LWBK1006-03 LWW-Govindan-Review November 24, 2011 11:19
Chapter 3•Etiology of Cancer Part 1 47damage persists, the cells remain in an irreversible G1 arrest or undergo
apoptosis. Mutations in p53 are found in the majority of sporadic cancers,
and it is hypothesized that p53 function may be compromised in some way
in all cancers. p53 mutations are the cause of Li–Fraumeni syndrome. The
most common cancers found in patients with Li–Fraumeni are sarcomas,
breast cancer, and brain tumors.Answer 3.17. The answer is B.
Hereditary cancer syndromes more commonly occur as a result of muta-
tions that result in loss of function. Thus, Li–Fraumeni syndrome,
HNPCC syndrome, FAP, BRCA1, and BRCA2 are caused by mutations
that result in the loss of function of the gene. It is hypothesized that
most oncogenic gain-of-function mutations are incompatible with embry-
onic development, explaining their rarity in hereditary cancer syndromes.
Examples of hereditary cancer syndromes resulting from gain-of-function
mutations are multiple endocrine neoplasia type 2, which results from
mutations of the receptor tyrosine kinase RET; hereditary papillary renal
cancer resulting from mutations in theMETgene; and hereditary gastroin-
testinal stromal tumor resulting from mutations in theKITgene. Muta-
tions in genes that regulate angiogenesis may also lead to hereditary cancer
syndromes. VHL is a genetic disorder that results from loss-of-function
mutation of theVHLgene leading to increased expression of angiogenic
factors. Hereditary leiomyomatosis and renal cancer is another familial
cancer syndrome that might result from genes affecting angiogenesis.Answer 3.18. The answer is A.
VHLgene encodes a ubiquitin ligase to target HIF 1and HIF 2
for degradation under normoxic conditions. In hypoxic conditions, the
expression of VHL is downregulated, resulting in accumulation of HIF
1 and HIF 2, which act as transcription factors, and the expression of
angiogenic factors, such as vascular endothelial growth factor, is upreg-
ulated. In VHL syndrome, mutations in theVHLgene result in loss of
function of the VHL protein, resulting in accumulation of HIF 1and
HIF 2even under normoxic conditions. Individuals with VHL syndrome
have an increased risk of developing renal cysts, renal cancer, and heman-
gioblastomas of the central nervous system. VHL function is also altered
in 70% to 80% of the clear cell renal carcinomas.Answer 3.19. The answer is B.
PTEN operates as a haploinsufficient tumor suppressor to oppose tumor
initiation. Cancer can develop in individuals with loss of one PTEN allele
resulting in cellular proliferation and survival advantages. However, com-
plete PTEN loss is detrimental to the cancer cell because it triggers a “cel-
lular senescence” response. This cellular senescence response to complete
loss of PTEN is being evaluated for cancer chemoprevention and therapy.
Many tumor suppressor genes have been found to be haploinsufficient for
specific functions. The PTEN paradigm also highlights the importance of
subtle incremental variations in the expression levels of tumor suppressor