Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

124 Applying Pharmacogenomics in Therapeutics
and variants of cancer susceptibility genes and/or loci, including high-penetrance
mutations, intermediate or moderate risk mutations, and low-penetrance variants
(LPVs). High-penetrance mutations usually result in dramatic alteration of the function
of the corresponding gene and are associated with a significantly increased
risk of related cancer. High-penetrance mutations usually result in autosomal-dominant
predispositions recognizable by pedigree analysis. There are also established
medical managements for such high-penetrance mutations. For example, endoscopy
and prophylactic colectomy are usually recommended for high-penetrance mutations
in APC with risk of colorectal adenocarcinoma. Intermediate or moderate
risk mutations refer to those that result in less dramatic increases in cancer risk:
for example, the APC p.I1307K mutation in colon cancer risk and the CHEK2
c.1100delC mutation in breast cancer. Unlike the high frequency of pharmacokinetic
or pharmacodynamic polymorphisms, high-penetrance and moderate-penetrance
mutations are rare or uncommon. Common in the context of cancer risk
testing refers to a frequency of 1% or more, by convention. The third type of variants
refers to LPVs that have been identified by large-scale GWASs. Compared
to the high-penetrance and moderate-penetrance mutations that usually result in
alteration of the function of the corresponding gene product, the LPVs are usually
SNPs that are strongly associated with cancer risk in large case–control studies,
without changes in the function of the relevant gene product. It is hypothesized
that these LPVs are located in close proximity to unidentified causative variants.
LPVs associated with cancer risk are common with allele frequencies as high as up
to 50% in the population studied, but they only confer a modest increase in cancer
risk, usually with per-allele odds ratio of <1.5. The examples of low-penetrance
SNPs include rs10505477 at 8q24 associated with risk for colon cancer and prostate
cancer with lifetime relative risk at 1.27 and 1.43, respectively (Haerian et al. 2014),
rs13281615 at 8q24 with lifetime relative risk at 1.21 for breast cancer (Gong et al.
2013), and rs1219648 at FGFR with lifetime relative risk at 1.23 for breast cancer
(Andersen et al. 2013). Unlike the high-penetrance mutations, the impact of LPVs
on clinical care is not proven, and the clinical validity for the genetic test on PLVs is
uncertain. Therefore, they are not currently considered as part of standard oncology
or preventive care (Robson et al. 2010).
Traditionally, cancer genetic testing is performed for the most likely genetic
causes based on the evaluation of family history and/or personal clinical history
such as disease histology and age at diagnosis. However, cancer susceptibility can
be very complicated because of the fact that a mutation in one particular gene may
increase risk for several types of cancers, or that the risk of one type of cancer may
be elevated by mutations in one of a group of different genes. For example, multiple
studies indicate that mutations in the CHEK2 gene confer an increased risk of developing
many types of cancer, including breast (Nevanlinna and Bartek 2006), prostate,
colon, thyroid, and kidney (Nevanlinna and Bartek 2006). On the other hand,
breast cancer risk can be increased by mutations in a number of different genes,
including BRCA1, BRCA2, ATM, CHEK2, CDH1, NF1, MUTYH, and genes involved
in the Fanconi anemia (FA)–BRCA pathway such as BARD1, BRIP1, MRE11A, NBN,
PALB2, RAD50, and RAD51C. Given this complexity, serial testing is time consuming
and expensive. Simultaneous testing of a panel of multiple cancer susceptibility