According to current models, tumor development is a continuous process of mutation accumulation that ultimately leads to cellular autonomy, unlimited growth and metastasis [7]. One of the most important events in this process is the initial destabilization of homeostasis that allows mutations to accumulate in genes that regulate cell proliferation, development, and differentiation. The genetic mechanisms involved in the earliest stages are not clear, but certain phenotypic features are notable. The cancer cell phenotype can be described by six hallmark features: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, avoidance of programmed cell death, limitless replicative potential, sustained angiogenesis, tissue invasion, and metastasis [7]. Generally it has been thought that three to seven successive mutations are required for the malignant conversion [8–10]. Various sources of spontaneous DNA damage are estimated to alter about 25,000 bases per human genome per cell per day out of the 3 × 10⁹ base pairs in the genome [11]. However, cells are endowed with specific mechanisms for repairing the damage and for maintaining mutations at reasonable levels. Consequently, the mutational load at any given time in both germ-line and somatic cells can be viewed as a dynamic equilibrium between the extent of DNA damage and the efficiency of DNA repair [12]. In principle, the likelihood that a single cell will acquire enough independent mutations necessary for malignant cancer development is quite low and statistically unlikely, given that the normal mutation rate is approximately 1.4 × 10⁻¹⁰ mutations per base pair per cell generation [13]. However, it is now well recognized that this theory is contradicted by the rate of incidence of various cancers. Not surprisingly, cancer biology and genetics have found a way around these statistical predictions. It has been suggested that two major mechanisms could result in higher mutation rates that would make cancer development more probable. First, highly selective mutations could occur that enhance cell proliferation, creating an expanded target cell population for the next mutation [14]. Second, mutations could occur that affect the stability of the entire genome at the DNA and/or the chromosomal level, thereby increasing the overall mutation rate [13, 15].

Tumorigenesis is associated with alterations (mutations) in two main classes of genes—oncogenes and tumor-suppressor genes—each of which can drive neoplasia by increasing the tumor cell burden through stimulating cell division or inhibiting cell death or cell-cycle arrest.

Less than 10 % of patients with cancer have highly penetrant inherited (germ-line) mutations that predispose to cancer. Germ-line mutations of genes known to be responsible for inherited forms of cancer and their syndromes are summarized in Table 22.1. A mutation within this context is defined as any change in the sequence of the gene, including single base pair substitutions, large or small deletions/insertions and amplifications or translocations of chromosomal segments. In the germ line, the most common mutations are subtle (point mutations or small deletions/insertions), whereas all types of mutation can be found in tumor cells.

Neoplasia is initiated by a mutation in a cancer gene that results in a clonal expansion, with subsequent mutations in additional genes resulting in further rounds of expansion as part of the process of tumor progression [16, 17]. An individual with a germ-line mutation in a cancer predisposition gene has an early start on tumor development, because a mutation that can contribute to cancer is already present in every cell. As such, these individuals may readily develop multiple tumors that are detectable at an early age. In many dominantly inherited cancer syndromes, the acquired first somatic mutation affects the normal copy of the gene inherited from the unaffected parent [18].

Under normal conditions, proto-oncogenes (the normal, non-mutated form of an oncogene) stimulate cell proliferation and differentiation. These genes mainly encode proteins involved in signal transduction pathways and include growth factors, growth factor receptors, signal transducers, and transcription factors (e.g., the RET and MET genes). When mutated (activated) these genes become oncogenes and gain the ability to dominantly promote neoplastic processes. In contrast, tumor suppressors are genes whose loss of function promotes malignancy [19, 20]. They are usually negative regulators of growth or other functions that may affect invasive and metastatic potential [21]. Tumor suppressor genes can be divided into two broad functional classes: (1) gatekeepers which directly regulate cell proliferation and are rate limiting for tumorigenesis; (2) caretakers which maintain the integrity of the genome and promote cancer growth indirectly by causing an increased mutation rate [22]. Interestingly, the most common forms of hereditary cancer predisposition are caused by inherited mutations of caretaker genes.

The contribution of tumor suppressors to tumorigenesis was initially proposed by Alfred Knudson in 1971, based upon epidemiological studies of retinoblastoma [23]. According to Knudson’s two-hit model, both copies of a tumor suppressor gene need to be inactivated for tumor formation. In the familial form of a disorder associated with a tumor suppressor gene, one mutated allele is inherited from one of the parents and the second allele is somatically inactivated. When the second hit involves a large deletion or mitotic recombination (reduces the mutation to homozygosity), it is referred to as loss of heterozygosity (LOH). Knudson’s model has later been applied to other forms of familial cancer as well [18, 24]. However, not all loss-of-function mutations in tumor suppressor genes are truly recessive [25]. Evidence suggests that haploinsufficiency (functional loss of one allele) of some genes might provide a growth advantage [26]. Thus, lower gene-dosage, rather than biallelic inactivation of a tumor suppressor gene may be sufficient to exert a cellular phenotype that leads to tumorigenesis. This may be particularly true for caretaker genes, where haploinsufficiency could result in mildly increased genomic instability [27].

In contrast to classical monogenic Mendelian disorders , such as Duchenne muscular dystrophy or cystic fibrosis, wherein mutations in a single gene cause disease, a single gene defect or alteration does not cause cancer. The vast majority of genetic alterations in cancer are somatic and found only in tumor cells. In an individual with a dominant cancer predisposition syndrome, all cells in the body are a priori heterozygous, carrying one mutated and one wild-type allele [19]. The germ-line mutation can be considered as the first hit required for tumorigenesis. The next genetic change in a cell often involves the loss of the remaining wild-type allele (second step in the Knudson’s two hit hypothesis) [18]. Even though additional somatic changes are still needed, the presence of a constitutional mutation greatly quickens the process of malignant conversion, and individuals with such mutations are at higher risk of developing cancer. Mutations with strong effects are likely to cause early onset of the disease and development of multiple primary tumors; they are inherited in simple Mendelian fashion, tend to cause familial clustering of disease and show dominant pattern of inheritance [28, 29]. However, the cancers develop only after additional somatic genetic mutations occur. Importantly, clinicians must also consider the pattern of these multiple primary cancers (e.g., breast and ovarian cancers in carriers of BRCA1 and BRCA2 mutations; medullary thyroid carcinoma and pheochromocytoma in the carriers of a RET mutation, etc.) which could then guide them toward the correct diagnosis.

Most cancer susceptibility syndromes result from inherited mutations in tumor suppressor genes rather than proto-oncogenes [19]. Germ-line mutations in only a limited number of proto-oncogenes (e.g., RET, MET, KIT, PDGFRA, and CDK4) (Table 22.1), have been shown to be involved in hereditary cancer predisposition [30–32]. Although they are rare, these syndromes are of vast biological importance. The study of genes responsible for such disorders, and the cellular pathways disrupted by the mutated proteins, provides significant insights into the molecular origin and pathogenesis of both inherited and sporadic forms of cancer [28].

A subclass of tumor suppressor genes, known as caretakers or stability genes, promotes tumorigenesis in a completely different way when mutated. This group includes the mismatch repair (MMR), nucleotide-excision repair (NER), base-excision repair (BER), and homologous recombination repair genes responsible for correcting subtle errors made during normal DNA replication or induced by mutagenic exposure. In normal cells, genetic alterations are kept to a manageable minimum by stability genes, and mutation rates are much higher when these genes are inactivated [33]. As a result, all genes are potentially at risk for mutations, but only mutations in oncogenes and tumor suppressor genes will provide a selective advantage to the cancer cell.

From this, it is best to picture mutated cancer genes as contributors to cancers, rather than the sole cause. In most cases involving genes associated with hereditary cancer syndromes, the individual with the mutation faces a high probability of developing cancer, but not 100 % certainty. Penetrance is defined as the probability that a person who has the genotype will manifest the expected phenotype. For example, a carrier of a mutation in the BRCA1 gene (breast and ovarian cancer susceptibility) has an approximate 70–85 % chance of developing breast cancer during their lifetime. Although this is a very high risk, the penetrance is incomplete and not everyone with a mutation will develop the disease. There are some important exceptions to incomplete penetrance; virtually all carriers of a pathogenic mutation in the TP53 gene (Li–Fraumeni syndrome) or the APC gene (familial adenomatous polyposis coli) develop cancer. Differences in penetrance between carriers of a germ-line mutation can be associated with environmental exposures and an individual’s genetic makeup (modifier genes).

Oncogenes are altered (mutated) in ways that cause the gene product to be constitutively activated or active under conditions in which the normal gene (proto-oncogene) is not active. Activation of an oncogene can result from chromosomal translocation (BCR-ABL), gene amplification (MYC), or intragenic mutations (RET) affecting key functional moieties that regulate the activity of the gene product. Activation of an oncogene through the alteration of a single allele is usually sufficient to bestow a cell with a selective growth advantage. Examples of oncogenes associated with inherited cancer syndromes and the associated tumors are included in Table 22.1. Such genes include RET and MET , which encode receptor tyrosine kinases involved in essential processes such as cell cycle progression, proliferation, differentiation, motility, and survival [34]. Many oncogenic tyrosine kinases are constitutively activated due to specific gain-of-function mutations [34, 35].