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

128 Applying Pharmacogenomics in Therapeutics
position 4039 is replaced by thymine (T), resulting in replacement of the amino
acid lysine (K) at position 1347 by a premature stop codon (TAA). Figure 5.2a
shows Sanger sequencing results and Figure 5.2b shows the same mutation by
NGS. Please note that Sanger sequencing at the mutation position exhibits a mixed
peak of G and T, whereas NGS can exhibit each read. The Sanger sequencing
result is for the sense strand, whereas NGS displays the result for the antisense
strand to better reflect that the BRCA1 gene is oriented toward the centromere of
chromosome 17. Figure 5.3c shows the CMA result for a different female patient
diagnosed with LCIS at the age of 43. This patient carries a heterozygous germline
gross deletion, including coding exons 5–9. Both patients are diagnosed with
HBOC syndrome.
Similar to breast cancer, CRC can also be caused by a hereditary syndrome. CRC
is the third most commonly diagnosed cancer in both men and women, and the
second leading cause of cancer-related deaths when combined, affecting about 1
in 20 (5.1%) of men and women in their lifetime (NCI 2015). The NCI estimates
that approximately 96,830 (colon) and 40,000 (rectum) new cases will be diagnosed,
and that 50,310 CRC deaths will occur in the United States in 2014. Most colon and
rectal cancers (over 95%) are adenocarcinoma. There are some other, more rare,
types of tumors of the colon and rectum. Although the majority of CRC are sporadic,
it is estimated that at least 30% of CRC are familial, a subset of which are
caused by hereditary cancer syndromes (Hampel 2009), including Lynch syndrome
(also known as hereditary nonpolyposis colorectal cancer, HNPCC), familial adenomatous
polyposis (FAP), MUTYH-associated polyposis, PTEN-Related disorders,
CHEK2-related cancers, HDGC, Li–Fraumeni syndrome (LFS), Peutz–Jegher syndrome,
and juvenile polyposis syndrome.
Lynch syndrome, named after Dr. Henry Lynch (Lynch et al. 1966), is an
autosomal-dominant inherited syndrome, accounting for 2–5% of all colon cancer
and 2% of uterine cancer. Familial history is the second most common risk factor
for CRC. Lynch syndrome is caused by mutations in mismatch repair (MMR) genes,
including EPCAM, MLH1, MSH2, MSH6, and PMS2. Mutations in MLH1 and
MSH2 account for more than 95% of Lynch syndrome. In addition to a significantly
increased risk for colon cancer (60–80% lifetime risk), Lynch syndrome is associated
with other cancers, including uterine/endometrial cancer (20–60% lifetime
risk in women), stomach cancer (11–19% lifetime risk), and ovarian cancer (4–13%
lifetime risk in women). Risks for cancers of the small intestine, hepatobiliary tract,
upper urinary tract, and brain are also elevated (Bonadona et al. 2011; Capelle et al.
2010; Engel et al. 2012; Hegde and Roa 2009; Win et al. 2012). Dependent on the
mutations in the MMR genes, the age incidence and spectrum of cancer in Lynch
syndrome vary significantly. Individuals with Lynch syndrome have a higher risk
of developing CRC, usually before the age of 50. The diagnosis of Lynch syndrome
can be made by molecular genetic testing for germline mutations in the MMR genes
or by the Amsterdam clinical criteria. The revised Amsterdam criteria (must meet
all of them) include three or more relatives with a histologically verified Lynch syndrome
(HNPCC)–related cancer, and one of whom is a first-degree relative of the
two others; and two successively affected generations, and one or more Lynch syndrome
(HNPCC)–related cancers diagnosed before the age of 50.