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

Pharmacogenomics and Laboratory Medicine
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genes (also known as multiplex testing) by NGS has the advantage of turnaround
time and cost-effectiveness.
It is important to provide appropriate genetic counseling and obtain proper
informed consent in the practice of responsible and effective genetic testing for
patients with possible inherited susceptibility to cancer. The major indications for
genetic counseling and testing include a strong family history of cancer, adequate
interpretation of the testing result, and clinical management of the patient and/or
family member. Genetic counseling should be provided by the qualified specialist
who is credentialed by an appropriate organization, such as the American Board of
Genetic Counseling, Inc. (www.abgc.net). Informed consent should include basic elements,
such as information on the specific test, implication of a positive or negative
test result, possibility that the test will not be informative, options for risk estimation
without genetic testing, risk of passing a mutation or predisposition to children, technical
accuracy of the test, risks of psychological distress, options and limitations of
medical surveillance and screening following the testing, and confidentiality issues.
In addition to possible benefits and risks of cancer’s early detection and medical
management, genetic counseling can also provide information on the possible participation
of research studies and/or cooperative studies or registries.
In the following section, we will discuss examples of genetic test on high- and
moderate-penetrance mutations of genes associated with the increased risk of breast
cancer, CRC, and HDGC.
Breast cancer occurs in both men and women, although it is rare in males. Breast
cancer is the most common cancer in women in developed countries with a lifetime
risk of about 1 in 8 (~12.29%) women. The NCI estimates that there will be approximately
232,670 new cases of female breast cancer and 2360 new cases of male breast
cancer diagnosed in the United States in 2014. *
Risk factors for breast cancer include genetic alterations and other factors, such as
age, gender, reproductive and menstrual history, radiation, alcohol, hormone therapy,
obesity, and benign breast diseases, including atypical ductal hyperplasia (ADH) and
lobular carcinoma in situ (LCIS). Although the majority of breast cancer is sporadic, it
is estimated that about 5–10% of breast cancers are due to a specific genetic cause. An
additional 20–30% of breast cancers are “familial,” which means more breast cancer
found in a family than expected by chance. Compared to sporadic cases, hereditary
breast cancers tend to occur earlier in life and are more likely to involve both breasts.
Germline mutations of the highly penetrant BRCA1 and BRCA2 genes cause
hereditary breast–ovarian cancer (HBOC) syndrome, accounting for approximately
25–50% of hereditary breast cancer cases (Castera et al. 2014; Easton 1999; van der
Groep et al. 2011; Walsh et al. 2010) and about 5–10% of all breast cancers (Campeau
et al. 2008). BRCA1 and BRCA2 are tumor suppressor genes that have an essential
role in both DNA repair and cell-cycle control systems. Mutations in these two highly
penetrant genes would increase the risk for developing cancer of the breast, ovaries
and fallopian tubes, pancreas, and prostate. Studies suggest that female carriers of
BRCA1 mutations would have a 57–87% risk to develop breast cancer, and a 39–40%
risk to develop ovarian cancer by the age of 70 or higher (Antoniou et al. 2003;
* http://www.cancer.gov/cancertopics/types/breast