Cancer occurs from pathogenic genetic variants (formerly referred to as mutations) that involve changes in the order of the base pairs, including substitutions, deletions, additions, or shifts. Pathogenic variants can be divided into two broad categories based on the tissue from which they originate.
Somatic or acquired genomic variants are the most common cause of cancer, occurring from damage to genes in an individual cell during a person’s life. They are classified in terms of the actionability of an available effective therapy. Cancers that occur because of somatic variants are referred to as sporadic cancers. Somatic variants are not found in every cell in the body, and they are not passed from parent to child. Some common carcinogens that cause pathogenic variants include tobacco use, ultraviolet light or radiation, viruses, chemical exposures, and aging.
Germline variants are far less common, accounting for only about 5%–10% of all cancers. A germline variant occurs in a sperm cell or an egg cell and is passed directly from a parent to a child at the time of conception. As the embryo grows into a baby, the pathogenic variant from the initial sperm or egg cell is copied into every cell in the body. Because the pathogenic variant affects reproductive cells, it can pass from generation to generation.
Cancers caused by germline pathogenic variants are called inherited or hereditary. More than 50 different hereditary cancer syndromes have been identified that can be passed from one generation to the next. Family and personal histories suggestive of germline pathogenic variants include:
- Early-onset cancer (breast, colon, or endometrial cancer in people younger than 50)
- Rare cancers (breast cancer in those assigned male at birth, pancreatic cancer, pheochromocytoma, paraganglioma, medullary thyroid cancer, ovarian cancer, retinoblastoma, or metastatic or Gleason 7 or higher prostate cancer)
- Certain pathologies (triple-negative breast cancer or microsatellite unstable cancer)
- More cancers in a family than expected by chance
- More than one primary cancer in one person or bilateral cancer in a paired organ (e.g., breast cancer in both breasts)
- Evidence of autosomal-dominant inheritance (e.g., two or more generations affected, with both sexes affected)
- Any pattern of cancer associated with a known cancer syndrome (e.g., breast, ovarian, pancreatic and prostate cancer; colon, endometrial, and ovarian cancer)
- Presence of premalignant conditions (e.g., 20 colorectal adenomatous polyps over a lifetime)
- Individuals from families with a known germline pathogenic or likely pathogenic variant associated with increased cancer risk
See the sidebar for more red flags that might indicate germline risk.
Identifying the Difference
In general, cancer cells have more genetic changes than normal cells, but each person’s cancer has a unique combination of genetic alterations. Some changes may be the result of cancer cells dividing, rather than the initiating event that led to the cancer’s development. As the cancer continues to grow, additional changes will occur, even within the same tumor.
A form of biomarker testing, DNA sequencing may identify both germline and somatic pathogenic variants by comparing the DNA sequence of cancer cells to healthy cells. Germline pathogenic variants are identified through a blood sample or with buccal cells from a saliva sample. Somatic variants are detected by either testing the tumor directly or liquid biopsy of a blood sample with circulating tumor cells to identify the DNA sequencing changes driving tumor growth. Understand the variants for a particular malignancy may help providers determine which therapies might be most effective.
Information provided by germline and somatic biomarker testing may overlap. For example, a person with a malignancy harboring a BRCA pathogenic variant may or may not have an inherited BRCA germline variant. Depending on the cancer type, both tumor and germline testing may be used to help select treatment options. Patients should be referred for germline testing if they have a personal or family history suggestive of hereditary risk, the tumor has microsatellite instability, the variant is a cancer susceptibility gene, the gene is considered pathogenic or likely pathogenic, or the allele frequency approaches 50%.
What Oncology Nurses Need to Know
Oncology nurses should understand when to refer patients for germline testing and how to provide patient education about the difference between germline and somatic variants. Educating patients and families about the different types of variants enables patients to have insight into the development of cancer and what it means for their treatment and recommendations for prevention and early detection of other cancers.
During an already confusing and stressful time, patients and families may have trouble coping with both a cancer diagnosis and learning about germline risk because of the possibility that other family members may also have a hereditary susceptibility to develop malignancy. Knowledge of germline pathogenic variants allows nurses to guide the entire family on appropriate cancer prevention and early detection strategies.