Biology Reference
In-Depth Information
hypersensitivity of HNSCC cell lines.
193
Other data do
not support a link of FA/BRCA defects with cisplatin
sensitivity in HNSCC cell lines, and evidence for a loss
of BRCA1 function in human tumors is still lacking.
179,194
One clue regarding the potential presence of FA/
BRCA defects in human HNSCC may come from the
observation that HNSCC seen in FA patients can be
frequently associated with human papillomavirus
(HPV), at least in North America.
195
In addition, based
on recent mouse modeling it has been hypothesized
that the FA pathway may attenuate the oncogenic effects
of the HPV16 E7 protein.
196
Interestingly, about 20% of
sporadic HNSCC are associated with HPV, suggesting
that a search for FA/BRCA defects in this subpopulation
of patients could prove successful.
a recent study, HRR defects measured by an impaired
cellular ability to form damage-induced RAD51 foci
were detected in ~20% of NSCLC cell lines and human
tumor samples.
183
Reduced expression of the ERCC1
gene has been reported in patients with NSCLC (as
well as other cancers) (reviewed in
184
). ERCC1 together
with XPF forms a structure-specific endonuclease that
functions not only in NER of intrastrand adducts but
also in the repair of ICL where its activity is linked to
the FA pathway and HRR (reviewed in
185
).
HRR may also be disrupted by genetic or epigenetic
alterations in upstream regulators, although in such
cases, additional DNA repair and damage checkpoint
responses may be affected. To this end, in a large
sequencing study on 188 lung adenocarcinomas, 13
tumors with 14
ATM
mutations were detected (7%).
186
These mutations were non-recurrent and comprised
mostly missense mutations spanning about 75% of
the protein length. Whether all of these mutations are
functionally significant remains to be shown. Known
mechanisms of functional impairment include haploin-
sufficiency, especially when the mutation is located in
the PI3K domain, and dominant-negative effects.
187
Conceivably, effects may be variable and could include
impairment of HRR, checkpoint responses, or/and other
ATM-dependent repair functions. At least one report
suggests that a NSCLC-associated
ATM
mutation is
linked to a functional HRR defect.
183
ATR kinase is also
involved in the regulation of HRR and ATR inactivation
leads to compromisedHRR.
56
An
ATR
mutation has been
found associated with severe HRR defect in one NSCLC
cell line.
183
Lastly, expression of MDC1 protein, which
promotes HRR,
188
was reduced or absent in 28% of
lung cancers,
189
but whether reduced MDC1 expression
might overlap with downregulation of other HRR
components is unknown. Conceivably, tumors may
epigenetically downregulate more than one pathway
component to ensure robust pathway inactivation.
Overall, the available data suggest that up to 20
e
25%
of NSCLC may harbor genetic or epigenetic HRR
defects.
Other Cancers
Defects in the FA/BRCA pathway as well as
ATM defects have been described in a variety of other
malignancies, for example in prostatic adenocarcinoma,
colorectal cancer, leukemia, lymphoma, and med-
ulloblastoma.
197
e
201
With regard to defects of HRR
proteins in human cancers, point mutations in
conserved regions of the
hRAD54
and
RAD54B
genes
have been found in lymphoma and colon cancer, but
the functional consequences of these mutations on
gene function and their causal relationship to the tumor
phenotype are not established.
202,203
Mutations in other
RAD51 paralogs or RAD51 itself have generally not been
identified. It is likely that a loss of RAD51 function
would be too severe and not compatible with cell
growth and tumor progression. However, recently
RAD51C
germ line mutations were linked to inherited
breast and ovarian cancer,
134
raising the possibility that
RAD51C and perhaps other RAD51 paralogs might
also be inactivated in sporadic cancers, which will be
an important focus of future studies.
Overall, the emerging picture indicates that while
mutations in HRR genes or upstream regulators and
mediators are observed in familial cancers, these muta-
tions are generally not or only rarely detected in
sporadic cancers. A caveat is that there appears to exist
a large number of HRR proteins (perhaps
Head and Neck Squamous Cell Carcinoma
(HNSCC)
Because of the high incidence of HNSCC in FA
patients,
190
there has been interest in trying to identify
defects in the FA/BRCA pathway in sporadic HNSCC.
However, there exist only limited data to date.
179,191
Whether hypermethylation of the
FANCF
promoter is
a common alteration in sporadic cancers has been contro-
versial.
179,192
Furthermore, there is no clear evidence
that loss of FANCF function is specifically associated
with impaired HRR, although it does lead to crosslinker
sensitivity. It has been suggested that reduced BRCA1
function may
200) most of
which remain to be identified and characterized, so that
additional mutations or deletions may still be found.
204
Alternatively, HRR may be compromised by epigenetic
or other mechanisms in sporadic tumors (see below).
>
Alternative Mechanisms of HRR Impairment
In addition to genetic mutation and epigenetic
silencing, as reviewed above, additional mechanisms
of HRR impairment may be present in tumors. Three
of these are summarized below.
First, there are numerous studies on the association of
single nucleotide polymorphisms in known HRR genes
underlie
the
observed
cisplatin
