Hereditary cancer syndrome
A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.
Many of these syndromes are caused by mutations in tumor suppressor genes, genes that are involved in protecting the cell from turning cancerous. Other genes that may be affected are DNA repair genes, oncogenes and genes involved in the production of blood vessels. Common examples of inherited cancer syndromes are hereditary breast-ovarian cancer syndrome and hereditary non-polyposis colon cancer.
Background
Hereditary cancer syndromes underlie 5 to 10% of all cancers and there are over 50 identifiable hereditary forms of cancer. Scientific understanding of cancer susceptibility syndromes is actively expanding: additional syndromes are being found, the underlying biology is becoming clearer, and genetic testing is improving detection, treatment, and prevention of cancer syndromes. Given the prevalence of breast and colon cancer, the most widely recognized syndromes include hereditary breast-ovarian cancer syndrome and hereditary non-polyposis colon cancer.Some rare cancers are strongly associated with hereditary cancer predisposition syndromes. Genetic testing should be considered with adrenocortical carcinoma; carcinoid tumors; diffuse gastric cancer; fallopian tube/primary peritoneal cancer; leiomyosarcoma; medullary thyroid cancer; paraganglioma/pheochromocytoma; renal cell carcinoma of chromophobe, hybrid oncocytic, or oncocytoma histology; sebaceous carcinoma; and sex cord tumors with annular tubules. Primary care physicians can identify people who are at risk of a hereditary cancer syndrome.
Genetics of cancer
Two copies of every gene are present in all cells of the body and each one is called an allele. Most cancer syndromes are transmitted in a mendelian autosomal dominant manner. In these cases, only one faulty allele has to be present for an individual to have a predisposition to cancer. Individuals with one normal allele and one faulty allele are known as heterozygous. A heterozygous individual and a person with two normal alleles will have a 50% chance of producing an affected child. The mutation in the inherited gene is known as a germline mutation and a further mutation in the normal allele results in the development of cancer. This is known as Knudson's two-hit hypothesis, where the first hit of the gene is the inherited mutation and the second hit occurs later in life. As only one allele needs to be mutated, the individual has a higher chance of developing the cancer than the general population.Less often, syndromes may be transmitted as an autosomal recessive trait. Both alleles of a gene must be mutated in autosomal recessive disorders for an individual to have a predisposition to cancer. A person with two recessive alleles is known as homozygous recessive. Both parents must have at least one faulty allele in order for a child to be homozygous recessive. If both parents have one mutant allele and one normal allele then they have a 25% chance of producing a homozygous recessive child, 50% chance of producing a heterozygous child and 25% chance of produced a child with two normal alleles.
Examples of autosomal dominant cancer syndromes are autoimmune lymphoproliferative syndrome, Beckwith–Wiedemann syndrome, Birt–Hogg–Dubé syndrome, Carney syndrome, familial chordoma, Cowden syndrome, dysplastic nevus syndrome with familial melanoma, familial adenomatous polyposis, hereditary breast–ovarian cancer syndrome, hereditary diffuse gastric cancer, Hereditary nonpolyposis colorectal cancer, Howel–Evans syndrome of esophageal cancer with tylosis, juvenile polyposis syndrome, Li–Fraumeni syndrome, multiple endocrine neoplasia type 1/2, multiple osteochondromatosis, neurofibromatosis type 1/2, nevoid basal-cell carcinoma syndrome, Peutz–Jeghers syndrome, familial prostate cancer, hereditary leiomyomatosis renal cell cancer, hereditary papillary renal cell cancer, hereditary paraganglioma-pheochromocytoma syndrome, retinoblastoma, tuberous sclerosis, von Hippel–Lindau disease and Wilm's tumor.
Examples of autosomal recessive cancer syndromes are ataxia–telangiectasia, Bloom syndrome, Fanconi anemia, MUTYH-associated polyposis, Rothmund–Thomson syndrome, Werner syndrome and Xeroderma pigmentosum.
Examples
Although cancer syndromes exhibit an increased risk of cancer, the risk varies. For some of these diseases, cancer is not their primary feature.Fanconi anemia
is a disorder with a wide clinical spectrum, including: early onset and increased risk of cancer; bone marrow failure; and congenital abnormalities. The most prominent manifestations of this disorder are those related to hematopoeisis ; these include aplastic anemia, myelodysplastic syndrome and acute myeloid leukemia. Hepatic tumors and squamous cell carcinomas of the esophagus, oropharynx and uvula are solid tumors commonly linked to FA. Congenital abnormalities include: skeletal anomalies, cafe au lait spots and hypopigmentation. To date, the genes known to cause FA are: FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP and BRCA2. Inheritance of this syndrome is primarily autosomal recessive, but FANCB can be inherited from the maternal or paternal x-chromosome. The FA pathway is involved in DNA repair when the two strands of DNA are incorrectly joined. Many pathways are coordinated by the FA pathway for this including nucleotide excision repair, translesion synthesis and homologous recombination.Familial adenomatous polyposis
is an autosomal dominant syndrome that greatly increases the risk of colorectal cancer. Around 1 in 8000 people will have this disease and it has approximately 100% penetrance. An individual with this disease will have hundreds to thousands of benign adenomas throughout their colon, which will in most cases progress to cancer. Other tumors increased in frequency include; osteomas, adrenal adenomas and carcinomas, thyroid tumors and desmoid tumors. The cause of this disorder is a mutated APC gene, which is involved in β-catenin regulation. Faulty APC causes β-catenin to accumulate in cells and activate transcription factors involved in cell proliferation, migration, differentiation and apoptosis.Hereditary breast and ovarian cancer
is an autosomal dominant genetic disorder caused by genetic mutations of the BRCA1 and BRCA2 genes. In women this disorder primarily increases the risk of breast and ovarian cancer, but also increases the risk of fallopian tube carcinoma and papillary serous carcinoma of the peritoneum. In men the risk of prostate cancer is increased. Other cancers that are inconsistently linked to this syndrome are pancreatic cancer, male breast cancer, colorectal cancer and cancers of the uterus and cervix. Genetic mutations account for approximately 7% and 14% of breast and ovarian cancer, respectively, and BRCA1 and BRCA2 account for 80% of these cases. BRCA1 and BRCA2 are both tumor suppressor genes implicated in maintaining and repairing DNA, which in turn leads to genome instability. Mutations in these genes allow further damage to DNA, which can lead to cancer.Hereditary non-polyposis colon cancer
, also known as Lynch syndrome, is an autosomal dominant cancer syndrome that increases the risk of colorectal cancer. It is caused by genetic mutations in DNA mismatch repair genes, notably MLH1, MSH2, MSH6 and PMS2. In addition to colorectal cancer many other cancers are increased in frequency. These include; endometrial cancer, stomach cancer, ovarian cancer, cancers of the small bowel and pancreatic cancer. Hereditary non-polyposis colon cancer is also associated with an early onset of colorectal cancer. MMR genes are involved in repairing DNA when the bases on each strand of DNA do not match. Defective MMR genes allow continuous insertion and deletion mutations in regions of DNA known as microsatellites. These short repetitive sequences of DNA become unstable, leading to a state of microsatellite instability. Mutated microsatellites are often found in genes involved in tumor initiation and progression, and MSI can enhance the survival of cells, leading to cancer.[Hereditary paraganglioma-pheochromocytoma syndrome]
Most cases of familial paraganglioma are caused by mutations in the succinate dehydrogenase subunit genes.PGL-1 is associated with SDHD mutation, and most PGL-1 individuals with paraganglioma have affected fathers rather than affected mothers. PGL1 and PGL2 are autosomal dominant with imprinting. PGL-4 is associated with SDHB mutation and is associated with a higher risk of pheochromocytoma, as well as renal cell cancer and non-medullary thyroid cancer.