveillance strategies and clinical prophylaxis should begin at an early age.28,29 Other similar syndromes correspond to attenuated FAP, Gardner syndrome, adenomatous polyposis associated with MUTYH, and the group of hamartomatous polyposis, such as Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome.

Other less frequent familial cancer syndromes  

Other syndromes in which one or two gene mutations are inherited in an autosomal dominant manner and that predispose to cancer are the autoimmune lymphoproliferative syndrome, Birt-Hogg-Dubé syndrome, Carney syndrome, familial chordoma, dysplastic nevus syndrome with familial melanoma (P-O), hereditary diffuse gastric cancer, esophageal cancer with tylosis, Li-Fraumeni syndrome, multiple endocrine neoplasia 1/2, multiple osteochondromatosis, neurofibromatosis 1 and 2 (P/O), nevoid basal-cell carcinoma syndrome, family prostate cancer, hereditary leiomyomata and kidney cancer, hereditary papillary kidney cancer (P/O), hereditary paraganglioma-pheochromocytoma syndrome, retinoblastoma, tuberous sclerosis, von Hippel Lindau syndrome, and Wilms tumor (Table I).

Oncogenetics consultation as a tool in the care of families with genetic susceptibility to cancer

Molecular oncogenetics consultation, also called genetic advice or counseling in people with familial cancer, is the procedure of informing the person about the chances of susceptibility to developing cancer for them or their offspring, and advising them on possible alternatives to reduce this susceptibility. Oncogenetics consultation includes 1) evaluation of personal and family history of cancer through the analysis of clinical information for the patient of three generations of family, 2) the estimation of cancer risk and selection of the most appropriate molecular study according to the information collected, 3) referral to individual specialists for molecular studies done in a competent laboratory, 4) comprehensive evaluation of clinical information and results of molecular testing, 5) informing and discussing the results with the patient / individual, 6) establishing recommendations to reduce risk and referring the patient to specialized cancer care services, and 7) planning and execution of family testing (consultation with family members) as well as, where appropriate, case monitoring (Figure 1).4,7,8

Figure 1 Diagram of the steps of molecular oncogenetics consultation in patients with suspected familial cancer. It describes the main activities of the competent professional in domains of human genetics and molecular biology of cancer, in the evaluation of a patient with treated cancer who is suspected of belonging to a family with predisposition to cancer. HHSDC = cancer susceptibility syndrome; CPG = cancer predisposition genes

In most human diseases the genetic component is crucial; some of them are due to the alteration of one gene (monogenic), which is present in all cells of the body (germline mutation), whereas in chronic degenerative diseases, which are the most abundant, these are due to cooperative alteration of multiple genes (polygenic), which develop in some specific groups of somatic cells.

Cancer is a disease caused by abnormalities in chromosomes and genes predominantly affecting different somatic cells (sporadic cancers), not affecting the individual’s germline. A small percentage of cancer incidence in the population, between 5 and 10%, is due to mutations in genes that are inherited from parents and passed on to descendants, who inherit a high susceptibility to develop tumors.

Identifying families with a possible cancer predisposition syndrome involves, as we have noted previously, recognizing eight clinical conditions. Identification can be facilitated by developing a family tree with information from at least three generations and the relevant histopathological data of tumors, indicating the affected and healthy members, age at tumor diagnosis, tumor types, dates and causes of death, etc.;30 that tree must also have information on other genetic diseases or birth defects and data on potentially hazardous environmental exposures. 

The main inheritance model to estimate the probability of susceptibility of developing cancer is monogenic, which consequently is inherited following relatively simple to identify Mendelian patterns, particularly the four basic patterns of Mendelian inheritance: autosomal dominant, autosomal recessive (MAR), dominant sex-linked (MALS), and recessive sex-linked (MRLS). Mendelian inheritance patterns depend on the chromosomal localization of the responsible gene and phenotype expression. The autosomal dominant model (ADM) is the most common inheritance pattern in cancer predisposition syndromes; it manifests in both heterozygosis and homozygosis. ADM is the model followed by hereditary breast and ovarian cancer, Lynch syndrome, FAP, and many more.1,2 In cancer susceptibility ADM, the transformation of somatic cells requires the accumulation of another mutation in the other allele of the gene involved. In ADM, the probability that an individual transmits the mutated gene to their offspring is 50%, while in MAR and MALS is 25 and 50%, respectively. These probabilities of predisposition to a specific cancer are also modified by the penetrance (probability that a gene manifests in the phenotype), which may be complete or incomplete, and by the variable phenotypic expression (variations in the development of the same type of tumor in different locations, number of tumors, and their appearance at different ages).31 If one does not have present the incomplete penetrance and the variable expressivity, this can lead to incorrect estimates. To estimate the risk for developing breast / ovarian cancer in members of families with HBOC, you can resort to the use of bioinformatics programs that help estimate this probability; such programs are the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA)32 and others.

In the practice of oncogenetics consultation, the case index (patient / individual) relevant in the test is cited, and an interview is conducted, from which the family tree or genogram is prepared and they are informed what the testing consists of as well as its implications and consequences. Physicians should be trained to assess family history so they can discriminate between a possible family aggregation or an inherited cancer susceptibility pattern. Once the patient decides to proceed, they must sign informed consent and they are sent to a molecular oncology laboratory to test the genes involved.

Indication for molecular genetic testing

The indication for each molecular genetic test should be evaluated by a professional trained in the areas of human genetics and molecular biology of cancer. Faced with the evidence to identify a personal or family clinical history to suggest a predisposition to cancer, the recommendation is to do the molecular genetic test of the gene associated with the susceptibility syndrome for developing a specific cancer. It is necessary that the gene determination test to be explored can be performed easily and reliably, and that the results will help the diagnosis or influence the medical or surgical management of the patient or their family members at risk.

The patient who has been treated for a tumor with clinical suspicion of belonging to a family with familial cancer, or a member of a family who, in assessing the clinical algorithm, is more likely to be carrying the genetic alteration, are candidates for molecular genetic testing. For example, in families with hereditary breast and ovarian cancer syndrome, the first candidates to search for mutations in the BRCA genes are young women affected by ovarian cancer, women with breast cancer diagnosed at an earlier age or bilateral presentation, or men diagnosed with breast cancer. Molecular genetic testing in the child population is justified only in hereditary syndromes where the susceptibility to illness starts in childhood.

Techniques available for molecular testing  

To study the altered genes in cancer predisposition syndromes, techniques to explore gene mutation are used. The most sound analysis to identify mutations is DNA sequencing based on the use of second generation sequencers, with which the study of the full exome, complete genome, or commercial multiplex panels (multiple genes related with one particular HHSDC).4 An example of the latter type is the HISPANEL panel, made for the detection of 27 of the 40 BCRA gene mutations prevalent in the Mexican population.11 However, often it is preferred to start testing with simpler, lower-resolution molecular screening techniques, which identify genetic alterations without identifying the specific mutation; some of these techniques correspond to SSCP (single-stranded conformation polymorphism) used in the microsatellite instability test, CSGE (conformation-sensitive gel electrophoresis), DGGE (denaturing gradient gel electrophoresis), DHPLC (denaturing high-performance liquid chromatography), HRMA (high-resolution melting analysis), and MLPA (multiplex ligation-dependent probe amplification),6 which, together with sequencing, can also detect changes in the copy number of the query sequence. Molecular studies must be applied by highly trained staff in genetic/molecular oncology laboratories.

Benefits and limitations of genetic molecular tests

Molecular oncogenetics consultation in patients with familial cancer is a structured process of analysis, evaluation, and communication of the problems associated with hereditary susceptibility to cancer; it seeks to identify a genetic alteration that may be the indicator responsible for increased cancer risk, and helps define risk levels and preventive strategies.6,30,33 If the result is positive, the analysis should be extended to other members the family. If it is negative and the risk of the presence of an unidentified family mutation persists, it should be considered a polygenic disorder, or possibly a monogenic model with variable penetrance and gene expression. The main objective of the tests is to detect the mutation responsible for cancer in the family and to consider whether its members are carriers of the familial mutation; those who turn out to be carriers may benefit from the use of intensive monitoring protocols and protocols aimed at reducing the risk of developing cancer.

The communication of the results to the patient or family is one of the crucial stages of oncogenetics consultation. Doctors should know to report on the usefulness of genetic counseling and rely on psycho-oncology professionals who may see significant emotional disorders. Complete and objective information should be conveyed while maintaining an empathetic attitude, reviewing this understanding with the patient, particularly the risks of developing specific tumors, risks to offspring, prevention measures, and so on.

The main objective of oncogenetics consultation for familial cancer is to reduce mortality from cancer, through assessment, prevention, and research on family and hereditary forms of the disease. For the most common cancer predisposition syndromes there are clinical practice guidelines or expert recommendations for primary prevention (risk reduction) and secondary prevention (early detection) for each hereditary cancer syndrome, aimed at protecting the patient and their family. General measures related to intensive clinical monitoring are periodic medical surveillance, the adoption of healthy habits and lifestyles, the use of prophylactic surgery to reduce risk (e.g. HBOC, FAP, and to a lesser extent HNPCC), and chemoprevention (e.g. prescribing aspirin to prevent CRC); these measures should be explained and discussed extensively with patients, evaluating alternatives, benefits, and drawbacks.6,29 Clinical surveillance of members of families with high risk of developing various cancers should be done in specialized cancer care units.  

Among the main challenges present in clinical care of members of families with hereditary cancer is the application of modern techniques of mass sequencing of the second and third generation genome, which will make it possible to test the multiple genes predisposing to cancer in less time and with greater precision.4,34 The main challenge for the near future is to apply the knowledge of progress in genomics in the clinical management of individuals with high predisposition to develop cancer to do oncological prevention.4

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Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.

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