The following Glossary contains terms you may encounter throughout this CD.

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Adenomatous Polyposis Syndromes
A term that collectively refers to the hereditary syndromes that involve adenomatous polyps: familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), and MYH-associated polyposis (MAP).

1. One member diagnosed with colorectal cancer before age 50.
2. Two affected generations.
3. Three affected relatives, 1 of them a first-degree relative of the other 2.
4. Familial adenomatous polyposis should be excluded.
5. Tumors should be verified by pathological examination.

However, these criteria do not accommodate the range of cancers that can be present in HNPCC families. To address these issues and to improve the clinical diagnosis of HNPCC, the ICG developed revised criteria in 1999, and these are known as "Amsterdam criteria II":

1. There should be at least 3 relatives with an HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis).
2. One should be a first-degree relative of the other 2.
3. At least 2 successive generations should be affected.
4. At least 1 should be diagnosed before age 50.
5. Familial adenomatous polyposis should be excluded in the colorectal cancer cases.
6. Tumors should be verified by pathological examination.

These criteria provide a general approach to identifying HNPCC families but they were designed to identify families with the highest probability of having HNPCC. As a result, they are too stringent for clinical use and have been shown to miss a significant amount of patients with HNPCC mutations.

Ashkenazi Jewish
The Eastern European Jewish population primarily from Germany, Poland, Lithuania, Ukraine and Russia, as opposed to the Sephardic Jewish population primarily from Spain, parts of France, Italy, and North Africa. The majority of Jewish individuals in the United States are of Ashkenazi descent.

Attenuated Familial Adenomatous Polyposis (AFAP)
Attenuated FAP (AFAP) is characterized by a significant risk for colon cancer, but fewer colonic polyps (average of 30) than seen in classic FAP. Polyps tend to be found more proximally (right-sided) in the colon than in classic FAP. The average age of colon cancer diagnosis in individuals with AFAP is 50-55 years, which is 10-15 years later than that observed in classic FAP, but younger than that of individuals in the general population. AFAP has been diagnosed in patients with very few polyps (0 to 9) but is more likely in patients with between 10 and 99 cumulative colorectal adenomas.

Autosomal Dominant
A pattern of Mendelian inheritance whereby an affected individual possesses one mutated gene copy and one normal gene copy. (In contrast, recessive diseases require that the individual have two copies of the mutant allele.) Individuals with autosomal dominant diseases have a 50% chance of passing the mutated gene copy, and hence the disorder, on to their children.

Autosomal Recessive
A pattern of Mendelian inheritance whereby an affected individual possesses two copies of a mutated gene, one inherited from each parent. Individuals with autosomal recessive diseases will have children that are "carriers" of a single mutated gene but it is unlikely their children will be affected with the disease. Siblings, however, have a 25% chance to also carry both mutated genes and be affected with the disease.

Bethesda Guidelines
These guidelines were initially published in 1997 and were the result of a workshop sponsored by the National Cancer Institute. They state that tumors from individuals should be tested for microsatellite instability (MSI) in the following situations:

1. Individuals with cancer in families that meet the Amsterdam criteria.
2. Individuals with two HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers.
3. Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed at age <45 yr, and the adenoma diagnosed at age <40 yr.
4. Individuals with colorectal cancer or endometrial cancer diagnosed at age <45 yr.
5. Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/cribiform) on histopathology diagnosed at age <45 yr.
6. Individuals with signet-ring-cell-type colorectal cancer diagnosed at age <45 yr.
7. Individuals with adenomas diagnosed at age <40 yr.

The Bethesda guidelines were designed to identify patients who should be offered tumor testing via MSI. However, in some instances, they may also be used to determine who should be offered genetic testing for germline MMR mutations. For example, the 2001 American Gastroenterological Association Medical Position Statement on Hereditary Colorectal Cancer and Genetic Testing states that genetic testing for germline MMR mutations may be appropriate for individuals meeting 1 of the first 3 Bethesda guidelines.

The Bethesda guidelines were revisited and updated in 2004 and are known as the revised Bethesda guidelines. These guidelines state that tumors from individuals should be tested for MSI in the following situations:

1. Colorectal cancer diagnosed in a patient who is less than 50 years of age.
2. Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors (endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain tumors-usually glioblastoma, sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel), regardless of age.
3. Colorectal cancer with the MSI-H histology (presence of tumor-infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern) diagnosed in a patient who is less than 60 years of age.
4. Colorectal cancer diagnosed in 1 or more first-degree relatives with an HNPCC-related tumor, with 1 of the cancers being diagnosed under age 50 years.
5. Colorectal cancer diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumors, regardless of age.

Biallelic
A term used when referring to both copies of one gene (i.e. one inherited from the mother and one from the father).

BRCA1
A tumor suppressor gene located on chromosome 17. When mutated the BRCA1 (BR for Breast CA for Cancer) gene is one of the genes responsible for hereditary breast and ovarian cancer.

BRCA2
A tumor suppressor gene located on chromosome 13. When mutated the BRCA2 (BR for Breast CA for Cancer) gene is one of the genes responsible for hereditary breast and ovarian cancer.

Chemoprevention
The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer.

Chromosomes
One of the threadlike "packages" of genes and other DNA in the nucleus of a cell. Different kinds of organisms have different numbers of chromosomes. Humans have 23 pairs of chromosomes, 46 in all: 44 autosomes and two sex chromosomes. Each parent contributes one chromosome to each pair, so children get half of their chromosomes from their mothers and half from their fathers.

Colectomy
The surgical removal of the colon. A total colectomy is the surgical removal of the colon and rectum. A subtotal colectomy is the surgical removal of the colon or portions of the colon only (not the rectum).

Colonoscopy
An examination of the inside of the colon using a thin, lighted tube (called a colonoscope) inserted into the rectum. If abnormal areas are seen, tissue can be removed and examined under a microscope to determine whether disease is present.

Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)
CHRPE are discrete, flat, pigmented lesions of the retina that do not cause clinical problems. It is thought that CHRPE are present at birth. Observation of multiple or bilateral CHRPE may be an indication that an at-risk family member has inherited FAP, whereas isolated or unilateral lesions may be seen in the general population. Visualization of CHRPE may require examination of the ocular fundus with an indirect ophthalmoscope through a dilated pupil.

de novo Mutation
An alteration in a gene that is present for the first time in a family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents or in the fertilized egg itself. de novo mutations can be passed onto the carrier's offspring. Approximately 20%-30% of FAP mutations are considered de novo.

Deoxyribonucleic Acid (DNA)
The molecule which encodes the genes responsible for the structure and function of an organism and allows for transmission of genetic information from one generation to the next.

Desmoid Tumors
Proliferative, locally invasive, nonmetastasizing, fibromatous tumors in a collagen matrix. Although they do not metastasize, they can grow very aggressively and be life threatening. Studies have found that 10% of FAP patients develop desmoids.

Disease-Causing Mutation
A gene alteration that causes or predisposes an individual to a specific disease.

DNA Replication
The process by which the DNA double helix unwinds and makes an exact copy of itself.

DNA Sequencing
Determining the exact order of the base pairs in a segment of DNA.

Familial Adenomatous Polyposis (FAP)
A colon cancer predisposition syndrome in which hundreds to thousands of precancerous colonic polyps develop, beginning at a mean age of 16 years (range 7-36 years). By age 35 years, 95% of individuals with FAP have adenomas. Without colectomy, the colon cancer risk approaches 100%. The mean age of colon cancer in untreated individuals is 39 years (range 34-43 years). Extracolonic manifestations are variably present and include polyps of the gastric fundus, periampullary region, and duodenum, as well as osteomas, dental anomalies, congenital hypertrophy of the retina pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, and other associated cancers.

First Degree Relative
Parents, children, and full siblings of an individual.

Flexible Sigmoidoscopy
A procedure using a lighted scope to examine the sigmoid/distal colon (left side) and rectum. This procedure has the ability to visualize 40-50% of the colon.

Gene
The basic unit of heredity, consisting of a segment of DNA arranged in a linear manner along a chromosome. A gene codes for a specific protein or segment of protein leading to a particular characteristic or function.

Gene Sequence Analysis
Process by which the nucleotide sequence is determined for a segment of DNA.

Genetic Counseling
A short-term educational counseling process for individuals and families who have a genetic disease or who are at risk for such a disease. Genetic counseling provides patients with information about their condition and helps them make informed decisions.

Genetic Discrimination
Unique treatment of an individual or members of that individual's family solely because of real or perceived differences from the 'normal' genome of that individual.

Hereditary
Transmission from parent to child of information contained in the genes.

Hereditary Mutation
A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
An inherited disorder in which affected individuals have up to an 80% lifetime risk of colorectal cancer and up to a 71% lifetime risk of endometrial cancer. Other primary cancers included in the HNPCC syndrome are cancers of the ovary, stomach, ureter/renal pelvis, biliary tract, small bowel, pancreas, brain, and sebaceous adenomas. Also called Lynch syndrome.

HNPCC-Related Cancers
Cancers associated with HNPCC are colorectal, endometrial, ovarian, gastric, ureter/renal pelvis, biliary tract, small bowel, pancreatic, brain, and sebaceous adenoma.

Inherited
Transmission of a trait through genes from parents to offspring.

Informed Consent
Permission given by an individual to proceed with a specific test or procedure, with an understanding of the risks, benefits, limitations, and potential implications of the procedure itself and its results.

Mismatch Repair Mechanism (MMR)
The DNA 'proof-reading' system controlled by certain genes that identifies, excises, and corrects errors in the pairing of the bases during DNA replication. Mutations in the genes responsible for this mechanism can lead to certain genetic diseases and some forms of cancer. MLH1 and MSH2, the primary genes responsible for HNPCC, are mismatch repair genes.

MLH1
Located on chromosome 3p21, the primary function of the MLH1 (mutL homolog 1) gene is mismatch repair during DNA replication. When mutated, the MLH1 gene is one of the genes responsible for hereditary nonpolyposis colorectal cancer.

MSH2
Located on chromosome 2p16, the primary function of the MSH2 (mutS homolog 2) gene is mismatch repair during DNA replication. When mutated, the MSH2 gene is one of the genes responsible for hereditary nonpolyposis colorectal cancer.

MSH6
Located on chromosome 2p16, the primary function of the MSH6 (mutS homolog 6) gene is mismatch repair during DNA replication. When mutated, the MSH6 gene is one of the genes responsible for hereditary nonpolyposis colorectal cancer.

Metachronous
Multiple separate occurrences, such as multiple primary cancers developing at intervals.

Microsatellite
Repetitive segments of DNA two to five nucleotides in length (dinucleotide/trinucleotide/tetranucleotide/pentanucleotide repeats), scattered throughout the genome in non-coding regions between genes or within genes (introns). These regions are inherently unstable and susceptible to mutations.

Microsatellite Instability (MSI)
The presence of a discrepancy between the sizes of microsatellites in DNA from tumor tissue compared to non-tumor tissue from the same person, often resulting from mutations in a gene in the DNA mismatch repair (MMR) pathway that would normally correct these errors.

Mutation
A change or alteration in a gene which may cause it to lose normal function. Mutations can be passed on to children.

MYH (mutY homolog)
A caretaker gene located on chromosome 1 that is involved in the base excision repair (BER) pathway. When both copies are mutated, MYH-associated polyposis (MAP) results.

MYH-Associated Polyposis (MAP)
MYH-associated polyposis (MAP) is an autosomal recessive disorder that is characterized by multiple cumulative colorectal adenomas. Due to the relationship between MAP and multiple polyps, the colorectal cancer risk is thought to be increased, although the exact risk is unknown. MAP has been diagnosed in patients with very few polyps (0 to 9) but is more likely in patients with 10 or more cumulative colon adenomas. MAP patients may also look similar to classic FAP and present with up to 1000 colon adenomas.  Due to the autosomal recessive inheritance pattern of this disease, there will often be no family history of multiple colon polyps in parents or children but siblings are at-risk for MAP.

Osteomas
Bony growths that can be associated with FAP. They are found most commonly on the skull and mandible but may occur in any bone of the body. Osteomas do not usually cause clinical problems and do not become malignant. They may appear in children with FAP prior to the development of colonic polyps.

p16
A tumor suppressor gene located on chromosome 9. When mutated, the p16 gene is the greatest known genetic cause of hereditary melanoma.

Pedigree
A graphic representation of a family tree, often showing a particular disease state.

Pre-symptomatic
The stage prior to an individual presenting with symptoms that are clinically relevant to the disease in question.

Prophylactic Mastectomy
The removal of breast tissue prior to the detection of disease. Both subcutaneous mastectomy and simple (total) mastectomy have been used for prophylaxis. Only 90% to 95% of breast tissue is removed with subcutaneous mastectomy. In a total or simple mastectomy, removal of the nipple-areolar complex increases the proportion of breast tissue removed compared to subcutaneous mastectomy. However, some breast tissue is usually left behind with both procedures.

Prophylactic Oophorectomy
Surgical removal of the ovaries prior to the detection of disease.

Selective Estrogen Receptor Modulator (SERM)
A drug that acts like estrogen on some tissues but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs.

Serum CA-125
A blood test that measures the level of CA-125, a substance found in blood, other body fluids and some tissues. Increased levels of CA-125 may be a sign of ovarian cancer.

Sporadic cancer
Cancer occurring in individuals without a family history of cancer or in individuals who do not carry a high-risk mutation.

Synchronous cancer
Multiple primary cancers occurring simultaneously.

Transvaginal (endovaginal) Ultrasound
High-resolution images of the uterus and ovaries may be used to screen for endometrial or ovarian cancer.

Tumor Suppressor Gene
A protective gene that normally limits the growth of tumors. When a tumor suppressor gene is mutated, it may fail to keep a cancer from growing. BRCA1 and BRCA2 are tumor suppressor genes.

© 2004-06, Myriad Genetic Laboratories, Inc.