Genetics



Genetics


Jennifer Dunn Bucholtz



I. Genetic Overview

A. Basic Genetics

1. Information discovered in the past 20 years has advanced all aspects of cancer care including prevention, screening, diagnosis, and treatment.

2. Genetic information helps to identify and test people at risk for hereditary cancers and to offer individualized screening and prevention strategies.

3. Cancer genetic data also help diagnose and identify certain malignancies and can be used to tailor treatments based on a person’s genetic profile and the tumor’s genetic changes.

4. Gene therapies are now emerging to treat certain cancers.

5. Nurses need to be familiar with cancer genetics information to best help people and families throughout the cancer care continuum (Jenkins, 2002). Oncology nurses, in particular, can be instrumental in helping people and families incorporate data regarding the rapidly evolving field of cancer genetics into all areas of clinical practice (Tranin, Masny & Jenkins, 2002).

6. An understanding of basic genetics is helpful in understanding cancer genetics, inherited cancer syndromes, and targeted cancer diagnostics and therapies (National Cancer Institute, 2002: Cancer genetics overview).

B. Genetic Structure

1. All genetic information is stored in the nucleus of our cells.

2. Inside the nucleus are chromosomes made of DNA proteins.

3. A genome is the complete set of DNA sequences in a species.

4. The human genome has 23 pairs of chromosomes.

5. Chromosomes contain thousands of genes, the smallest functional unit of genetic information.

6. Genes determine how a person’s body will grow and function.

7. Genes come in pairs. One copy is inherited from each parent.

8. A gene can have different forms in its DNA sequence. These variant forms are called alleles.

9. Everyone inherits two alleles for each gene—one copy of each chromosome from each parent.

10. Not all mutated alleles or genes lead to cancer.

11. The probability that a given mutated gene will cause disease is referred to as penetrance.

12. Alleles can be dominant or recessive, or x-linked.

13. If one parent carries a dominant allele (eg, mutation in BRCA1 or BRCA2), there is a 50/50 chance of each offspring inheriting the diseased allele. This is referred to as autosomal dominant inheritance.


C. Genetic Mutations

1. A mutation is a change in the usual DNA sequence of a particular gene. Mutations can be harmful, beneficial, or neutral. The term mutation is commonly used to refer to changes in the DNA that affect its protein structure.

2. All cancers arise from mutations in genes that can be inherited (germline mutations) or develop over a person’s lifetime from exposure to carcinogens or other mutagens (acquired or somatic mutations).

3. Inherited mutations are referred to as germline mutations because they are present in the ova and sperm from the parents and passed to every cell in the offspring. Because all cells contain the inherited mutation, the chance of developing cancers at earlier ages, as well as multiple cancers, is increased.

4. The majority of cancers are thought to be noninherited, somatic cancers and occur in older years of life. Somatic mutations arise in DNA of individual cells.

5. When a somatic mutation alters a gene in a normal cell, copies of the mutation will be present only in the descendants of that particular cell.

6. DNA mutations can alter protein function, resulting in a complete absence, underexpression, or overexpression of the protein.

7. Benign changes in DNA that do not alter protein function are referred to as polymorphisms and are used to track possible inherited disease patterns.

8. Dominant inherited mutations of the genes are found on autosomes, not sex hormones; therefore, both males and females can transmit the mutation. These mutations usually do not skip generations.

9. With autosomal recessive genes, one copy of the mutated allele must come from each parent. In general, one in four offspring will inherit the associated disease if both parents carry the mutated allele.

10. Autosomal recessive mutations may skip generations but are also transmitted equally by men and women.

11. Recessive X-linked mutations are carried on the X chromosome. Men are more likely to inherit a disease stemming from an X-linked mutation, because only one mutated allele is needed. Women are more likely to be mutation carriers.

12. Genetic testing can involve looking at a person’s DNA, which is obtained most often from his or her blood and occasionally from other body fluids or tissue. Examining key proteins that can signal abnormal genes is also a form of genetic testing (eg, Her2 neu testing).


II. Cancer Genetics

A. In general, all cancer is triggered by genetic changes.

B. Most cancers stem from random mutations caused by somatic mutations over a person’s lifetime.

C. It is estimated that only 5% to 10% of all cancers are caused by known inherited germline mutations.

D. Genes associated with cancer have been placed into three classes: oncogenes, tumor suppressor genes, or DNA-repair genes (see Chapter 1).

E. Microsatellite instability refers to an effect on a cell’s inability to repair DNA mismatches. Microsatellites are repetitive sequences of DNA located on the genome. Microsatellite instability can be found in a high percentage of certain hereditary cancers (eg, this is found in about
90% of hereditary nonpolyposis colorectal cancer [HNPCC] related cancer versus 15% of sporadic colorectal cancer).

F. Normal cells turn into cancer cells by a multistep process with specific genetic events. The best example of a known multistep progression is the colon cancer carcinogenesis model developed by Fearon and Vogelstein (1990). Other cancers are believed to have similar multistep progression in genetic changes.

G. All cancers originate from a single cell. When one cell acquires enough mutations to become cancerous, it can form a tumor.

H. In the future, it is likely that additional molecular discoveries will find other cancer genetic changes and causes and will isolate additional mutations.

I. Certain families may appear to have a higher incidence of cancers that are not inherited but result from a complex interaction between multiple genes and the shared environment. These are referred to as family clusters of cancer.


III. Hereditary Cancer Syndromes

A. General Overview

1. Represent 5% to 10% of known cancers in adults and children (American Society of Clinical Oncology, 1999).

2. Estimated that 1 in 300 people have mutations that predispose them to cancers of the breast, colon, uterus, and ovary.

3. People who inherit genetic mutations associated with certain cancers have a high risk of developing these cancers, and at early ages.

B. Assessing for Familial Cancers

1. Because hereditary cancers represent only a small number of all cancer cases, it is important to be able to recognize people and their family members who are at high risk for inherited cancers.

2. Common features seen in families with a hereditary cancer predisposition are listed in Box 2-1.

3. Families do not need to have all of these common features to have a genetic mutation.

4. Table 2-1 lists known family cancer syndromes and the associated types of cancers.



BOX 2-1 Common Features Seen in Families With Hereditary Cancer



  • Cancer diagnosis in two or more close family members on same side of family


  • Diagnosis of cancers occurred at earlier ages than normally seen with particular cancers


  • Bilateral or multiple rare cancers


  • Multiple primary tumors


  • Evidence of autosomal dominant inheritance


  • Tumors in family consistent with specific cancer syndrome (eg, breast and ovary in BRCA; colon, uterine in HNPCC)










TABLE 2-1 Family Cancer Syndrome, Identified Mutation, and Associated Cancers















































































































Family Cancer Syndrome (Mutated Gene)

Type of Cancers


Adenomatous polyposis (FAP) (APC, Attenuated APC)

Colon/rectum, liver, hepatoblastoma, small bowel, intestine, stomach, thyroid, medulloblastoma


Ataxia-telangectasia (ATM)

Breast, pancreas, stomach, uterine, leukemias, glioma, non-Hodgkin’s lymphoma, medulloblastoma, basal cell, ACA


Basal cell-nevus (PTC)

Ovarian, fibrosarcoma, medulloblastoma, basal cell


Bloom syndrome (BLM)

Breast, colon/rectum, esophagus, cervix, larynx, tongue, leukemias, non-Hodgkin’s lymphomas, lung cancer, basal cell, squamous cell


Breast/ovarian (BRCA1)

Breast, ovarian, colon/rectum/prostate


Breast/ovarian (BRCA2)

Breast, ovarian, colon/rectum, prostate, pancreas, ACA


Carcinoid, familial

Carcinoid


Carney’s syndrome

Adrenal, cortical, pituitary, thyroid, testicle, schwannoma


Chordoma

Chordoma


Colon (hereditary nonpolyposis cancer) (HNPCC) (MLH1, MSH2, MSH6, PMS1, PMS2)

Colon/rectum, biliary, liver, hepatocellular, pancreas, colorectal ACA, stomach, bladder, kidney, renal clear cell, renal transitional, ureter, uterine, ovaries, glioma, sebaceous gland


Cowden syndrome (PTEN)

Breast, small bowel, thyroid


Esophagus with tylosis

Esophagus


Fanconi’s anemia (FACC, FACA)

Liver, hepatocellular, cervix, leukemias, glioma, medulloblastoma, squamous cell


Gastric cancer, familial

Esophagus, stomach, tongue


Hodgkin’s disease

Hodgkin’s disease


Li-Fraumeni syndrome (TP53)

Breast, pancreas, ACA, adrenal cortical, prostate, testicle, germ cell, ovarian, larynx, leukemias, lung, glioma, non-Hodgkin’s lymphomas, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma


Melanoma (CDKN2A, BDRF)

Melanoma, pancreas, glioma, ACA


Multiple endocrine neoplasia 1 (MEN 1)

Adrenal cortical, apudoma, carcinoid, pancreas, islet cell, parathyroid, pheochromocytoma, pituitary, schwannoma


Multiple endocrine neoplasia 2 (MEN 2) (RET)

Paraganglioma, parathyroid, pheochromocytoma, pituitary, thyroid, medullary


Neurofibromatosis 1

Acoustic neuroma, glioma, meningioma, schwanoma, neuroblastoma, carcinoid, Wilms’ tumor, leukemias, paraganglioma, pheochromocytoma, rhabdomyosarcoma


Neurofibromatosis 2

Acoustic neuroma, glioma, meningioma, schwannoma


Osteochondromatosis

Chondrosarcomas, osteosarcoma


Pancreatic cancer, familial

Pancreas, adenocarcinoma (ACA)


Paraganglioma, familial

Paraganglioma, pheochromocytoma


Peutz-Jeghers syndrome

Breast, colon/rectum, pancreas, ACA, small bowel, stomach, testicle, cervix, ovarian


Prostate cancer, familial

Prostate


Renal cancer, familial

Renal clear cell, kidney, renal papillary


Retinoblastoma (RB1)

Retinoblastoma, leukemias, non-Hodgkin’s lymphomas, chondrosarcomas, fibrosarcoma, osteosarcoma, soft tissue sarcoma, pinealblastoma, melanoma


Rothmund-Thomson syndrome

Osteosarcoma, squamous cell


Testicular carcinoma, familial

Testicle, germ cell


Tuberous sclerosis

Paraganglioma, thyroid, kidney, renal clear cell, glioma


Von Hippel-Lindau disease (VHL)

Pancreas, ACA, stomach, apudoma, carcinoid, pancreas, islet cell, paraganglioma, kidney, renal clear cell


Werner’s syndrome

Breast, liver, hepatocellular, thyroid, leukemias, osteosarcoma, rhabdomyosarcoma, neuroblastoma


Wilms’ tumor (WT1 and others)

Wilms’ tumor, liver, hepatocellular, adrenal cortical, germ cell, rhabdomyosarcoma, neuroblastoma


Xeroderma pigmentosum

Breast, stomach, tongue, leukemias, lung,

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Sep 16, 2016 | Posted by in NURSING | Comments Off on Genetics

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