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[19] Focarelli D, Nicelli A. Il sistema assicurativo italiano: sfide e opportunità di un mercato

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**Provisional chapter**

### **Environmental Health Surveillance for Health Risk Assessment Following Radionuclide Release Assessment Following Radionuclide Release**

**Environmental Health Surveillance for Health Risk** 

DOI: 10.5772/intechopen.73073

#### Robert Wålinder Robert Wålinder Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73073

#### **Abstract**

The currently established linear nontreshold (LNT) risk model is used for radiation protection and is actually not intended for risk assessment. Also dose concepts such as effective dose are constructions used for radiation protection, focusing on the regulatory use in standards for workers but is seldom useful for members of the public. Both the LNT model, as well as use of the concept effective dose, are also not applicable in the low dose area. An alternative method for public health risk assessment and disease surveillance can be the combination of environmental radiation monitoring and health databases. For example, after the Chernobyl accident, airborne measurements of cesium-137 gamma spectrum from the ground, activity data from food samples and high quality national health registries were used for the risk assessment of cancer development.

**Keywords:** cancer, health surveillance, ionizing radiation, nuclear accident, risk assessment

### **1. Introduction**

The golden standard for risk assessment of health effects from ionizing radiation are mortality data from the LSS (Life Span Study) cohort of survivors after the atomic bombings in Hiroshima and Nagasaki in 1945. Based on epidemiological data from the 93,000 survivors, the currently accepted linear nontreshold (LNT) risk model has been established. There are however several important shortcomings of this model. Firstly the LSS cohort is mainly based on mortality data. It is well-known that mortality data is inexact in diagnostic criteria, mostly lacking autopsy data. Cancer registries for cancer incidence data using histologically verified sampling have better diagnostic accuracy. Secondly the LSS cohort is based on acute exposure at the time of the bombing, but very little chronic exposure due to local fallout.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

Most radioactivity was spread in the atmosphere after the bombings giving relatively little local fallout. Thirdly the LNT model is poorly verified in the so called low dose region (<100 mGy/mSv). A recent follow-up of the LSS-cohort after 52 years point at uncertainties of the shape of the dose response curve supporting a linear-quadratic model [1]. Perhaps the most debated detail about the LNT model is the introduction of a risk reduction for the low dose region. The so called "dose and dose-rate effectiveness factor", DDREF, suggest that the risk of malignancy should be lowered by a factor of 2 in the low dose region (<100 mSv) introduced by the International Commission on Radiological Protection (ICRP). The theoretical argument for this arbitrary halving of risk estimates was that cellular repair mechanisms ought to be more efficient at low doses and low dose-rates. Perhaps a corrected radiation risk model will be considered in the light of new data and based on both physical, epidemiological and biologic data. Most other biological, medical and toxicological systems have exponential or s-shaped relationships between exposure and outcome, instead of linear. Models for radiation protection are also made mainly for regulatory purposes and do not directly reflect risk of disease, especially for exposures to populations in the low dose region. Therefore, nuclear accidents, such as in Harrisburg, Chernobyl or Fukushima, differ substantially from the conditions on which the LSS cohort and the LNT model are based. Other approaches using national health databases and environmental monitoring to detect health risks might be useful.

### **2. Assessment of dose**

#### **2.1. Uncertainties in dose measurements**

The currently used dose estimates, such as equivalent dose or effective dose, are constructions used for radiation protection, focusing on the regulatory use in standards for workers but are seldom useful for members of the public. These dose estimates make use of several weighing factor, depending on type of radiation and the organ affected.

However, environmental exposure are often complex, including multiple tissues or whole body exposure. It is also often a combination of both external and internal exposure. For that purpose the International Commission on Radiological Protection (ICRP) recommends a weighing factor for effective dose, specific for 14 different organ/tissue categories. This weighing factor is based on years of life lost and also genetic effects, rather than the biological risk of cancer development. As a consequence thyroid cancer is weighed one third of bone marrow malignancy, breast cancer and stomach cancer, which is not related to the biological risk of developing a malignancy from a certain radiation dose.

The currently used dose estimates are primarily not constructed to be used in epidemiological studies on cancer incidence, since the weighing factors are evaluating the severity of health outcomes, mortality and even genetic effects. Therefore a discussion should be introduced about what dose risk estimates might be more suitable for epidemiological studies of cancer incidence, for example using absorbed dose energy with both radiophysically and biologically based correction factors.

#### **2.2. Alternative biological dosimetry techniques**

Most radioactivity was spread in the atmosphere after the bombings giving relatively little local fallout. Thirdly the LNT model is poorly verified in the so called low dose region (<100 mGy/mSv). A recent follow-up of the LSS-cohort after 52 years point at uncertainties of the shape of the dose response curve supporting a linear-quadratic model [1]. Perhaps the most debated detail about the LNT model is the introduction of a risk reduction for the low dose region. The so called "dose and dose-rate effectiveness factor", DDREF, suggest that the risk of malignancy should be lowered by a factor of 2 in the low dose region (<100 mSv) introduced by the International Commission on Radiological Protection (ICRP). The theoretical argument for this arbitrary halving of risk estimates was that cellular repair mechanisms ought to be more efficient at low doses and low dose-rates. Perhaps a corrected radiation risk model will be considered in the light of new data and based on both physical, epidemiological and biologic data. Most other biological, medical and toxicological systems have exponential or s-shaped relationships between exposure and outcome, instead of linear. Models for radiation protection are also made mainly for regulatory purposes and do not directly reflect risk of disease, especially for exposures to populations in the low dose region. Therefore, nuclear accidents, such as in Harrisburg, Chernobyl or Fukushima, differ substantially from the conditions on which the LSS cohort and the LNT model are based. Other approaches using national health databases and environmental monitoring to detect

The currently used dose estimates, such as equivalent dose or effective dose, are constructions used for radiation protection, focusing on the regulatory use in standards for workers but are seldom useful for members of the public. These dose estimates make use of several weighing

However, environmental exposure are often complex, including multiple tissues or whole body exposure. It is also often a combination of both external and internal exposure. For that purpose the International Commission on Radiological Protection (ICRP) recommends a weighing factor for effective dose, specific for 14 different organ/tissue categories. This weighing factor is based on years of life lost and also genetic effects, rather than the biological risk of cancer development. As a consequence thyroid cancer is weighed one third of bone marrow malignancy, breast cancer and stomach cancer, which is not related to the biological risk of

The currently used dose estimates are primarily not constructed to be used in epidemiological studies on cancer incidence, since the weighing factors are evaluating the severity of health outcomes, mortality and even genetic effects. Therefore a discussion should be introduced about what dose risk estimates might be more suitable for epidemiological studies of cancer incidence, for example using absorbed dose energy with both radiophysically and biologically based cor-

health risks might be useful.

250 Risk Assessment

**2. Assessment of dose**

rection factors.

**2.1. Uncertainties in dose measurements**

factor, depending on type of radiation and the organ affected.

developing a malignancy from a certain radiation dose.

There are no biological markers for the assessment of low dose or low dose-rate exposes to humans [2]. After receiving larger external doses, nail and tooth enamel magnetic resonance analysis might be used, though with a large inaccuracy of dosimetry of 30–50 mGy, high costs and advanced laboratory equipment limiting the practical use [3]. Examples of other physical and biological dosimetry techniques being evaluated, though not yet practically applicable are: protein biomarkers, hematological changes, chromosomal damages, micronuclei and thermoluminescence [4].

#### **2.3. Indirect dose assessment in non-occupational populations**

Personal dosimetry is mainly used for the protection of radiation workers to ensure that the exposure to ionizing radiation is kept within dose equivalent limits. When a larger population is exposed to radionuclides dosimeters are not available in sufficiently large numbers. An exception is the internal dose to the thyroid gland which can be accessed via direct thyroid scans of radio-iodine uptake. The external dose contribution and the contributions from other radionuclides are more difficult to assess, especially multi-organ or whole-body doses.

Instead environmental monitoring from both stationary and mobile dosimeters can map geographical patterns of contamination. From these environmental data indirect dose assessments can be calculated for larger populations. External radiation doses to a population can be estimated via deposition maps, meteorological modeling or distance from the radiation source, including factors such as shielding. Internal doses can be measured for a limited amount of subjects via whole-body counting or thyroid scanners, but for most of the population estimations of doses can be made based on residence, inhalation and ingestion assumptions. An example of a well-developed model for indirect dose assessment is the Radiation Effects Research Foundation (RERF) dose estimation model (DS02R1) from an atomic bomb. The model takes into account distance to the hypocenter, shielding from buildings and terrain [1].

#### **2.4. An example of indirect dose assessment among Swedish hunters**

Using transfer factors based on whole-body counting from the Swedish population an example of a model for the assessment of life-time (70 years) extra dose from the Chernobyl fall-out was calculated for 16,000 hunters with families in the three mostly contaminated counties in Sweden. An extra life-time dose up to 9.4 mSv was calculated, depending on the factors age, gender and habitat. About 75% of the life-time dose was from internal contamination from food [5].

If only the external dose contribution is accounted for during the first year the relative dose contribution from so called short-lived fission products was 36%, 37% for cesium-134 and 27% for cesium-137. After 70 years the proportions were 11%, 29% and 60% respectively [6].

#### **2.5. Dose assessment among reindeer herders**

The highest radionuclide exposure to a population outside the former Soviet Union after the Chernobyl accident was received among Nordic reindeer herders, receiving about 10–100 times higher doses than urban populations, according to Swedish whole-body counts [7]. The reindeer livelihood was severely affected by the Chernobyl fall-out. Due to radiation protection actions about 80% of the Swedish reindeer meat was destroyed the first years following the accident, and the slaughter had to be moved from winter season to summer, when browse was less contaminated. Middle aged reindeer herdsmen also received similar or even higher doses from the global fall-out during the 1950ies and 1960ies making them exposed twice [8]. According to population data from Statistics Sweden there are only about 700 reindeer herders by occupation in Sweden, which gives too low power for epidemiological analyses on cancer incidence, but a combined study from all Nordic countries might be possible.

### **3. Use of national health data registries**

Although the LSS-cohort outcome is the supposedly golden standard for cancer risk there is a fundamental shortcoming due to lack of early data covering the Hiroshima and Nagasaki prefecture populations, since prefecture cancer registries were not in use until 1958. Furthermore the LSS-cohort is mainly based on mortality data although cancer incidence registries usually are based on histological sampling with higher diagnostic accuracy. This gives uncertainties to the LSS-data concerning early health effects for the cancer risk models. In japan a "National Health Promotion" law put in place in Japan in the early 2000s said that prefectures must track illnesses including cancer. This law led to the introduction of some new cancer registries in Japan. The Fukushima prefecture begun a cancer registry in 2010 using a standardized database system governed by the Japanese National Cancer Center. But the data produced in the first few years the cancer registry was of poor quality and is still being developed by the year 2017. This is a great drawback for the estimation of health outcomes, including cancer, for the population of the Fukushima prefecture following the nuclear accident in 2011.

The lack of official health data or a national health data base were even more striking in the former Soviet union at the time of the Chernobyl accident in 1986. The absence of data for researchers has made follow-up of health outcomes difficult in the former Soviet states, though national cancer registries are now built up in Belarus, Ukraine and the Baltic states.

In the Nordic countries there are national cancer registries at the individual level covering all population. In Sweden a national cancer registry is in use since 1958 [9]. Good quality cancer registries make it possible to register changes in baseline incidences following environmental changes such as radio-nuclide releases to the population, especially as a complement when dosimetry is absent or very inexact.

#### **3.1. The example of detecting increased cancer incidence in South Wales around Windscale**

The first population study apart from the LSS-cohort showing a possible increased risk of cancer was in South Wales. From a fuel reprocessing plant at Windscale waste was discharged into the Irish See via a pipeline and deposition occurred in the sea bottom, fish and sea weed. The fission product ruthenium-106 was taken up very efficiently and concentrated in the sea weed *Porphyra umbilicales*. It was harvested and used in laver bread, consumed mainly in South Wales. The use had to be stopped. The activity in fish was mainly from cesium-137. When an ecosystem is contaminated with radionuclides and local food is the main source of internal exposure to radiation the individual doses to the population are very difficult to assess since food habits and lifestyle differ fundamentally between individuals and regions. Whole-body counting can be made to a small sample of the population, mainly concerning gamma-radiation from gamma-emitting nuclides and indirectly from alpha-emitters with gamma-decay, but has lower sensitivity for detecting the beta-radiation, such as from ruthenium-106. Therefore health surveillance via national cancer registries was fundamental to monitor the health effects to the population with an ecosystem is contaminated by radionuclides. Several epidemiological studies have shown increased incidences of cancer of the population around Windscale [10].

times higher doses than urban populations, according to Swedish whole-body counts [7]. The reindeer livelihood was severely affected by the Chernobyl fall-out. Due to radiation protection actions about 80% of the Swedish reindeer meat was destroyed the first years following the accident, and the slaughter had to be moved from winter season to summer, when browse was less contaminated. Middle aged reindeer herdsmen also received similar or even higher doses from the global fall-out during the 1950ies and 1960ies making them exposed twice [8]. According to population data from Statistics Sweden there are only about 700 reindeer herders by occupation in Sweden, which gives too low power for epidemiological analyses on

cancer incidence, but a combined study from all Nordic countries might be possible.

Although the LSS-cohort outcome is the supposedly golden standard for cancer risk there is a fundamental shortcoming due to lack of early data covering the Hiroshima and Nagasaki prefecture populations, since prefecture cancer registries were not in use until 1958. Furthermore the LSS-cohort is mainly based on mortality data although cancer incidence registries usually are based on histological sampling with higher diagnostic accuracy. This gives uncertainties to the LSS-data concerning early health effects for the cancer risk models. In japan a "National Health Promotion" law put in place in Japan in the early 2000s said that prefectures must track illnesses including cancer. This law led to the introduction of some new cancer registries in Japan. The Fukushima prefecture begun a cancer registry in 2010 using a standardized database system governed by the Japanese National Cancer Center. But the data produced in the first few years the cancer registry was of poor quality and is still being developed by the year 2017. This is a great drawback for the estimation of health outcomes, including cancer, for the population of the Fukushima prefec-

The lack of official health data or a national health data base were even more striking in the former Soviet union at the time of the Chernobyl accident in 1986. The absence of data for researchers has made follow-up of health outcomes difficult in the former Soviet states, though national cancer registries are now built up in Belarus, Ukraine and the Baltic states.

In the Nordic countries there are national cancer registries at the individual level covering all population. In Sweden a national cancer registry is in use since 1958 [9]. Good quality cancer registries make it possible to register changes in baseline incidences following environmental changes such as radio-nuclide releases to the population, especially as a complement when

The first population study apart from the LSS-cohort showing a possible increased risk of cancer was in South Wales. From a fuel reprocessing plant at Windscale waste was discharged into

**3.1. The example of detecting increased cancer incidence in South Wales around** 

**3. Use of national health data registries**

ture following the nuclear accident in 2011.

dosimetry is absent or very inexact.

**Windscale**

252 Risk Assessment

### **3.2. The example of detecting increased cancer incidence for people living at the Techa river**

In 1949 the Mayak Production Association, located in the Southern Urals, started production of plutonium for the Soviet Nuclear weapons program. A cohort of 30,000 residents of 40 rural villages along the Techa river or the Chelyabinsk City with low-dose and low-dose-rate exposures have been followed for more than 50 years for incident cases of cancer. Individual radiation doses were based on geographic information of residence and food habits. Calculated external exposures were due to gamma rays from contamination of the soil and the internal exposures were assessed from expected consumption of water, milk and food containing uranium fission products. All solid cancers as a group were related to stomach doses ranging from 0 to 960 mGy with a mean of 60 mGy. Dose–response between estimated radiation dose and solid cancers and leukemia were shown with an excess relative risk (ERR) after exposure to 100 mGy of 0.08 [11].

### **3.3. The example of detecting increased incidence of thyroid cancer in Ukraine after the Chernobyl accident**

Chemical composition, deposition, uptake and metabolism of iodine make thyroid dosimetry complicated, but direct measurement using a gamma-meter of the thyroid gland can be made. To estimate individual thyroid absorbed doses from radioiodine in the Ukrainian population from May–June 1986, more than 150,000 individual examinations were carried out by special dosimetric teams. The collective thyroid dose was 64,000 person-Gy, which theoretically could give about 300 extra cases of thyroid cancer [12].

Another study was performed on behalf of the International Agency for Research on Cancer (IARC). A population-based case–control study was designed of thyroid cancer among young people who lived in the areas that were heavily contaminated by the Chernobyl accident, Indirect dosimetry was performed based on data of the habitat and dietary habits of 1615 cases and controls aged 0–18 y at the time of the accident. A strong dose–response relationship was observed between estimated radiation dose to the thyroid received in childhood and thyroid cancer risk [13].

### **3.4. The example of detecting increased cancer incidence in Sweden after the Chernobyl accident**

Sweden received the largest deposition of radionuclides outside the former USSR, where about 4.4% of the total Chernobyl fall-out was deposited [14]. Deposition was strongly dependent on local weathering giving highest deposition in coastal areas around the Bothnian sea. A food regulation program was introduced to assure that the annual extra dose did not exceed 1 mSv in the population. In a study indirect individual doses were assessed for 734,537 persons living in the three most contaminated counties in Sweden. Personal dosimetry could not be performed 30 years after the accident, so a cumulative exposure based on measured ground activity of cesium-137 of the residence of the subjects. A cumulative exposure estimate during 5 years following the accident was used as proxy for received dose. 82,495 cases of cancer were diagnosed from 1991 to 2010 and retrieved from the Swedish national cancer registry. A non-parametric dose–response could be shown between the deposition of cesum-137 and cancer incidence [15].

### **4. Conclusion**

A paradigm shift is needed from the dominance of radiation protection to a more biologically based health risk assessment from ionizing radiation. Models for radiation protection are made for regulatory purposes and do not directly reflect the risk of disease. Also dose estimates are poorly applicable for risk assessment for populations exposed in the low dose region. Only to rely on technical surveillance could be insufficient. Instead other approaches using national health databases in combination with environmental monitoring could be more efficient for the detection of health risks. Medical surveillance and health registries are good complements, especially in the absence of dosimeter data, complex environmental exposures and when large populations are exposed. When nuclear facilities are in use national health registries could be the most sensitive source for the detection of increased cancer incidence and other disease from nuclear accidents or other emission of radionuclides to the environment. Apart from nuclear power plants possible exposure could emanate from uranium mining, fuel processing, nuclear waste processing and nuclear waste repositories.

### **Author details**

#### Robert Wålinder

Address all correspondence to: robert.walinder@medsci.uu.se

Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden

### **References**

[1] Grant EJ, Brenner A, Sugiyama H, Sakata R, Sadakane A, Utada M, et al. Solid cancer incidence among the life span study of atomic bomb survivors: 1958-2009. Radiation Research. 2017 May;**187**(5):513-537

[2] Boice JD Jr. The linear nonthreshold (LNT) model as used in radiation protection: An NCRP update. International Journal of Radiation Biology. 2017 Oct 3;**93**(10):1079-1092

**3.4. The example of detecting increased cancer incidence in Sweden after the** 

Sweden received the largest deposition of radionuclides outside the former USSR, where about 4.4% of the total Chernobyl fall-out was deposited [14]. Deposition was strongly dependent on local weathering giving highest deposition in coastal areas around the Bothnian sea. A food regulation program was introduced to assure that the annual extra dose did not exceed 1 mSv in the population. In a study indirect individual doses were assessed for 734,537 persons living in the three most contaminated counties in Sweden. Personal dosimetry could not be performed 30 years after the accident, so a cumulative exposure based on measured ground activity of cesium-137 of the residence of the subjects. A cumulative exposure estimate during 5 years following the accident was used as proxy for received dose. 82,495 cases of cancer were diagnosed from 1991 to 2010 and retrieved from the Swedish national cancer registry. A non-parametric dose–response could be shown between the deposition of cesum-137 and cancer incidence [15].

A paradigm shift is needed from the dominance of radiation protection to a more biologically based health risk assessment from ionizing radiation. Models for radiation protection are made for regulatory purposes and do not directly reflect the risk of disease. Also dose estimates are poorly applicable for risk assessment for populations exposed in the low dose region. Only to rely on technical surveillance could be insufficient. Instead other approaches using national health databases in combination with environmental monitoring could be more efficient for the detection of health risks. Medical surveillance and health registries are good complements, especially in the absence of dosimeter data, complex environmental exposures and when large populations are exposed. When nuclear facilities are in use national health registries could be the most sensitive source for the detection of increased cancer incidence and other disease from nuclear accidents or other emission of radionuclides to the environment. Apart from nuclear power plants possible exposure could emanate from uranium mining, fuel processing, nuclear waste processing and nuclear waste repositories.

**Chernobyl accident**

254 Risk Assessment

**4. Conclusion**

**Author details**

Robert Wålinder

**References**

University, Uppsala, Sweden

Research. 2017 May;**187**(5):513-537

Address all correspondence to: robert.walinder@medsci.uu.se

Occupational and Environmental Medicine, Department of Medical Sciences, Uppsala

[1] Grant EJ, Brenner A, Sugiyama H, Sakata R, Sadakane A, Utada M, et al. Solid cancer incidence among the life span study of atomic bomb survivors: 1958-2009. Radiation


**Provisional chapter**

### **Challenges and Perspectives of the Risk Assessment of the Genetic Susceptibility to Cancer in the Next-Generation Sequencing Era Challenges and Perspectives of the Risk Assessment of the Genetic Susceptibility to Cancer in the Next-Generation Sequencing Era**

DOI: 10.5772/intechopen.72379

Israel Gomy Israel Gomy

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72379

#### **Abstract**

The risk assessment of the genetic susceptibility to cancer is the process of addressing and communicating the genetic risks to individuals and families with cancer. The recent breakthroughs of the next-generation sequencing era are adding new challenges to the precision clinical care.

**Keywords:** susceptibility, next-generation sequencing, cancer genetics

### **1. Introduction**

New molecular biology technologies, such as whole-exome and whole-genome sequencing have been shedding new light on the understanding of inherited cancer susceptibility. At the same time, translational oncology researches on somatic and germline mutations in actionable genes have been opening new dilemmas of the next-generation sequencing era. A critical issue of the so-called precision medicine is the genetic counseling of individuals with cancer susceptibility.

Susceptibility to cancer depends on the penetrance of germline variants or inherited alleles, which may be classified into three groups such as highly penetrant, moderately penetrant and lowly penetrant alleles.

Alleles with high penetrance have the highest lifetime risk of cancer, frequently more than 10 times the relative risk, dramatically affecting the quality of life and decreasing its expectancy. More than 50 rare Mendelian cancer syndromes are caused by germline mutations affecting either tumor suppressor genes, DNA repair genes or proto-oncogenes, mostly with autosomal dominant inheritance (**Table 1**).

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Endometrial cancer

Challenges and Perspectives of the Risk Assessment of the Genetic Susceptibility to Cancer… http://dx.doi.org/10.5772/intechopen.72379 259


**Table 1.** Hereditary cancer syndromes.

**Syndrome Gene Mutation status Penetrance Tumors**

Lynch syndrome *MLH1* Heterozygous High Colorectal cancer

MMR cancer syndrome MMR genes Homozygous High Rhabdomyosarcoma

MYH-associated polyposis *MUTYH* Homozygous High Colorectal cancer

Bloom syndrome *BLM1* Homozygous High Leukemia

Nijmegen syndrome *NBS1* Homozygous High Lymphoma

Li-Fraumeni syndrome *TP53* Heterozygous High Breast cancer Li-Fraumeni-like syndrome *CHEK2* Moderate Sarcoma

Cowden syndrome *PTEN* Heterozygous High Hamartomatous polyps

*BRCA1* Heterozygous High Breast cancer *BRCA2* Ovarian cancer *RAD51 (B,C,D)* Moderate Pancreatic cancer *ATM* Moderate Prostate cancer *CHEK2* Moderate Colorectal cancer

*MSH2* Endometrial cancer *MSH6* Ovarian cancer *PMS2* Gastric cancer

*EPCAM* Leukemia, lymphoma

adenomas Colorectal cancer Duodenal cancer

Colorectal cancer Wilms tumor

Medulloblastoma Rhabdomyosarcoma

Medulloblastoma Wilms tumor

Adrenocortical cancer

Brain tumor

Skin tumors Breast cancer Thyroid cancer Endometrial cancer

*APC* Heterozygous High Gastrointestinal

*POLE* Heterozygous high Colorectal cancer *POLD1* Endometrial cancer

Homozygous High Leukemia

Hereditary breast and/or

Familial adenomatous

Polymerase proofreadingassociated polyposis

Fanconi anemia *FANC* genes (includes

*BRCA2*, *PALB2*, *BRIP1*)

polyposis

ovarian cancer

258 Risk Assessment

Alleles with moderate or intermediate penetrance increase the relative risk of about two to five times. Although they are rare in most populations, they may be frequently found in populations with consanguineous families due to founder effects. Affected relatives can be often identified, but the reduced penetrance of the alleles may skip generations and jeopardizes the family history.

Lowly penetrant alleles were discovered by genome-wide association studies (GWAS) and may put individuals to risk of cancer at slightly higher rates than those of the general population. This is due to a polygenic model, in which several alleles, mainly single nucleotide polymorphisms (SNPs), each one carrying a low risk, combine additively or multiplicatively to confer a range of risks in the population. In this model, individuals with few alleles would be at a reduced risk, whereas those with many alleles might suffer a lifetime risk as high as 50% [1]. It is estimated that more than 100 common variants with low risk may contribute to cancer susceptibility. Actually, they explain part of the excess familial risk, and the so-called "missing heritability" remains largely unknown [2]. Thus, it is very important to identify lowly penetrant alleles responsible for cancer genetic susceptibility. Most of these alleles are intergenic—lie between genes—and many neighbor tumor suppressor genes and proto-oncogenes, possibly affecting their expression. Nowadays, with the advance of nextgeneration sequencing and genotyping assays, more variants have been identified, shedding new light on the genomic architecture of the inherited susceptibility of cancer.

### **2. Risk assessment of the genetic susceptibility to cancer**

The risk assessment of the genetic susceptibility to cancer (RAGSC) is a process to evaluate a personal risk of carrying a germline variant that is associated to the cancer development. RAGSC may be performed through statistical models that incorporate factors such as personal and familial history of tumors, ethnic background, and so on [3]. The advent of new sequencing technologies and bioinformatics has led to improvements of estimating more precisely risks of germline variants in many genes and assessing empiric risks of cancer.

Being part of this dynamic process [4], genetic counseling involves the analysis of pedigrees and risk assessment models to determine whether a family history is suggestive of sporadic, familial or hereditary cancer [5]. The main goal of genetic counseling is to inform susceptible individuals about their chances of developing cancer, helping them to make decisions about genetic testing, screening, prevention and treatments. Pretest and posttest genetic counseling are essential for the efficacy of implementing evidence-based protocols, in terms of reducing mortality rates [6].

**Table 2** summarizes the RAGSC process. Three main risk categories can be derived on the basis of patient and family genetic information. In the low-risk category (near-population risk), management is based on population screening, and genetic tests are generally not costeffective; in the moderate-risk group, genetic counseling, genetic testing and management are individual-based; in the high-risk group, genetic counseling, testing and management are evidence-based and improve survival [7].

Challenges and Perspectives of the Risk Assessment of the Genetic Susceptibility to Cancer… http://dx.doi.org/10.5772/intechopen.72379 261


DTC: direct-to-consumer tests; WGS: whole-genome sequencing; WES: whole-exome sequencing. 1 Some evidence-based screening recommendations exist for breast and colorectal cancers. &Restricted by the US Food and Drug Administration.

**Table 2.** Overview of the risk assessment of the genetic susceptibility to cancer.

### **3. Referrals for RAGSC**

Besides sex and age, familial history is the main unmodifiable risk factor of developing cancer.

Assessing the risk factors of cancer in an individual or family is complex and raises psychological, social and ethical issues. It requires the understanding of areas of medical genetics

#### **Personal history**

Alleles with moderate or intermediate penetrance increase the relative risk of about two to five times. Although they are rare in most populations, they may be frequently found in populations with consanguineous families due to founder effects. Affected relatives can be often identified, but the reduced penetrance of the alleles may skip generations and jeopardizes the

Lowly penetrant alleles were discovered by genome-wide association studies (GWAS) and may put individuals to risk of cancer at slightly higher rates than those of the general population. This is due to a polygenic model, in which several alleles, mainly single nucleotide polymorphisms (SNPs), each one carrying a low risk, combine additively or multiplicatively to confer a range of risks in the population. In this model, individuals with few alleles would be at a reduced risk, whereas those with many alleles might suffer a lifetime risk as high as 50% [1]. It is estimated that more than 100 common variants with low risk may contribute to cancer susceptibility. Actually, they explain part of the excess familial risk, and the so-called "missing heritability" remains largely unknown [2]. Thus, it is very important to identify lowly penetrant alleles responsible for cancer genetic susceptibility. Most of these alleles are intergenic—lie between genes—and many neighbor tumor suppressor genes and proto-oncogenes, possibly affecting their expression. Nowadays, with the advance of nextgeneration sequencing and genotyping assays, more variants have been identified, shedding

new light on the genomic architecture of the inherited susceptibility of cancer.

The risk assessment of the genetic susceptibility to cancer (RAGSC) is a process to evaluate a personal risk of carrying a germline variant that is associated to the cancer development. RAGSC may be performed through statistical models that incorporate factors such as personal and familial history of tumors, ethnic background, and so on [3]. The advent of new sequencing technologies and bioinformatics has led to improvements of estimating more precisely risks of germline variants in many genes and assessing empiric risks

Being part of this dynamic process [4], genetic counseling involves the analysis of pedigrees and risk assessment models to determine whether a family history is suggestive of sporadic, familial or hereditary cancer [5]. The main goal of genetic counseling is to inform susceptible individuals about their chances of developing cancer, helping them to make decisions about genetic testing, screening, prevention and treatments. Pretest and posttest genetic counseling are essential for the efficacy of implementing evidence-based protocols, in terms of reducing

**Table 2** summarizes the RAGSC process. Three main risk categories can be derived on the basis of patient and family genetic information. In the low-risk category (near-population risk), management is based on population screening, and genetic tests are generally not costeffective; in the moderate-risk group, genetic counseling, genetic testing and management are individual-based; in the high-risk group, genetic counseling, testing and management are

**2. Risk assessment of the genetic susceptibility to cancer**

family history.

260 Risk Assessment

of cancer.

mortality rates [6].

evidence-based and improve survival [7].

Early onset of cancer diagnosis (e.g., breast cancer <45 years, colorectal cancer <50 years) Multiple associated primary cancers: breast/ovary, colorectal/endometrium Male breast cancer Ovarian, fallopian tube, primary peritoneal cancer Breast cancer and thyroid, sarcoma, adrenocortical carcinoma Multiple colon polyps (>10 cumulative) Colorectal or endometrial cancer with microsatellite instability and/or lack of expression of mismatch repair protein(s) by immunohistochemistry **Family history** Three close relatives (same side of family) with cancer of the same or syndromically related type (breast/ovary, colorectal/endometrium) Two close relatives (same side of family) with cancer of the same or related type with at least one affected under 50 years One first-degree relative with early onset cancer (breast <45 years, colorectal <50 years) One fist-degree relative with multiple primary cancers Two or more relatives with uncommon cancers (sarcoma, glioma, hemangioblastoma, etc.) Relatives of patients with known *BRCA, APC, MYH*, Lynch syndrome mutations Many relatives with cancer but no criteria for testing

**Table 3.** Referrals for hereditary cancer risk assessment.

and oncology, besides the ability of communication, and it demands more time than just a regular consultation. The American Society of Clinical Oncology (ASCO), the National Society of Genetic Counselors (NSGC) and the Oncology Nursing Society (ONS) have published guidelines for the practice of genetic counseling, risk assessment and genetic testing [6, 8]. Moreover, it includes management of at-risk individuals so that they can make informed choices about cancer screening, prevention and targeted therapies [9]. In **Table 3**, there are some indications of referral for RAGSC.

### **4. Next-generation sequencing**

In 2013, at first, Roberts and Klein reported the use of next-generation sequencing (NGS) to identify a hereditary cancer syndrome. They found pathogenic germline variants in the *ATM* gene of six pancreatic cancer relatives from two different kindreds [10]. Jaeger et al. used whole-genome sequencing for the description of hereditary mixed polyposis syndrome [11].

More recently, multigene NGS panels have been used to analyze many highly and moderately penetrant variants. Although they use the same NGS technology, there is less information on predefined genes. In comparison with single-gene sequencing, panels are more time- and cost-efficient in many cases such as (1) when there is genetic or locus heterogeneity, (2) when there are actionable mutations in several genes and (3) when phenotype or family history is too unspecific or noninformative (e.g., adoption) [12].

One advantage of NGS is the possibility of including multiple genes in panels tailored to a certain familial aggregation of tumors such as breast or colon cancer. However, because of its economic viability, NGS has shifted the phenotype-driven hypothesis approach that is based on the characteristics of the syndrome. Slavin et al. found some interesting results about multigene panels. When they included only high-risk genes, the results were seldom positive, and there were more variants of unknown significance (VUS), probably because of the inclusion of more genes in the so-called "off-phenotype" pan-cancer panels [13]. Recently, evidence-based guidelines have included the utilization of multigene testing for hereditary breast and ovarian cancer risk assessment [14].

An important disadvantage of NGS is the probability of disclosing inconclusive or undetermined results. The interpretation of a VUS based on phenotype and genotype data is a difficult task and often jeopardizes the genetic counseling process. Choosing a panel with limited genes of high clinical utility specifically driven to the phenotype instead of pan-cancer panels with many low-risk genes can diminish the chances of finding variants with stressful interpretation [13]. Moreover, databases of variants with high and moderate risks are often not population-specific and may lead to misinterpretation of results.

Some ethical challenges are critical for implementing NGS in the clinics.

In March 2013, the American College of Medical Genetics and Genomics (ACMG) published recommendations on the reporting of incidental or secondary findings from NGS. The ACMG suggested the identification of 56 genes whose variants result in a high risk of developing a severe disease. Germline mutations of 16 of these genes cause hereditary cancer syndromes (**Table 4**) [15].


**Table 4.** ACMG list of hereditary cancer syndromes.

In 2015, the ACMG reviewed it based on the consensus that patients could opt out of the analysis of secondary findings. This decision must be made during the process of informed consent, before testing. As some of these cancer syndromes may have the onset during childhood, these guidelines may also be applied to children, whose parents should make the decision whether or not to opt out [16].

A recent review showed that following the recommendations of international human genetic societies, parents and their children must be previously informed by a written consent about which findings should be reported. The ordering clinician must discuss with the children´s parents all the possibilities of results, including the reporting of incidental findings, the "right not to know," the risks and the benefits, as well is responsible to obtain the informed consent and to provide pre- and posttest genetic counseling [17].

### **5. Conclusions**

and oncology, besides the ability of communication, and it demands more time than just a regular consultation. The American Society of Clinical Oncology (ASCO), the National Society of Genetic Counselors (NSGC) and the Oncology Nursing Society (ONS) have published guidelines for the practice of genetic counseling, risk assessment and genetic testing [6, 8]. Moreover, it includes management of at-risk individuals so that they can make informed choices about cancer screening, prevention and targeted therapies [9]. In **Table 3**,

In 2013, at first, Roberts and Klein reported the use of next-generation sequencing (NGS) to identify a hereditary cancer syndrome. They found pathogenic germline variants in the *ATM* gene of six pancreatic cancer relatives from two different kindreds [10]. Jaeger et al. used whole-genome sequencing for the description of hereditary mixed polyposis syndrome [11]. More recently, multigene NGS panels have been used to analyze many highly and moderately penetrant variants. Although they use the same NGS technology, there is less information on predefined genes. In comparison with single-gene sequencing, panels are more time- and cost-efficient in many cases such as (1) when there is genetic or locus heterogeneity, (2) when there are actionable mutations in several genes and (3) when phenotype or family history is

One advantage of NGS is the possibility of including multiple genes in panels tailored to a certain familial aggregation of tumors such as breast or colon cancer. However, because of its economic viability, NGS has shifted the phenotype-driven hypothesis approach that is based on the characteristics of the syndrome. Slavin et al. found some interesting results about multigene panels. When they included only high-risk genes, the results were seldom positive, and there were more variants of unknown significance (VUS), probably because of the inclusion of more genes in the so-called "off-phenotype" pan-cancer panels [13]. Recently, evidence-based guidelines have included the utilization of multigene testing for hereditary breast and ovarian

An important disadvantage of NGS is the probability of disclosing inconclusive or undetermined results. The interpretation of a VUS based on phenotype and genotype data is a difficult task and often jeopardizes the genetic counseling process. Choosing a panel with limited genes of high clinical utility specifically driven to the phenotype instead of pan-cancer panels with many low-risk genes can diminish the chances of finding variants with stressful interpretation [13]. Moreover, databases of variants with high and moderate risks are often not

In March 2013, the American College of Medical Genetics and Genomics (ACMG) published recommendations on the reporting of incidental or secondary findings from NGS. The ACMG suggested the identification of 56 genes whose variants result in a high risk of developing a severe disease. Germline mutations of 16 of these genes cause hereditary cancer syndromes (**Table 4**) [15].

there are some indications of referral for RAGSC.

too unspecific or noninformative (e.g., adoption) [12].

population-specific and may lead to misinterpretation of results.

Some ethical challenges are critical for implementing NGS in the clinics.

**4. Next-generation sequencing**

262 Risk Assessment

cancer risk assessment [14].

Inevitably, more challenges will arise with the application of NGS in RAGSC.

First, pretest counseling and informed consent models need to be redesigned to address the multiplex testing. Novel approaches must be developed to ensure that individuals understand the risks and benefits of choices regarding these tests. Second, the clinical management of carriers of moderately penetrant variants is still poorly defined, although some evidencebased guidelines may include them [14]. Third, finding VUS is always a potential risk, and such identification complicates data interpretation and often requires further investigation and variant reclassification. In addition, management of patients with VUS is unclear. Finally, many hereditary cancer syndromes have locus heterogeneity, incomplete penetrance and may represent phenocopies, adding difficulty in RAGSC.

In summary, the biggest challenge in counseling families with cancer is conferring precise information regarding genetic susceptibilities because it allows a better informed decisionmaking process about risk management, clinical surveillance, targeted therapies and preventive measures.

### **Author details**

#### Israel Gomy

Address all correspondence to: isgomy@gmail.com

Institute of Hematology and Oncology, Hospital de Clínicas da Universidade Federal do Paraná, Curitiba, Brazil

### **References**


[8] Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K. American Society of Clinical Oncology policy statement update: Genetic and genomic testing for cancer susceptibility. Journal of Clinical Oncology. 2010;**28**:893-901

In summary, the biggest challenge in counseling families with cancer is conferring precise information regarding genetic susceptibilities because it allows a better informed decisionmaking process about risk management, clinical surveillance, targeted therapies and preven-

Institute of Hematology and Oncology, Hospital de Clínicas da Universidade Federal do

[1] Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA. Polygenic susceptibility to breast cancer and implications for prevention. Nature Genetics. 2002;**31**:

[2] Stadler ZK, Tom P, Robson ME, Weitzel JN, Kauff ND, Hurley KE, Devlin V, Gold B, Klein RJ, Offit K. Genome-wide association studies of cancer. Journal of Clinical Oncology.

[3] Riley BD, Culver JO, Skrzynia C, Senter LA, Peters JA, Costalas JW, Callif-Daley F, Grumet SC, Hunt KS, Nagy RS, et al. Essential elements of genetic cancer risk assessment, counseling, and testing: Updated recommendations of the National Society of

[4] Peters JA, Stopfer JE. Role of the genetic counselor in familial cancer. Oncology. 1996;**10**:

[5] Schneider K, Garber J. Counseling About Cancer: Strategies for Genetic Counselors. 2nd

[6] Trepanier A, Ahrens M, McKinnon W, Peters J, Stopfer J, Grumet SC, Manley S, Culver JO, Acton R, Larsen-Haidle J, et al. Genetic cancer risk assessment and counseling: Recommendations of the National Society of Genetic Counselors. Journal of Genetic

[7] Schwartz GF, Hughes KS, Lynch HT, Fabian CJ, Fentiman IS, Robson ME, Domchek SM, Hartmann LC, Holland R, Winchester DJ, The Consensus Conference Committee. (2009) Proceedings of the international consensus conference on breast cancer risk, genetics &

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**Author details**

Paraná, Curitiba, Brazil

Address all correspondence to: isgomy@gmail.com


**Section 5**
