Familial cancer syndromes are defined as cancers that arise in families with a genetic predisposition to develop cancer.
To date, up to 10% of all cancer diagnoses are in individuals with an inherited genetic mutation causing increased risk. Most of the common syndromes are a result of autosomal dominant mutations and result in earlier age at cancer diagnosis than those found in the general population.
Familial cancer predisposition may refer to syndromes where one or two types of cancer are dominant, such as breast and ovarian cancer in BRCA1 mutation carriers. Alternatively, familial cancer syndromes may refer to syndromes which result in multiple affected organs, such as the case with HNPCC (Lynch syndrome) whereby mutations in DNA mismatch repair genes confer an increased risk to multiple types of cancers, for example, large and small bowel, uterus, stomach, ovaries, urinary tract, etc.
As the ability to identify and understand the genetic and genomic changes in an individual progresses, our understanding of inherited risk is likely to change. Models which incorporate multifactorial genetic and environmental influences will evolve to better assess familial risk.
The differential diagnosis includes sporadic cancers and environmental or carcinogen risk-associated cancers. The differential must include careful consideration of a patient’s family history and consideration of identifiable risk factors (such as tobacco use, asbestos exposure, etc). A careful assessment of familial and environmental risk factors is essential to determining whether to pursue genetic testing.
Several examples of a single gene causing cancer are known. The most common examples include but are not limited to p53 (Li-Fraumeni syndrome), BRCA1 or BRCA2 (breast or ovarian syndromes), mismatch repair genes (Lynch syndrome), and the APC gene (familial adenomatous polyposis [FAP]).
Taking a detailed family history is critical for identifying a familial cancer syndrome. This includes obtaining information on first-, second-, and third-degree relatives. For many of the cancer syndromes, there are established diagnostic criteria for determining whether a family may harbor a predisposing gene.
To date, twin studies are limited by the challenge of differentiating common environmental factors from heritable risk. However, twin studies do suggest an increased risk among twins when one twin is affected. This is particularly true for colorectal, lung, breast, prostate, and stomach cancer and if the affected individual is young at the time of cancer diagnosis.
There are numerous environmental factors (carcinogens) which are associated with an increased cancer risk. Carcinogens are identified as any substance (including radiation) with the capacity to perturb the cellular metabolic functions or genome directly. Furthermore, heritable risk is not independent of environmental risk. The environment can uniquely affect predisposing heritable risks, by tipping the balance toward the development of cancer in those patients with underlying risk factors.
Genome wide associations with common variants:
With respect to cancer heritability, numerous genome-wide association studies (GWAS) have been conducted. GWAS studies have elucidated the complexity of heritable risk, illustrating that there may be numerable cancer susceptibility loci which individually confer only a modest increased risk of cancer. Efforts are underway to develop polygenic models which may account for the risks associated with multiple susceptibility loci. Currently, the use of GWAS associated risk factors is not clinically implemented.
Genetic testing for pharmacogenomic assays will likely to increase as the technology meets the necessity for clinical utility. Thus far, genetic testing for pharmacogenomic assessment is not routine with a few key examples summarized in Table 40-1.
Whole genome and exome sequencing:
Recently it has become possible to analyze both common and rare genetic variants, as well as structural changes across entire genomes. The results of this work are defining new syndromes of disease predisposition, as well as uncovering unsuspected ones. Clinical translation of these technologies remains a central challenge of genomic medicine.
|Gene||Associated Medications||Goal of Testing||Key Variants||Effect|
|Enzyme UGT1A1||Irinotecan (chemotherapy)||Chemotherapy metabolism||UGT1A1*28||Decreased UGTA1 enzyme variability may result in high irinotecan levels and potentially lethal side effects|
|Enzyme TPMT||Thiopurine drugs (azathioprine, 6-mercaptopurine, 6-thioguanine)||Chemotherapy metabolism||TPMT *2,*3A,*3B, *3C||Genetic variations in TPMT affect the metabolism of chemotherapy used for a number of cancers including acute lymphoblastic leukemia|
|Enzyme DPD||5-FU (chemotherapy)||Chemotherapy metabolism||DPYD*2A||Genetic variation in the enzyme DPD may result in toxic levels of 5-FU|
Diagnostic Criteria and Clinical Characteristics
There is no one diagnostic criterion for familial cancer syndromes. Specific criteria are largely dependent on the specific cancer syndrome and the patient population. In general, criteria for identifying a syndrome are based on noting the early onset of family members with specific cancers and the clustering of associated cancers with the involvement of multiple generations. Criteria may be qualified by the increased prevalence of certain cancers within a given population. For example, BRCA