Hereditary cancer syndromes involve an increased risk of developing certain cancers due to inherited genetic mutations, unlike sporadic cancers that arise from random changes. Understanding these predispositions helps individuals and families make informed health decisions and consider proactive management.
Genetic Foundation
Genes provide instructions for cell growth, function, and repair. A genetic mutation is a change in a gene’s DNA sequence. When these changes occur in genes regulating cell processes, they can lead to uncontrolled cell growth, a hallmark of cancer.
Germline mutations are inherited from a parent and present in every cell. They differ from somatic mutations, which are acquired during life and found only in specific cells or tissues. Germline mutations in certain genes increase an individual’s lifetime cancer risk, often at an earlier age.
Many hereditary cancer syndromes follow an autosomal dominant inheritance pattern. This means inheriting one copy of a mutated gene from either parent is sufficient to increase cancer risk. Individuals with such a mutation have a 50% chance of passing it to each child. While one mutated gene increases risk, cancer development often requires additional acquired mutations in the remaining healthy gene copy.
Major Hereditary Cancer Syndromes
Hereditary Breast and Ovarian Cancer (HBOC) syndrome is primarily linked to mutations in the BRCA1 and BRCA2 genes, which normally help prevent rapid cell growth. Women with these mutations face an increased lifetime risk of breast (36-85%) and ovarian (20-60%) cancers. Men also have elevated risks for prostate and male breast cancer, and both sexes have an increased risk for pancreatic cancer and melanoma.
Lynch syndrome (HNPCC) results from inherited mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). These genes correct errors during DNA replication. Individuals with Lynch syndrome have a higher lifetime risk of colorectal (10-80%) and endometrial (15-60%) cancers, plus increased risks for stomach, ovarian, small bowel, urinary tract, central nervous system, and pancreatic cancers. Cancers often develop at an earlier age.
Familial Adenomatous Polyposis (FAP) is caused by mutations in the APC gene, which regulates cell growth and death. FAP is characterized by hundreds to thousands of polyps in the colon and rectum, often starting in the mid-teens. If untreated, nearly all individuals with classic FAP will develop colorectal cancer, often by age 40. FAP also increases the risk of cancers of the stomach, duodenum, small bowel, thyroid, and liver (hepatoblastoma).
Li-Fraumeni Syndrome (LFS) is a rare condition linked to germline mutations in the TP53 tumor suppressor gene. This syndrome is associated with a high lifetime likelihood of developing various cancers, approaching 75% in males and nearly 100% in females. Cancers often occur at an early age and can include soft tissue sarcomas, osteosarcomas, breast cancer, brain tumors, adrenal cortical carcinomas, and leukemia. Individuals with LFS may also develop multiple primary cancers.
Screening and Prevention
Genetic counseling is an important first step for individuals considering hereditary cancer risk assessment. Those with a strong family history of cancer, early-onset cancers, or multiple primary cancers are often advised to seek counseling. Genetic counselors evaluate family history, discuss potential risks, and explain genetic testing implications.
Genetic testing involves a blood or saliva sample to identify specific inherited gene mutations. Results can confirm a diagnosis, allowing for predictive testing of at-risk relatives. Pre- and post-test genetic counseling ensures informed decision-making regarding testing and medical management.
For individuals identified with a hereditary cancer syndrome, specific management strategies are recommended to reduce cancer risk. Increased surveillance and screening are common, such as earlier and more frequent mammograms and breast MRIs starting at age 25 for women with BRCA mutations, and regular colonoscopies for those with FAP or Lynch syndrome. These proactive measures aim to detect cancers at their earliest, most treatable stages.
Risk-reducing surgeries are another option for some syndromes. For example, risk-reducing mastectomy can lower breast cancer risk by about 90% in women with BRCA1 or BRCA2 mutations, while risk-reducing salpingo-oophorectomy (removal of ovaries and fallopian tubes) can reduce ovarian cancer risk by 80%. Lifestyle modifications, such as maintaining a balanced diet and regular exercise, may also contribute to overall health and cancer risk management. Chemoprevention, using medications to reduce cancer risk, is also explored for high-risk individuals.