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Principles of genetic predisposition to malignancies.

Debniak T, Lubinski J - Hered Cancer Clin Pract (2008)

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Affiliation: International Hereditary Cancer Centre, Department of Genetics and Pathology, Szczecin, Poland. debniak@wp.pl

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In the majority of cases, malignancies are caused by mutations of the tumour suppressor genes such as p53, or DNA repair genes such as MSH2, which show a recessive pattern at the molecular level... Pedigrees of monogenic diseases with autosomal dominant inheritance are characterised by occurrence of the disorder in all generations (vertical transmission), among men and women, among almost 50% of the relatives... In this particular family cancers occur at a younger age in each subsequent generation (so-called anticipation)... Autosomal dominant inheritance does not show characteristic pedigree features in cases of: • germline (present in sex cells) mutations arising "de novo" - disease absent among ancestors and siblings of the proband (individuals undergoing genetic counselling); subsequent generations can be affected - Figure 2; • mosaic mutation present only in some of the tissues; such alterations arise in the fetus "de novo" during pregnancy; single individuals in the family are affected; mutation can be inherited only if it is present in sex cells; • "low penetrance" mutations; penetrance is defined as the proportion of carriers of mutation who develop cancer; in strong cancer familial aggregations it reaches 80-90%, but in cases with low penetrance mutations it is much lower, and thus single individuals only are affected ; an example is presented in Figure 3; • mutations predisposing to disease occurring among one gender only, e.g. mutations of the BRCA1 gene are detected among both males and females, but only women develop ovarian cancer; • small families with low numbers of relatives... Figure 4 shows an example of a family with 4 breast cancers caused by BRCA1 mutation and one breast cancer in a woman without BRCA1 mutation... In polygenic type of inheritance single individuals are usually affected... As the results of the studies performed in our centre panels of DNA mutations/polymorphisms, which increase the risk of malignancies, were identified in over 90% of unselected breast cancers (96% of cases with BC diagnosed over 50, 99% of lobular cancer cases - Tables 1, 2, 3), 89% of colorectal cancers, 72% of malignant melanomas, 36% of ovarian and 27.5% of prostate cancers... DNA alterations associated with "moderate" risk may have a significant clinical impact... Accumulation (linear association) of the DNA alterations can be identified when the total risk of cancer is the sum of risks of single DNA alterations, e.g. total risk of cancer development increased twofold in compound carriers of two mutations in genes A and B (both mutations associated with 50% increased cancer risk)... In other cases a non-linear association (interaction) can be diagnosed (e.g. total risk increased fivefold in compound carriers of the previously mentioned mutations of genes A and B ).

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Pedigree of family with low penetrance Rb1 gene mutation.
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Figure 3: Pedigree of family with low penetrance Rb1 gene mutation.

Mentions: • "low penetrance" mutations; penetrance is defined as the proportion of carriers of mutation who develop cancer; in strong cancer familial aggregations it reaches 80-90%, but in cases with low penetrance mutations it is much lower, and thus single individuals only are affected [11-15]; an example is presented in Figure 3;


Principles of genetic predisposition to malignancies.

Debniak T, Lubinski J - Hered Cancer Clin Pract (2008)

Pedigree of family with low penetrance Rb1 gene mutation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2735752&req=5

Figure 3: Pedigree of family with low penetrance Rb1 gene mutation.
Mentions: • "low penetrance" mutations; penetrance is defined as the proportion of carriers of mutation who develop cancer; in strong cancer familial aggregations it reaches 80-90%, but in cases with low penetrance mutations it is much lower, and thus single individuals only are affected [11-15]; an example is presented in Figure 3;

View Article: PubMed Central - HTML - PubMed

Affiliation: International Hereditary Cancer Centre, Department of Genetics and Pathology, Szczecin, Poland. debniak@wp.pl

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In the majority of cases, malignancies are caused by mutations of the tumour suppressor genes such as p53, or DNA repair genes such as MSH2, which show a recessive pattern at the molecular level... Pedigrees of monogenic diseases with autosomal dominant inheritance are characterised by occurrence of the disorder in all generations (vertical transmission), among men and women, among almost 50% of the relatives... In this particular family cancers occur at a younger age in each subsequent generation (so-called anticipation)... Autosomal dominant inheritance does not show characteristic pedigree features in cases of: • germline (present in sex cells) mutations arising "de novo" - disease absent among ancestors and siblings of the proband (individuals undergoing genetic counselling); subsequent generations can be affected - Figure 2; • mosaic mutation present only in some of the tissues; such alterations arise in the fetus "de novo" during pregnancy; single individuals in the family are affected; mutation can be inherited only if it is present in sex cells; • "low penetrance" mutations; penetrance is defined as the proportion of carriers of mutation who develop cancer; in strong cancer familial aggregations it reaches 80-90%, but in cases with low penetrance mutations it is much lower, and thus single individuals only are affected ; an example is presented in Figure 3; • mutations predisposing to disease occurring among one gender only, e.g. mutations of the BRCA1 gene are detected among both males and females, but only women develop ovarian cancer; • small families with low numbers of relatives... Figure 4 shows an example of a family with 4 breast cancers caused by BRCA1 mutation and one breast cancer in a woman without BRCA1 mutation... In polygenic type of inheritance single individuals are usually affected... As the results of the studies performed in our centre panels of DNA mutations/polymorphisms, which increase the risk of malignancies, were identified in over 90% of unselected breast cancers (96% of cases with BC diagnosed over 50, 99% of lobular cancer cases - Tables 1, 2, 3), 89% of colorectal cancers, 72% of malignant melanomas, 36% of ovarian and 27.5% of prostate cancers... DNA alterations associated with "moderate" risk may have a significant clinical impact... Accumulation (linear association) of the DNA alterations can be identified when the total risk of cancer is the sum of risks of single DNA alterations, e.g. total risk of cancer development increased twofold in compound carriers of two mutations in genes A and B (both mutations associated with 50% increased cancer risk)... In other cases a non-linear association (interaction) can be diagnosed (e.g. total risk increased fivefold in compound carriers of the previously mentioned mutations of genes A and B ).

No MeSH data available.