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As technology advances, the identification of genetic factors that trigger cancer development in the hereditary setting is advancing as well. New conditions are being established, and genetic testing companies are offering an increasing catalog of genes associated with hereditary syndromes.

Cancer develops due to defects in genes involved in essential cellular processes. Hereditary cancer syndromes can be grouped based on defects in two overarching cellular processes:

  • DNA repair pathways; examples include hereditary breast and ovarian cancer syndrome 22(BRCA1/2, PALB2), Lynch syndrome (MLH1, MSH2, MSH6, PMS2), polyposis syndromes (MUTYH, NTHL1), Li-Fraumeni syndrome (TP53), Ataxia-telangiectasia (ATM), Fanconi anemia (FANCD), and DICER syndrome (DICER).

  • Cell proliferation and signaling pathways; examples include familial adenomatous polyposis (APC), neurofibromatosis type 1 (NF1), familial retinoblastoma (RB), multiple endocrine neoplasia type 1/2 (MEN1/2), Cowden syndrome (PTEN), Peutz-Jeghers syndrome (STK11), hereditary diffuse gastric cancer syndrome (CDH1), Carney syndrome (PRKAR1A), and juvenile polyposis (BMPR1A, SMAD4).

In the following sections we will discuss the types of germline defects that cause these syndromes and the most up-to-date methodology to identify those defects.


Small-Scale Alterations

At the single-gene level, there are two main types of variants that affect nucleotide sequence: single-base nucleotide variants and small insertions or deletions. Single-base nucleotide variants that are most likely to affect the protein encoded by a gene include missense (change in amino acid), nonsense (introduction of a premature termination codon), loss of the normal initiation codon, loss of the normal stop codon, and alteration of the splice sites in the intronic bases that flank the exons (Figure 4.1A). Occasionally synonymous variants, which do not alter an encoded amino acid, can affect gene function through effects on splicing. Splice sites are located at the boundary of an exon and an intron. Splicing variants in these sequences can disrupt ribonucleic acid (RNA) splicing, resulting in the loss of exons or the inclusion of introns. Insertion or deletions of small nucleotide sequences can result in frameshift variants or in-frame alterations. Frameshift variants almost always lead to a premature termination codon and act similarly to nonsense variants.


A. Nucleotide variants. B. Chromosomal variant.

Large-Scale Alterations

Structural variants include deletions, duplications, inversions, and translocations (Figure 4.1B) and can occur between chromosomal sequences affecting several exons of the same gene or several genes and bigger chromosomal regions.


Next-Generation Sequencing

Next-generation sequencing (NGS) has revolutionized molecular ...

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