Germline genetic testing can identify an individual’s hereditary risk for a number of cancers, including cancers of the breast, ovary, uterus, colon, stomach, thyroid and other primary sites. The identification of an inherited predisposition can have implications for clinical care, surveillance, chemoprevention, and preventive surgery.
In general, only a small proportion of any cancer type is hereditary; defined here as having a risk almost entirely attributable to germline mutations in a single gene. The line between hereditary and familial is not always clear. For common cancers, such as those of the lung, breast, colon, and prostate, less than 10% are hereditary. Another subset (15-25%) may be due to an interaction between multiple genes and the environment and they too can result in cancers clustering in families, but no specific testing is available for these familial cancers. Other less common types of cancer, such as ovarian, uterine, pancreatic, and renal cancers, have a proportion (albeit small) of cancer that is hereditary. Hereditary cancers may be identified by specific characteristics of the individual cancers and characteristics of the family history. Examples of individual characteristics of cancers that have a high likelihood of being hereditary include triple-negative breast cancer and high-grade serous ovarian cancer. Family history can be an important clue to a hereditary form of cancer, and important features of the family history include: cancer in several generations, early age of cancer onset, aggregation of cancer types in a family (such as breast and ovarian or uterine and colon cancer) and rare cancer types in a family (such as adrenal carcinoma or medullary thyroid carcinoma). The section below is meant to give a brief review of the more common cancer types and features that should lead a provider to consider genetic counseling and genetic testing.
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Genetics of Common Cancer Types
A family history of breast cancer is one of the more important risk factors for breast cancer, indicating the important role for heritable factors in the development of the disease. When compared with women who have no family history of breast cancer, the relative risk (RR) for breast cancer ranges from 1.4 for a woman whose mother was diagnosed after age 60 years to an RR of up to 4-6 for women with two affected first-degree relatives. (By comparison, there can be a 15-fold increase in risk for a 40-year-old woman with a BRCA1 mutation.) In addition, women who have had atypical hyperplasia have a fourfold elevated risk of breast cancer, and this risk may be higher in the setting of a positive family history of breast cancer.
Several clinical characteristics may distinguish an inherited form of breast cancer, especially one associated with an inherited BRCA1 or BRCA2 mutation, including early age at diagnosis (prior to age 50), triple- negative breast cancer, bilateral breast cancer, male breast cancer, Ashkenazi Jewish heritage, and the occurrence of additional cancer diagnoses (such as a second primary breast cancer or ovarian cancer). Characteristics of the family that may signify hereditary breast cancer include multiple affected family members from one lineage; specifically two or more relatives with breast cancer (one under age 50) or three or more relatives with breast cancer at any age, any relative with ovarian cancer or male breast cancer. This can be on the maternal or paternal side.
In addition to Hereditary Breast Ovarian Cancer Syndrome (due to BRCA1/2 mutations) , hereditary breast cancer may also be due to inherited mutations in:
- TP53 (Li-Fraumeni syndrome). TP53 mutations should be looked for in any woman diagnosed with breast cancer age 35 years or younger since therapeutic radiation should be avoided in mutation carriers. In addition, a family history of sarcoma, brain cancer, premenopausal breast cancer, adrenocortical cancer , leukemia or bronchoalveolar lung cancer also increases the chance of Li-Fraumeni syndrome.
- CDH1 (hereditary diffuse gastric syndrome). Individuals with invasive lobular cancer who also have a family history of diffuse gastric cancer should be evaluated for a germline CDH1 mutation (see also the section on gastric cancer).
- PTEN (Cowden syndrome). Individuals with Cowden syndrome have an increased risk of macrocephaly, GI and other hamartomas, thyroid cancer, endometrial cancer, and mucocutaneous and skin lesions such as trichilemmomas.
- STK11 (Peutz-Jeghers).
- PALB2- inherited PALB2 mutations are associated with a 33% lifetime risk of breast cancer. The risk is as high as 58% if a woman has two first degree relatives with breast cancer diagnosed by age 50. Inherited PALB2 mutations are also found in some families with hereditary pancreatic cancer.
About 5-10% of all colorectal cancers (CRCs) are a result of heredity. Many studies have shown that the stronger one’s family history of colorectal cancer, the greater one’s risk of developing the disease. In general, familial risk increases as the number of affected first-degree relatives increases. An early age at diagnosis of CRC in a first-degree relative is also a risk factor. CRC risk increases twofold in individuals with one affected first-degree relative and fourfold with two affected first-degree relatives. A dramatic increase in risk occurs in carriers of mismatch repair gene mutations associated with hereditary nonpolyposis colorectal cancer (HNPCC), commonly referred to as Lynch syndrome, whose lifetime CRC risk ranges from 60% to 80%.
A small proportion of all CRC results from inherited mutations in single cancer susceptibility genes. Lynch Syndrome is responsible for approximately 2% to 3% of all CRC. A personal or family history of CRC or endometrial cancer diagnosed at < age 50 years increases the chance that Lynch syndrome may be present. A family history of multiple cases of CRC or of CRC plus endometrial cancer, ovarian cancer, urothelial cancer (ureter or renal pelvis) or upper GI cancer (small bowel, stomach, biliary) also increases the likelihood of Lynch syndrome.
Polyposis syndromes also contribute to hereditary colorectal cancer. Familial adenomatous polyposis (FAP) accounts for about 1% or less of all CRC. Much rarer CRC-predisposing syndromes—such as Peutz-Jeghers syndrome, juvenile polyposis syndrome, and mixed hereditary polyposis—compose a small fraction of CRCs (less than 1%).
Similar to other cancers, about 10% of gastric cancers occur in a familial pattern and <3% appears to be hereditary. Individuals with a first-degree relative with gastric cancer have a 1.5 – 3.0 times increased risk of developing gastric cancer. Several hereditary predisposition syndromes are associated with gastric cancer. The most common is hereditary diffuse gastric cancer (HDGC) associated with germline CDH1 mutations. Gastric cancer in these families is of the diffuse type (vs. intestinal type), often occurring at very young ages. The prevalence of germline mutations of CDH1 in families meeting criteria for HDGC ranges from <20 to 40% depending on the incidence of gastric cancer in the country (countries with high incidence of gastric cancer having lower prevalence of CDH1 mutations). Criteria for consideration of HDGC include either two or more documented cases of diffuse gastric cancer in ﬁrst/second degree relatives, with at least one diagnosed before the age of 50; or three or more cases of documented diffuse gastric cancer in ﬁrst/second degree relatives, regardless of age. An increased frequency of invasive lobular cancer is also seen in families with hereditary diffuse gastric cancer. Gastric cancer is seen in other hereditary syndromes such as; Lynch syndrome, Li-Fraumeni syndrome, familial adenomatous polyposis (FAP), and hereditary breast and ovarian cancer (associated with BRCA2 mutations).
The majority of lung cancer is related to smoking. There are some families in which lung cancer appears to occur at early ages, and there may be genes linked with susceptibility to smoking-related cancers, such that low exposure is associated with cancer development. However, to date there is no genetic testing available for susceptibility to smoking-related cancers. There are, however, two cancer family syndromes that should be considered when evaluating someone with lung cancer at an early age (under age 45) or without a history of tobacco exposure; Li-Fraumeni syndrome and hereditary retinoblastoma. Both of these syndromes are associated with an excess of lung cancer as well as other cancers (see Retinoblastomas below for more complete descriptions).
Five to ten percent of all melanoma is related to a hereditary predisposition. Clues to hereditary melanoma include early onset disease, multiple primary melanomas, family history of pancreatic cancer, presence of dysplastic nevi, and family history of melanoma. Familial atypical multiple-mole and melanoma (FAMMM) syndrome, associated with CDKN2A and CDK4 mutations, is the most common syndrome. Rarely, melanoma can be seen in Li-Fraumeni syndrome and hereditary retinoblastoma, although melanoma in this setting may be related to prior radiation. The risk of melanoma is also increased in individuals who inherit a BRCA2 mutation.
Approximately 15% of ovarian cancer is inherited (although this may be as high as 40% in the Ashkenazi Jewish population). Clues to a hereditary form of ovarian cancer include early onset (diagnosis at age 45 or younger), high-grade serous histology, and fallopian tube carcinomas. Most hereditary ovarian cancers occur in families with breast and ovarian cancer and are associated with germline mutations in BRCA1 or BRCA2. In families with predominantly ovarian cancer, more cases are attributable to BRCA1 mutations compared with BRCA2 mutations. A small percentage of hereditary ovarian cancers are associated with Lynch syndrome, which is caused by germline mutations in the DNA mismatch repair genes (MSH2, MLH1, MSH6, PMS2, EPCAM). A family history of ovarian cancer, colon and/or endometrial cancer may be suggestive of Lynch syndrome. The remainder of hereditary ovarian cancer is due to less commonly identified syndromes such as LiFraumeni syndrome (associated with TP53 mutations) and Peutz-Jeghers (associated with STK11 mutations) and genes such as BRIP1, RAD51C, and RAD51D.
A small percentage (5-10%) of pancreatic cancer is thought to be hereditary. Pancreatic adenocarcinoma can be seen in families with hereditary pancreatitis, but this is quite rare. More commonly pancreatic adenocarcinoma is a feature of cancer family syndromes such as hereditary breast and ovarian cancer (associated with BRCA2 mutations; BRCA 1/2 mutations were found in 12% of Ashkenazi Jewish pancreatic cancer patients in one series) and familial atypical multiple-mole and melanoma (FAMMM) (associated with CDKN2A mutations). Pancreatic adenocarcinoma may also be seen in Peutz-Jeghers syndrome (associated with STK11 mutations), in individuals with inherited PALB2 mutations, in Lynch syndrome ( associated with mutations in MLH1, MSH2, MSH6, PMS2 or EPCAM), in familial adenomatous polyposis, and rarely in Li-Fraumeni syndrome (LFS) (associated with TP53 mutations). Pancreatic neuroendocrine tumors are a feature of multiple endocrine neoplasia type 1 (MEN1) syndrome or von Hippel-Lindau syndrome. Germline mutations in ATM have been identified in families with hereditary pancreatic cancer. The absolute risk of pancreatic cancer in mutation carriers is still being determined.
Fifteen to 20% of pheochromocytomas are considered familial. In addition to family history, primary clues for inherited causes of this rare tumor include bilateral or multifocal pheochromocytomas, extra-adrenal tumors, and an early age of diagnosis (mean age of diagnosis of 25 years). von-Hippel Lindau (VHL) syndrome is caused by mutations in the VHL gene and is divided into subtypes based on clinical phenotype. The type II VHL syndromes are associated with increased risk of pheochromocytoma. Pheochromocytoma occurs in approximately half of individuals with multiple endocrine neoplasia (MEN) syndrome type 2A and type 2B. This syndrome should be suspected in those with a family history of medullary thyroid cancer, primary hyperparathyroidism, or hyperganglionic megacolon in addition to the pheochromocytoma. Patients with neurofibromatosis type 1 also have an increased risk of pheochromocytoma. Familial paraganglioma is closely related to familial pheochromocytoma and can cause catecholamine hypersecretion as well. Germline mutations in the succinate dehydrogenase genes (SDHD, SDHC, SDHAF2, and SDHB) are responsible for most cases of inherited paragangliomas.
Approximately 5-10% of all prostate cancer is attributed to heredity, but few genes have been found to explain the familial aggregations. Hereditary prostate cancer is responsible for approximately 30-40% of early onset disease, but otherwise demonstrates no difference in clinical characteristics.
A family history of prostate cancer is a strong risk factor for this type of cancer. Epidemiological studies have demonstrated that having a family history of a first-degree relative with prostate cancer results in a twofold increase in the risk of the disease compared with the general population. Although the prostate cancer susceptibility genes have not yet been clarified, BRCA1 and BRCA2 play a role in this increased risk. Despite the increased cancer risk, it is unlikely that BRCA1 and BRCA2 account for a large percentage of familial prostate cancer. Data regarding the BRCA2 gene suggest that BRCA2 mutations account for only 2% of early-onset prostate cancer and 5% of familial prostate cancer. However, in one study of men with metastatic castrate-resistant prostate cancer, 12% had a germline mutation in either BRCA1 or BRCA2 (6%) or ATM (6%), which predicted for response to treatment with a PARP inhibitor. Prostate cancer that develops in men with a BRCA2 mutation is aggressive and associated with an increased mortality rate compared with non-hereditary prostate cancer.
Less than 10 percent of all renal cell carcinoma (RCC) appears to be hereditary. Clues to hereditary renal cancer include bilateral or multifocal cancers and family history of RCC. Age at RCC diagnosis is important, with early onset being recently defined as age 46. There are many syndromes associated with different histologic types of RCC as well as other benign and malignant tumors. More common examples include von Hippel-Lindau syndrome (VHL), which is associated with clear cell carcinoma; hereditary papillary renal cell carcinoma (HPRC), associated with Type 1 papillary carcinoma; and Birt-Hogg-Dube (BHD) syndrome, associated with chromophobe histology and oncocytomas. Other syndromes that can be associated with different types of RCC include hereditary leiomyomatosis and RCC (HLRCC), Cowden syndrome, succinate dehydrogenase kidney cancer (SDH-RCC), and tuberous sclerosis complex (TSC). Transitional cell cancer of the renal pelvis is associated with Lynch syndrome.
Retinoblastomas are rare but rapidly developing cancers that arise from immature cells in the retina. They are the most common form of malignant tumor in the eyes of children. Nearly 20-40% of all retinoblastomas are hereditary; the genetic abnormality has been traced to the RB gene. Most often, sporadic retinoblastoma is unilateral whereas hereditary retinoblastoma is most often bilateral. In nearly all cases, the cancer manifests by the age of 5; those with germline RB mutations present considerably younger. For patients with germline RB mutations, it is essential to suggest prenatal diagnosis as well as asymptomatic carrier testing because these patients can transmit the gene to half of their offspring who need early intervention. Children of these patients have a 50% chance of carrying this mutation as well.
Tumor histology is a particularly important consideration when evaluating inherited thyroid cancer risk. Germline mutations of the RET proto-oncogene have been implicated in 7- 20% of medullary thyroid carcinomas and resulting tumors are usually multifocal. Mutations in this gene are associated with three related clinical syndromes: multiple endocrine neoplasia types 2A (MEN2A) and 2B (MEN2B), and familial medullary thyroid cancer. Approximately three-quarters of medullary carcinoma patients with germline RET mutations do not have a family history of the disease. Therefore, consensus groups recommend testing for germline RET mutations in all individuals diagnosed with this type of thyroid cancer.
Non-medullary thyroid cancers (papillary, follicular, and anaplastic subtypes) can be associated with a number of different hereditary cancer syndromes; however, the overall proportion of these cancers that are attributed to inherited genes is extremely low. Papillary and follicular thyroid cancers can be seen in patients with Cowden syndrome (see Uterine Cancer section below). Individuals with familial adenomatous polyposis (FAP) also have an increased incidence of papillary thyroid cancer. Other, less common entities associated with non-medullary thyroid cancers include Carney syndrome, paraganglioma, tuberous sclerosis, and Werner syndrome.
Inherited genetic changes cause approximately 5% of uterine cancers. The majority of uterine cancers can be attributed to excessive physiologic or supplemental estrogen that is unopposed by progesterone. Clues to an inherited etiology of uterine cancer include family history of the disease and diagnosis at an earlier than expected age (mid-forties to mid-fifties rather than in the sixties). Most inherited uterine cancers have the endometrioid subtype, which is also the histology most commonly found in sporadic tumors. Lynch syndrome (hereditary non-polyposis colorectal cancer, or HNPCC) and Cowden syndrome are the primary hereditary cancer syndromes associated with a prevalence of uterine cancer. Families with uterine cancer, ovarian cancer, and/or gastrointestinal malignancies should be considered for evaluation for Lynch syndrome. Women with epithelial uterine tumors that have abnormal immunohistochemistry for mismatch repair proteins or microsatellite instability should also be evaluated for Lynch syndrome.
Major diagnostic criteria for Cowden syndrome consist of breast cancer, thyroid cancer, endometrial cancer, macrocephaly, and Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma). Peutz-Jeghers syndrome can also be a consideration for families with histories of uterine and gastrointestinal cancers. BRCA germline mutations have been associated with a mildly increased incidence of uterine cancer as well, but it remains controversial whether this effect is due to the germline mutation itself or the increased use of tamoxifen as a chemopreventive agent in this population.
The following resources provide detailed information regarding known hereditary disorders that may be identifiable through genetic testing:
- Concise Handbook of Familial Cancer Susceptibility Syndromes, Second Edition (N. Lindor et al, 2008) | Journal of the National Cancer Institute (JNCI)
- The Genetic Testing Registry (GTR®): Searchable genetic testing registry featuring concise regularly updated summaries of about 500 disorders
- National Cancer Institute (NCI) Physician Data Query (PDQ) Cancer Information Summaries: Genetics | NCI
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