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

126 Applying Pharmacogenomics in Therapeutics
Chen and Parmigiani 2007; Ferla et al. 2007; Ford et al. 1998; Janavicius 2010; Tulinius
et al. 2002). Similarly, male carriers of the BRCA1 mutations would have a cumulative
breast cancer risk of 1.2% by age 70 (Tai et al. 2007; Thompson et al. 2002).
Similar studies suggest that female carriers of the BRCA2 mutations would have a
45–84% risk of developing breast cancer, and an 11–18% risk of developing ovarian
cancer (including primary peritoneal and fallopian tube) by the age of 70 (Antoniou
et al. 2003; Chen and Parmigiani 2007; Folkins and Longacre 2013; Ford et al. 1998;
Shannon and Chittenden 2012). Male carriers of the BRCA2 mutations would have up
to a 15% prostate cancer risk, and a cumulative breast cancer risk of 6.8% by the ages
of 65 and 70, respectively (Kote-Jarai et al. 2011; Shannon and Chittenden 2012; Tai
et al. 2007; Thompson et al. 2002). Furthermore, carriers of the BRCA1/2 mutations
are at an increased risk for melanoma and cancer of the pancreas, gallbladder, bile
duct, and stomach. Cancer risks are further modified by family history, reproductive
choices, lifestyle and environmental factors, and other genetic factors.
Similar to other genetic variations in pharmacogenomics, the frequency of
BRCA1/2 mutations also varies across ethnic groups. BRCA1/2 mutations are more
common in individuals of Ashkenazi Jewish (AJ) descent, with a carrier frequency
of 1/40 or 2.6% (Ferla et al. 2007; Janavicius 2010) compared to a frequency of 0.2%
or 1/500 in the non-AJ general population. Three founder mutations, c.68_69delAG
(BIC: 185delAG), c.5266dupC (BIC: 5382insC) in BRCA1 gene, and c.5946delT
(BIC: 6174delT) in BRCA2, account for up to 99% of identified AJ mutations (Ferla
et al. 2007; Janavicius 2010). BRCA1 185delAG has a frequency of 1% and attributes
to 16–20% of breast cancer cases diagnosed before the age of 50; BRCA1 5382insC
with a frequency of 0.13%; and BRCA2 6174delT with a frequency of 1.52% in the
AJ population and attributes to 15% of breast cancer cases diagnosed before the age
of 50 (Ferla et al. 2007; Janavicius 2010).
The major indications for BRCA1/2 testing include a personal or family history
of early-onset breast cancer (aged 45 years) or bilateral breast cancer, two primary
breast cancers or clustering of breast and ovarian cancer, the presence of male breast
cancer, ovarian cancer at any age, or at-risk populations such as AJ descent.
Mutations in BRCA1 and BRCA2 can explain about 25–50% of hereditary breast
cancer (Castera et al. 2014; Easton 1999; van der Groep et al. 2011; Walsh et al.
2010). There are additional genes that have been shown to moderately increase the
risk for breast cancer (Castera et al. 2014; Meindl et al. 2011; van der Groep et al.
2011; Walsh and King 2007; Walsh et al. 2010). These genes include ATM, CHEK2,
CDH1, NF1, MUTYH, and genes involved in the FA-BRCA pathway, such as BARD1,
BRIP1, MRE11A, NBN, PALB2, RAD50, and RAD51C.
Breast cancer susceptibility genetic testing can be performed for BRCA1 and
BRCA2 by traditional Sanger DNA sequencing or for panels of multiple genes,
including those listed above by NGS. Gross deletion or duplication is often disruptive
to a gene function, and this can be detected by concurrent CMA. An example
of breast cancer susceptibility genetic testing results is shown in Figure 5.3a
and b. The female patient was diagnosed as LCIS at age 45, and previous testing
showed that the cancer was triple negative for ER, PR, and HER/neu. Multiplex
testing by NGS revealed that this patient carries a heterozygous germline mutation
p.K1347* (c.4039G>T) in the BRCA1 gene. The nucleotide guanine (G) at coding