There are, at last count, more than 50 described cancer-susceptibility syndromes, and the list continues to grow. Clues to identification of a cancer-susceptibility syndrome include characteristics of the personal and family history. Characteristics in a person that may provide a clue to a cancer-susceptibility syndrome include early age of onset of the cancer, multiple primary tumors (either in the same organ or two different organs) and rare tumor types. There are some rare tumors that can suggest the presence of a cancer-susceptibility syndrome. Characteristics within a family include multiple generations affected with cancer, often of the same type or related cancers (i.e. breast and ovarian cancer or colon and uterine cancer). Similar to a personal history of cancer, a family with early onset cancer can be a clue to a cancer-susceptibility syndrome. The majority of syndromes are inherited in an autosomal dominant pattern, often with incomplete penetrance. While some cancer-susceptibility syndromes can appear sex-linked (such as hereditary breast and ovarian cancer) they are equally transmitted through both the maternal and paternal sides of the family. The following is meant to be an introduction to cancer-susceptibility syndromes. It is not meant to be an exhaustive list of all syndromes or complete discussion of each syndrome. The reader is referred to relevant literature for more complete discussions and information on hereditary conditions not covered here, including MYH-associated polyposis, juvenile polyposis, and a variety of childhood-onset recessive disorders.
Cowden syndrome, also known as multiple hamartoma syndrome, is generally considered to be a rare disease, with an incidence of about 1 in 200,000 individuals. However, because of the wide phenotypic spectrum and the subtle nature of some of the associated features, it is likely that this condition is significantly under-recognized. Although mucocutaneous stigmata are the hallmark of Cowden syndrome, a number of internal neoplasms and other features are also associated with it (including breast cancer, with a lifetime risk of 25%-50%). In addition to this variable expressivity, penetrance is very high by a young age.
Familial Adenomatous Polyposis
Mutations in the APC gene lead to the condition termed familial adenomatous polyposis, or FAP. This gene generally functions in signal transduction and cell adhesion and has been found to be mutated early in the chromosomal instability pathway to colon carcinogenesis. Individuals with germline alterations in this gene classically have hundreds to thousands of polyps that develop in the colon, often before the third decade of life. If untreated, the lifetime risk of colon cancer approaches 100% in these individuals. An attenuated form of the disease is also well-described; in these patients, the polyposis develops at a later age and to a lesser extent.
Hereditary Breast and Ovarian Cancer
Hereditary breast and ovarian cancer is characterized by mutations in BRCA1 or BRCA2. Both BRCA1 and BRCA2 are DNA repair genes. The normal function of both of these genes is to repair double strand breaks in DNA by homologous recombination. Women with either a BRCA1 or BRCA2 mutation have a very high risk of breast cancer (45- 80% lifetime risk) with a median age of onset in the 40s. The risk of a second primary breast cancer is also quite high (>50% over their lifetime). Women with BRCA1 mutations have an approximately 45% lifetime risk of ovarian cancer, with median age of onset in the 50s. BRCA2 is associated with a lower risk of ovarian cancer (about 16%) but with a later age of onset (in the 60s). Other cancers associated with germline mutations of BRCA1 and BRCA2 include: male breast cancer, prostate cancer and pancreatic cancer. Melanoma can be seen with BRCA2 mutations. Individuals with mutations in BRCA1 and/or BRCA2 are candidates for high-risk breast cancer screening with MRI, ovarian cancer screening and prostate cancer screening. Prevention options may include chemoprevention, bilateral mastectomy and prophylactic salpingo-oophorectomy.
Hereditary Diffuse Gastric Cancer
Hereditary diffuse gastric cancer is characterized by mutations in the CDH 1 gene, which codes for E-cadherin. The protein product of this gene has a role in cell adhesion, motility, proliferation and differentiation. The loss of function of the CDH1 gene is associated with disaggregation, promotion of local invasion and metastases. Individuals from these families have early onset diffuse gastric cancer and lobular breast cancer. For individuals who carry a germline mutation in CDH1, the lifetime risk of gastric cancer (diffuse type) is 80%, with average age of onset of 38 years (range 14 to 69 years), and the lifetime risk of lobular type breast cancer is 39-52%, with average age of onset in the early 50s. Recent studies suggest an increased risk of colon cancer.
Li-Fraumeni syndrome is a rare disorder that predisposes to many different types of cancers. In approximately 70% of “classic families”, germline mutations are found in TP53, a tumor suppressor gene located on chromosome 17.
Li-Fraumeni syndrome is associated with a 50% risk of cancer by age 40 years (a significant proportion of risk occurs before age 20 years) and a 90% risk by age 60 years. The lifetime cancer risk for female individuals appears to be higher because of the risk of breast cancer (mean age at diagnosis is 37 years, with an elevated risk of bilateral disease). Male breast cancer and prostate cancer do not appear to be overrepresented in this syndrome. Bone and soft tissue sarcomas are the most common malignancies in children, but leukemia, brain tumors, adrenocortical tumors, and other early-onset cancers also occur. The risk of subsequent cancers in affected individuals is very high, especially for survivors of childhood cancer. Some of these cancers have occurred in the radiation field involved in treatment of a prior malignancy.
High-risk families are advised to undergo routine screening as there is preliminary data to suggest that this strategy may improve the survival of individuals with a TP53 mutation who do not have signs or symptoms of cancer.
Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer (HNPCC), is caused by mutations in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and EPCAM, a gene that affects methylation of MSH2. Germline alterations in these genes are characterized by a 52-82% lifetime incidence of colon cancer and a 25%-60% incidence of endometrial cancer. These cancers are generally diagnosed prior to the age of 50. Other malignancies associated with this syndrome include gastric, ovarian, hepatobiliary, renal pelvis, small bowel, and brain cancers, as well as cutaneous sebaceous carcinomas. An initial step in establishing this diagnosis is testing tumors for the absence of mismatch repair proteins by immunohistochemical staining; many institutions have developed universal screening of colorectal and endometrial cancers with these stains. Microsatellite instability (MSI) of Lynch-associated tumor types can also indicate the possibility of this syndrome. It is important to realize that an abnormal IHC result or an MSI-high result is not pathognomonic for this disorder. Both occur in about 15% of all colorectal cancers, so additional testing is needed for many patients to distinguish sporadic from germline causes. The specific mismatch repair mutations can be identified through genetic analysis of germline DNA.
Multiple Endocrine Neoplasia
Multiple Endocrine Neoplasia, Type 1
Multiple endocrine neoplasia, Type 1, is associated with mutations in the MEN1 gene, which encodes a protein known as menin. The role of this gene in carcinogenesis is not entirely clear. The frequency of identification of this mutation in families with clinical suspicion for MEN1 syndrome varies considerably, with higher detection rates in families with multiple instances of the associated cancer types. The primary clinical characteristics of MEN1 syndrome include parathyroid adenoma, usually occurring by age 50 and associated with primary hyperparathyroidism, pituitary tumors, and pancreatic islet cell tumors or gastrinomas. Up to 60% of MEN patients have Zollinger-Ellison syndrome, with elevated gastrin levels and multiple peptic ulcers. Screening regimens for individuals with MEN include biochemical monitoring of at least serum calcium levels, gastrin levels, and prolactin levels. Regular assessment of parathyroid hormone levels, fasting glucose, insulin, insulin-like growth factor 1, and chromogranin A has also been proposed. Imaging with MRI of the pituitary and CT or endoscopic ultrasound of the pancreas may be done every 1-3 years.
Multiple Endocrine Neoplasia, Type 2A
Germline mutations in the RET proto-oncogene cause the multiple endocrine neoplasia, type 2A, syndrome. RET mutations associated with MEN2A tend to increase the rate of cell proliferation, leading to carcinogenesis. The primary cancers associated with MEN2A are medullary thyroid cancer and pheochromocytoma, as well as primary parathyroid hyperplasia. Cutaneous lichen amyloidosis and Hirschsprung’s disease have also been associated with this syndrome. Individuals with MEN2A should undergo genetic testing to determine the specific RET mutation they carry, as this information can help determine the age at which prophylactic thyroidectomy should be considered; however, this surgery is often indicated in childhood. The frequency and starting ages for biochemical screening with plasma fractionated metanephrines and/or urinary catecholamines as well as serum calcium can also vary on the basis of the specific RET mutation, but often these tests are initiated in childhood as well.
Familial Medullary Thyroid Cancer
Family medullary thyroid cancer (FMTC) is considered a subgroup of MEN type 2A and often can be difficult to distinguish clinically from this group. Classically, families with FMTC do not have increased risks of pheochromocytoma or parathyroid disease. Criteria for differentiating these groups include: more than 10 carriers in the kindred, multiple carriers or affected members over the age of 50 years, an adequate medical history (particularly in older family members), and identification of a RET mutation only associated with FMTC. Prophylactic thyroidectomy is again a primary means of managing these patients and the specific RET mutation can be used to determine the timing of this procedure.
Multiple Endocrine Neoplasia, Type 2B
The RET proto-oncogene is also mutated in multiple endocrine neoplasia, type 2B, although these mutations have been reported to cause suppression of apoptosis rather than acceleration of cell proliferation. Like MEN2A, medullary thyroid cancer and pheochromocytoma are the primary manifestations of this syndrome, but, unlike type 2A, the parathyroid gland is not involved. The thyroid cancers with this type of MEN tend to be more aggressive than those with Type 2A, and prophylactic thyroidectomy may be indicated as early as the neonatal period. Other clinical characteristics of MEN2B include mucosal neuromas, intestinal ganglioneuromas, megacolon, and a Marfanoid habitus. As in type 2A, the specific mutation in RET can be used to determine the screening frequency and initiation for biochemical testing for pheochromocytoma.
von Hippel-Lindau Syndrome
von Hippel-Lindau syndrome is caused by germline mutations in the VHL gene, which is a tumor suppressor gene with multiple cellular functions, including cell cycle regulation. The clinical manifestations of VHL syndrome include clear cell carcinomas of the kidney, pheochromocytomas, and neuroendocrine tumors of the pancreas, as well as benign tumors such as retinal and central nervous system hemangioblastomas, endolymphatic sac tumors of the ear, and papillary cystadenomas of the epididymis or broad ligament. Surveillance of individuals with this syndrome includes regular retinal examination; magnetic resonance imaging of the central nervous system; annual imaging of the kidneys, adrenals, and pancreas starting in adolescence; and annual assessment of plasma metanephrines starting in childhood. Renal cell cancers in this population are often treated with a nephron-sparing approach to preserve as much kidney parenchyma as possible for as long as possible, as these patients have a propensity to develop multiple primary renal tumors.