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

Pharmacogenomics and Laboratory Medicine
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FAP, accounting for about 1% of all CRC cases (Lipton and Tomlinson 2006),
is an autosomal-dominant colon cancer predisposition syndrome, characterized by
hundreds to thousands of adenomatous polyps in the internal lining of the colon
and rectum. Individuals affected with classic FAP may begin to develop multiple
noncancerous colonic polyps (benign polyps) as early as their teenage years, and the
number of polyps tends to increase with age (Petersen et al. 1991). However, colon
cancer is inevitable without colectomy, and the average age of colon cancer diagnosis
in untreated individuals is at 35–40 years of age (Pedace et al. 2008). FAP and attenuated
familial adenomatous polyposis (AFAP) are caused by germline mutations in
the adenomatous polyposis coli (APC) gene located at chromosome 5. Mutations in
the APC gene can be detected in the peripheral blood of about 80–90% of families
with FAP. The missense mutation p.I1307K of APC gene is a moderate risk mutation
found in the subjects of AJ descent. The hypothesis is that this mutation does
not directly cause colon cancer but creates a weak spot in the gene that renders more
susceptibility to additional genetic changes leading to colon cancer. Family members
of the patient with the clinical syndrome of FAP should undergo clinical screening.
Variants of FAP are Gardner syndrome, Turcot syndrome, and AFAP.
The Cadherin-1 (CDH1) gene that encodes a calcium-dependent cell–cell adhesion
glycoprotein belongs to the cadherin superfamily. Loss of function of the CDH1
gene is associated with cancer progression by increasing proliferation, invasion, and/
or metastasis. Mutations in the CDH1 gene are associated with several types of cancer,
including gastric, breast, colorectal, thyroid, and ovarian. CDH1 germline mutations
have been associated with HDGC and lobular breast cancer in women. The
estimated cumulative risk of gastric cancer for CDH1 mutation carriers by the age
of 80 is 67% for men and 83% for women (Pharoah et al. 2001). HDGC patients
typically present with diffuse-type gastric cancer with signet ring cells diffusely
infiltrating the wall of the stomach and, at late stage, linitis plastica. An elevated risk
of lobular breast cancer is also associated with HDGC, with an estimated lifetime
breast cancer risk of 39–52% (Guilford et al. 2010).
Mutations in the TP53 tumor suppressor gene cause LFS and Li–Fraumeni-like
syndrome. An individual harboring a TP53 mutation has a 50% risk of developing
cancer by the age of 30 and a lifetime cancer risk of up to 90% (Hwang et al.
2003). The most common tumor types observed in LFS/LFL families include osteosarcoma,
soft tissue sarcoma, breast cancer, brain tumor, and adrenocortical carcinoma.
Several other types of cancer, including renal cell carcinoma (RCC) and
pancreatic cancer, also occur frequently in individuals with LFS (Birch et al. 1994;
Gonzalez et al. 2009; Olivier et al. 2003).
Molecular genetic testing can be performed for patients for germline mutations in
APC gene or MMR genes if clinically indicated. Multiplex testing by NGS is also an
option for testing patients at increased risk for CRC. For example, Ambry Genetics
(www.ambrygen.com) utilizes NGS to offer a genetic testing panel for CRC (named
ColoNext). Genes on this ColoNext panel include APC, BMPR1A, CDH1, CHEK2,
EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53.
Full gene sequencing and analysis of all coding domains plus at least 5 bases into
the 5′- and 3′-ends of all the introns, 5′-UTR and 3′-UTR are performed for 13 of the
14 genes (excluding EPCAM). Gross deletion/duplication analysis is performed for