Discovery and Characterization of Cancer Genetic Susceptibility Alleles
Summary of Key Points
• The discovery of cancer susceptibility regions across the genome provides opportunities to understand defining events in tumor development and identify cellular pathways that contribute to the complex development of cancer.
• Regions of the genome that harbor susceptibility alleles can be determined with use of association studies in families or populations and linkage studies within families.
• New technologies, together with the annotation of genetic variation across the human genome, are accelerating the pace of discovery and characterization of cancer susceptibility alleles. The conclusive identification of a gene or a regulatory region contributes to an understanding of defining events in tumor development.
• The spectrum of cancer susceptibility alleles includes mutations in genes that are highly penetrant, which indicates that persons born with a mutant allele have a high probability of developing cancer and common variants that impart a small additional risk for cancer.
• Association studies and linkage-based studies both require collection of accurate clinical and family history data by clinicians, and both offer hope for precision medicine. Precision medicine is based on a molecular understanding of cancer and specifically uses biomarkers, such as susceptibility alleles, to inform clinical and public health decisions.
1. In a linkage mapping study, data usually are collected for families who have an excess of family members with the disease in question. Of the following four choices, the best types of families for such a study when mapping a common cancer are families in which:
A A large number family members of all ages have a variety of forms of the disease.
B A small number of family members are affected, but they all have the same clinical presentation of varying ages.
C A small number of affected people have the same clinical presentation and unaffected family members also are available for sampling.
D A large number of affected individuals have various forms of the disease, but the unaffected persons available for sample are all of an older age.
2. In performing a genome-wide association study for the genetic disorder picklesilliosis, a single-nucleotide polymorphism (SNP) was found that is both closely linked to the disease and is clearly within a gene promoter. Is it likely to be the causative SNP?
A Yes, given its association and its position in a promoter, its functional significance is highly likely.
B No, because until you perform some functional study and examine the surrounding highly associated SNPs, you cannot say it is a causative SNP.
C It depends on what else is in the linkage disequilibrium (LD) block in which the SNP lies. If there are no other SNPs you recognize as causative, then it must be the causative SNP.
D It has to be the causative SNP if it is in a highly conserved region of the genome.
3. The key differences between genetic and physical maps are:
A A genetic map measures distance in recombination, whereas a physical map measures it in base pairs.
B Because recombination differs across the genome, the number of centimorgans that corresponds to Mb may not be 1 : 1.
C Physical maps take advantage of random breakage of chromosomes by an external agent, such as radiation rather than recombination.
4. Is LD mapping more useful when working in an inbred or an outbred population?
A It is most useful when working in an inbred population because then a smaller number of SNPs can be used to fully interrogate the genome, as each SNP marks a large piece of DNA.
B It is most useful when working in an outbred population because each person who is associated in a given region will share a small region of commonality that can then be reduced by looking at large numbers of persons and seeing where sharing stops.
C It is never really useful, because the number of SNPs available today is so great no one pays attention to LD any more.
5. Will all frame-shift mutations for a given gene have the same penetrance?
A Yes; if you knock out a given gene like BRCA, it will kill the protein and have the same age-dependent pattern of penetrance no matter what.
B No; sometimes proteins can be partially functional even when part of the protein is missing.
C No; genetic background can make a difference in penetrance. The same BRCA1 mutations are differentially penetrant in distinct populations.
6. If a parent gets tested for a mutation associated with an early to middle age onset disease in women, such as breast cancer (BRCA1 and BRCA2), and finds out she is positive, what obligation does she have to her children? Recall that even knockout BRCA1 and BRCA2 mutations are not fully penetrant (range 60% to 88%).
A For breast cancer they absolutely should tell their daughters, but it’s not such a big deal for their sons.
B Because both genes are autosomal, they have an equal responsibility to tell all their offspring. Children have a right to know if they are at risk for a lethal disease.
C One eighth of women get breast cancer at some point in their life, and thus parents should not burden their children with information about a disease they may get anyway, regardless of their genetics, or may not get, even if they carry the mutation.
D They should see a genetic counselor and let the counselor decide.
1. Answer: C. Information from unaffected family members can help establish linkage by giving phase information, but it is most important to have homogeneity and clinical clarity regarding disease presentations among affected persons.
2. Answer: B. Several criteria are required to establish causality, including functional assays, examination of other SNPs, and evolutionary conservation.
3. Answer: D. All of the answers are true.
4. Answer: D. Depending on where you are in an a genetic study and what your starting population was, LD can play different roles and roles of greater or lesser importance. In an inbred population with a single founder responsible for a disease, LD can be useful to reduce the initial region of association. In an outbred population with many founders, it can help establish whose disease is and is not associated with the marker SNP.
5. Answer: E. Genetic background makes a difference; for instance, in the Ashkenazi Jewish population, common BRCA1 mutations do not appear to be 88% penetrant because they were in the families in which the disease was originally described, which likely reflects differences in genetic background of the two data sets. Also, some mutations in BRCA2 close to the terminus of the protein, although producing a truncated protein, are not associated with disease.
6. Answer: E. Individual families must make choices depending on their beliefs, family dynamics, and a host of other factors. Although intuitively it would seem that parents would want to inform daughters that they might carry the mutations because it can cause breast cancer early in life, many persons are adamant about not wanting to know their genetic risk regarding a host of diseases. Some women would consider it a lifelong burden to know they might be a carrier, and that is information they would rather not have as a young woman.
