Mendelian (Monogenic) Disorders Compared With Polygenic Disorders

1
Mendelian (Monogenic) Disorders Compared With
Polygenic Disorders
A, Monogenic disorders result from variations
(mutations brown ovals) in single genes, whereas
complex ones arise from the interactions of
several different genes. B, In monogenic
disorders the disease phenotype is completely
driven by the genetic mutation. In complex
disorders, each mutation is insufficient to cause
the disease phenotype. C, In monogenic disorders,
all individuals who possess the mutant gene will
exhibit the disease. In complex disorders, the
percentage of risk due to any gene varies.
Peltonen and McKusick. Science.
20012911224-1229.
2
Timeline of Migrations of Modern Homo Sapiens
Cavalli-Sforza and Feldman. Nat Genet.
200333266-275.
3
Genetic Pedigree of World Populations
Adapted from Cavalli-Sforza and Feldman. Nat
Genet. 200333266-275, with permission.
4
Gene-Environment Interaction and Likelihood of
Developing Cancer
5
Gene-Environment Interaction and Likelihood of
Developing Cancer (cont)
6
High-Penetrance and Low-Penetrance Genes in
Breast Cancer
Balmain et al. Nat Genet. 200333(suppl)238-244.
7
Development of Cancer
A, Factors contributing to the generation of the
cancer cell. B, The effects of these factors on
the cell. C, The pathologic outcome of A and B,
with the progression from normal tissue to
invasive carcinoma highlighted.
8
Parallel Pathways of Tumorigenesis
A, The hallmarks of cancer and the mechanisms by
which they are acquired. B, Schematic of the
chronologic progression from normal cell to
cancer cell, illustrating the acquisition of the
hallmarks of cancer. From Hanahan and Weinberg.
Cell. 200010057-70.
9
Role of DNA Repair Mechanisms in Maintaining
Genomic Integrity
Exogenous and endogenous insults damage DNA. This
damage can be repaired by genes that detect and
respond appropriately. If these genes malfunction
or are maladapted to respond to environmental
insults, DNA damage is not repaired and mutations
can occur. Loeb and Loeb. Carcinogenesis.
200021379-385.
10
DNA Repair Mechanisms and Damaging Agents
de Boer and Hoeijmakers. Carcinogensis.
200021453-460.
11
Distribution of Histologic Grade of Breast Cancer
Lakhani et al. Nat Med. 20017408-410.
12
Probability of Local Control After
Breast-Conserving Therapy
Adapted from Pierce et al. J Clin Oncol.
2000183360-3369, with permission.
13
Time to Development of Contralateral Breast Cancer
Adapted from Pierce et al. J Clin Oncol.
2000183360-3369, with permission.
14
Use of Aspirin and Percentage Reduction of
Colorectal Adenoma
The population of patients with a history of
adenomas (left) is larger than those with a
history of carcinoma (middle). The percentage
reduction by aspirin (red) differs between the 2
groups, because the population with a history of
carcinoma is smaller. Theoretically, if therapy
could be targeted to the small group of patients
who possess the at-risk genetic marker, the
percentage of patients who benefit would increase.
Baron et al. N Engl J Med. 2003348891-899.Sandl
er et al. N Engl J Med. 2003348883-890.
15
l1307K Polymorphism of APC
A single nucleotide base-pair substitution
replaces an isoleucine with a lysine, thereby
doubling the rate of colon cancer in the
expressing population.
Lynch and de la Chapelle. N Engl J Med.
2003348919-932.
16
Pedigree Created From Patients Family History
A line through a symbol represents deceased
members of the family.