Principles of Molecular Disease;

Loss-of-Function Mutations
• The loss of function of a gene may result from alteration of its coding, regulatory, or other critical sequences

due to nucleotide substitutions, deletions, insertions, or rearrangements.

• A loss of function due to deletion, leading to a reduction in gene dosage, is exemplified by the α-thalassemias,

which are most commonly due to the deletion of α-globin genes;

• By chromosome-loss diseases, such as monosomies like Turner syndrome;

• By acquired somatic mutations—often deletions—that occur in tumor-suppressor genes in many cancers, such

as retinoblastoma.

• Many other types of mutations can also lead to a complete loss of function, illustrated by the β-thalassemias, a

group of hemoglobinopathies that result from a reduction in the abundance of β-globin, one of the major

adult hemoglobin proteins in red blood cells.

 Gain-of-Function Mutations
Mutations may also enhance one or more of the normal functions of a protein in a biological system, however, more is not necessarily better, and

disease may result. Gain-of-function mutations fall into two broad classes:

• Mutations that increase the production of a normal protein. Some mutations cause disease by increasing the synthesis of a normal protein in cells in

which the protein is normally present. The most common mutations of this type are due to increased gene dosage, which generally results from

duplication of part or all of a chromosome. The classic example is trisomy 21 (Down syndrome), which is due to the presence of three copies of

chromosome 21. Other important diseases arise from the increased dosage of single genes, including one form of familial Alzheimer’s disease due to a

duplication of the amyloid precursor protein (βAPP) gene, and the peripheral nerve degeneration Charcot-Marie-Tooth disease type 1A, which

generally results from duplication of only one gene, the gene for peripheral myelin protein 22 (PMP22).

• Mutations that enhance one normal function of a protein. Rarely, a mutation in the coding region may increase the ability of each protein molecule

to perform one or more of its normal functions, even though this increase is detrimental to the overall physiological role of the protein. For example,

the missense mutation that creates hemoglobin Kempsey locks hemoglobin into its high oxygen affinity state, thereby reducing oxygen delivery to

tissues. Another example of this mechanism occurs in the form of short stature called achondroplasia.
Cancer Genetics and Genomics
 Cancer
Cancer is the name used to describe the more virulent forms of neoplasia, a disease process characterized by uncontrolled cellular proliferation leading to a

mass or tumor (neoplasm). The abnormal accumulation of cells in a neoplasm occurs because of an imbalance between the normal processes of cellular

proliferation and cellular attrition. Cells proliferate as they pass through the cell cycle and undergo mitosis. Attrition, due to programmed cell death, removes

cells from a tissue. For a neoplasm to be a cancer, however, it must also be malignant, which means that not only is its growth uncontrolled, it is also capable

of invading neighboring tissues that surround the original site (the primary site) and can spread (metastasize) to more distant sites. Tumors that do not

invade or metastasize are not cancerous but are referred to as benign tumors, although their abnormal function, size or location may make them anything but

benign to the patient. Cancer is not a single disease but rather comes in many forms and degrees of malignancy. There are three main classes of cancer:

• Sarcomas, in which the tumor has arisen in mesenchymal tissue, such as bone, muscle, or connective tissue, or in nervous system tissue;

• Carcinomas, which originate in epithelial tissue, such as the cells lining the intestine, bronchi, or mammary ducts;

• Hematopoietic and lymphoid malignant neoplasms, such as leukemia and lymphoma, which spread throughout the bone marrow, lymphatic system, and

peripheral blood.
 Major genes that are correlated to cancer

• proto-oncogenes;

• tumor suppressor genes;

DNA repair genes

https://www.youtube.com/watch?v=cSXFjUpACWE
 “Cancer genes”
• Proto-oncogeneoncogene
• Proto-oncogenes foster/regulate cell growth, telling them when and where to
replicate
• Tumor suppressor gene
• Tumor suppressor genes tell cells NOT to grow—down-regulate cell
replication, regulate apoptosis
Proto-oncogene RAS

• RAS endcodes signal transduction protein that regulates cell growth—

RAS protein induces cell growth/proliferation
• Mutation in RAS (which is now an oncogene) leads to excessive RAS
productionexcessive cell growth
• What causes mutation?
• Point mutations that interfere with regulation (e.g., many pancreatic cancers)
• Duplications/chromosomal anomalies that lead to excess production of RAS
BRCA1 Breast Cancer susceptibility protein
Type 1
• BRCA1 protein encodes a DNA repair protein
• In a complex with other proteins, BRCA1 repairs damaged/mutated DNA, and
is part of a complex that monitors/repairs/shuts down genes that regulate cell
growth.
• If mutated, cells that should NOT replicate can proliferate--uncontrolled cell
growth. Common in cases of breast cancer.

• BUT—”Hundreds of different types of mutations in these genes have been

identified, some of which have been determined to be harmful, while others
have no proven impact. ”
 The Rate of Growth
Normal cells reproduce themselves and then stop when

enough cells are present.

Cancer cells reproduce rapidly before the cells have had a chance to mature.
 Maturation
Normal cells mature.
Cancer cells, because they grow
rapidly and divide before cells are
fully mature, remain immature. Some
use the term undifferentiated to
describe immature cells (in contrast
to differentiated to describe more
mature cells.)
Another way to explain this is to view
cancer cells as cells that don’t “grow
up” and specialize into adult cells.
Normal cells are either repaired or die (undergo apoptosis) when they are
damaged or get old.
Cancer cells are either not repaired or do not undergo apoptosis.
 Blood Supply

• Angiogenesis is the process by which cells attract

blood vessels to grow and feed the tissue. Normal
cells undergo a process called angiogenesis only as
part of normal growth and development and when
new tissue is needed to repair damaged tissue.

Cancer cells undergo angiogenesis even when growth is not necessary.

 Ability to Metastasize (Spread)
Normal cells stay in the area
of the body where they
belong.

Some cancer cells may lack

the adhesion molecules that
cause stickiness, and are able
to detach and travel via the
bloodstream and lymphatic
system to other regions of
the body—they have the
ability to metastasize.
 Energy Source
Normal cells get most of their energy (in the form of a molecule called ATP)
through a process called the Krebs cycle, and only a small amount of their
energy through a different process called glycolysis.
Many types of cancer cells produce their energy through glycolysis despite the
presence of oxygen (Warburg phenomenon).
 Functioning
Normal cells perform the function they are meant to perform,
whereas cancer cells may not be functional.

• For example, normal

white blood cells help fight off
infections. In leukemia, the number
of white blood cells may be very
high, but since the cancerous white
blood cells are not functioning as
they should, people can be more at
risk for infection even with an
elevated white blood cell count
Communication
Cancer cells don’t interact
with other cells as normal
cells do.
Normal cells respond to
signals sent from other
nearby cells that say,
essentially, “you’ve
reached your boundary.”
When normal cells “hear”
these signals they stop
growing. Cancer cells do
not respond to these
signals
 Evading the Immune System
• When normal cells become
damaged, the immune system (via
cells called lymphocytes) identifies
and removes them.
• Cancer cells are able to evade (trick)
the immune system long enough to
grow into a tumor by either by
escaping detection or by secreting
chemicals that inactivate immune
cells that come to the scene.
 Mortality/Immortality
Normal cells are mortal, that is, they have a lifespan. Cells aren’t designed to live forever, and just
like the humans they are present in, cells grow old. Researchers are beginning to look at
something called telomeres, structures that hold DNA together at the end of the chromosomes,
for their role in cancer.
One of the limitations to growth in normal cells is the length of the telomeres. Every time a cell
divides, the telomeres get shorter. When the telomeres become too short, a cell can no longer
divide and the cell dies.

Cancer cells have figured out a way to

renew telomeres so that they can continue
to divide. An enzyme called telomerase
works to lengthen the telomeres so that
the cell can divide indefinitely—essentially
becoming immortal.
 Genomic Instability
Normal cells have normal DNA
and a normal number of
chromosomes.
Cancer cells often have an
abnormal number of
chromosomes and the DNA
becomes increasingly
abnormal as it develops a
multitude of mutations.
Appearance
 The Concept of Cancer Stem Cells

You may be wondering if there

are differences between
cancer cells themselves. That
there may be a hierarchy of
cancer cells—some having
different functions than others
 Housekeeping chores
• Readings:
• Genes and cancer
https://www.cancer.org/cancer/cancer-causes/genetics/genes-and-cancer.ht
ml
• Inherited risk factors
https://www.cancer.org/cancer/cancer-causes/genetics/family-cancer-syndro
mes.html
• Chapters 11 and 15 in your textbook