LWBK1006-14 LWW-Govindan-Review November 24, 2011 11:28
Chapter 14•Genetic Counseling 155ANSWERS
Answer 14.1. The answer is D.
Penetrance may be defined as the proportion of individuals with a mutant
genotype who show any manifestation of the given disorder. A disorder
that is expressed in less than 100% of individuals with the mutant geno-
type is said to have reduced penetrance. For example, if only 60% of
individuals with the genotype express clinical features, the disease is con-
sidered to be 60% penetrant. Expression in hereditary cancer syndromes
occurs when an individual is diagnosed with one of the associated malig-
nancies or associated benign lesions. Almost all cancer syndromes show
reduced penetrance. This concept is important to understand because
many families believe that if a family member has not developed a spe-
cific cancer, he/she cannot pass on the gene mutation to a child.Answer 14.2. The answer is C.
HNPCC syndrome is an autosomal-dominant disease. Calculation of
Diane’s probability to have inherited the gene mutation is based on
straightforward autosomal-dominant inheritance. By assuming that indi-
vidual II-3 has the MSH2gene mutation, the calculated probability
Diane’s father (III-6) has inherited the mutation is 50%. The probability
Diane has inherited it from her father is 50%. Thus, Diane’s calculated
probability to have inherited theMSH2gene mutation is 25% (50%×
50%). Most hereditary cancer syndromes identified to date are inherited
in an autosomal-dominant manner with reduced penetrance. In a clinical
setting, it would be important not to assume that individual II-3 has the
mutation. Although she has been diagnosed with colon cancer, the car-
dinal feature of HNPCC syndrome, individuals may be diagnosed with
an associated cancer type and not have the causal gene mutation. That
is, an individual may develop a sporadic cancer that does not result from
the underlying family gene mutation. If individual II-3 does not have the
MSH2gene mutation, her sporadic colon cancer would be a phenocopy,
a mimic of the syndrome phenotype. II-3’s daughter, who died of breast
cancer at 39 years of age, does not provide any insight as to whether II-3
has the gene mutation. Breast cancer has been reported in some families
with HNPCC; however, an association in larger studies has not consis-
tently been demonstrated.Answer 14.3. The answer is C.
HNPCC syndrome is associated with a 70% to 80% lifetime risk for
colon cancer and a 20% to 60% risk for endometrial cancer. There are
also increased risks for gastric (intestinal type), ovarian, urinary tract,
and central nervous system tumors, with the level of risk varying for
each cancer type. Colonoscopy screening is recommended to begin by
20 to 25 years of age or 10 years before the youngest age of cancer
diagnosis and repeated every 1 to 2 years. Sigmoidoscopy is not rec-
ommended because of the predominance of right-sided colon cancers.