HNPCC

HNPCC

detecting inherited forms of cancer

Hudson Alpha

Institute for Biotechnology

1. Construct an accurate pedigree across multiple generations.

2. Modify a pedigree across multiple generations.

3. Recommend genetic testing and lifestyle changes for individuals based on data obtained during the activity.

4. Perform gel electrophoresis.

5. Generalize genetic testing procedures and the consequences of the results to a variety of examples.

6. Describe cancer as a multi-step process that includes the accumulation of multiple mutations.

7. Explain the role of caretaker genes in the development of cancer.

8. Role-play a genetic counselor communicating genetic testing results and the ethical dilemmas that arise from the results.

What is HNPCC?

Hereditary Non-Polyposis Colorectal Cancer

Also known as Lynch syndrome, HNPCC can cause polyps in the colon.

Average age of diagnosis is 44 years.

Accounts for approximately 3% of people who have colon cancer.

It's sometimes confused with another type of colorectal cancer known as FAP (familial adenomatous polyposis).

Difference between the two: FAP patients often have hundreds of polyps, while HNPCC patients generally only have a few polyps--usually on the right side of the colon.

(they scan the genome to identify and help repair specific types of DNA mutations)

Their are four identified causative genes located on chromosome 2, 3, and 7--they are known as "caretaker" genes.

Caretaker Genes

The process of DNA replication inherently places cells at risk of acquiring mutations.

Thus, caretaker genes are vitally important to cellular health.

Rounds of cell replication allow fixation of mutated genes into the genome.

Caretaker genes provide genome stability by preventing the accumulation of these mutations.

Upon mutation, caretaker genes lead to altered gene products that result in increased conversion of a normal cell to a cell of neoplasia, a cell that; (1) divides more often than it should or (2) does not die when conditions warrant cell death

Inactivation of caretaker genes is environmentally equivalent to exposing the cell to mutagens incessantly.

So, how does a person get HNPCC??

The caretaker gene mutation is usually passed down by one parent in an autosomal dominant fashion.

This leaves the person with only one working copy of the caretaker gene.

Having only one copy of this caretaker gene increases the chance of developing colon cancer by 80%.

If a single cell gets a mutation in it's other caretaker gene, there will no longer be any genes looking for or repairing mutations.

This will allow a continued accummulation of mutations which will eventually lead to the development of a cancer.

The Story

You are a genetic counselor whose job it is to advise patients of the risk for an inherited disorder and discuss appropriate testing options.

Bob is 45 years old and in good health.

Bob has a sister who was just diagnosed with colon cancer at the age of 50.

A pedigree is a way of visualizing a person’s family history by putting it on paper.

Pedigree

The figure below shows some of the more common symbols used when drawing a pedigree. When drawing a pedigree, sometimes it is helpful to write the names of the family members if given, as well as ages and any other important information about them.

So, who do you think might need to be tested for mutations?

How are individuals with HNPCC identified?

Family history of colon cancer with at least one relative diagnosed before the age of 50.

If a colorectal tumor is identified in a patient, the cancerous tissue can be tested for the presence or absence of the proteins produced by the HNPCC caretaker genes.

This test can be utilized on both individuals diagnosed with colorectal cancer and their at-risk family members.

For this lab activity we will focus on a restriction enzyme digest of a targeted mutation site.

This involves amplifying the DNA surrounding the mutation site with the polymerase chain reaction (PCR)

A protein that can be though of as a type of molecular scissors. They cut DNA only at specific nucleotide sequences.

These DNA copies are then exposed to a restriction enzyme.

In this activity, the HNPCC mutation has created a new restriction enzyme recognition site. If the amplified DNA contains the mutation, it will be cut in two when mixed with the restriction enzyme

Gel Electrophoresis is used to determine if the samples have been cut by the restriction enzyme.

Family members with two normal copies of this gene will show only a single non-cut amplified DNA frament (two bands). Individuals who have inherited a copy of the mutation will present three bands.

Their are two copies of each of the four genes in each cell (one from mom, one from dad)

Learning Objectives

9. Role play a genetic testing laboratory technician obtaining and analyzing testing results.