Biology Reference
In-Depth Information
TABLE 7.1 Human Cancer Predisposition Syndromes with Known or Likely HRR Alterationsdcont'd
Syndrome
Mutated gene(s)
Phenotype
Nijmegen Breakage
syndrome (NBS)
NBS1
(bi-allelic mutations)
Cancer:
B/T cell lymphoma
Neurological defects:
Microcephaly
Immunodeficiency
Other:
Facial dysmorphism, growth defects
Seckel syndrome (SS)
ATR, PCTN, SCKL2, SCKL3
(bi-allelic mutations)
Cancer:
Acute myeloid leukaemia ?
Neurological defects:
Microcephaly, mental retardation
Other:
Facial dysmorphism, growth defects
by negative estrogen, progesterone, and HER2 receptor
status (“triple-negative”), and comprise ~15% of all
breast cancers. Interestingly, low BRCA1 expression is
increasingly found in basal-like carcinomas compared
to the other breast cancer classes.
155
e
157
Possibly, other
components of BRCA1-dependent DNA repair will be
downregulated in basal-like cancers with normal
BRCA1 expression, which should be detectable by
gene expression profiling or comparative genome
hybridization screens. Features of BRCA1 deficiency in
sporadic cancers have been coined as “BRCAness”,
which applies mostly to triple-negative cancers.
153
However, whether the putative underlying defect in
the BRCA1 pathway renders at least a fraction of
triple-negative cancers hypersensitive to chemothera-
peutic drugs, such as platinum drugs, doxorubicin, or
other DNA damaging chemotherapeutics, is currently
of considerable interest.
157
However, non-triple-nega-
tive sporadic breast cancers may also harbor HRR
defects. It has been suggested that ~20% of these cancers
are defective in HRR as measured by an impaired ability
to mount RAD51 foci in response to chemotherapy.
158
Altogether, there is emerging evidence that approxi-
mately 10
e
20% of non-familial breast cancers harbor
HRR defects that may be useful targets for therapy.
phenomenon is due to impaired HRR or other cellular
processes that are impaired in FA-deficient cells.
163
e
166
In contrast to sporadic breast cancer, mutations in
BRCA1 and BRCA2 have recently been found in up to
20% of unselected ovarian cancers.
167
Thus, both genetic
and epigenetic mechanisms can create the BRCAness
phenotype as a marker of HRR deficiency in at least
a third of ovarian cancers.
Pancreatic Cancer
Approximately 5
e
10% of pancreatic cancers are due
to an inherited predisposition, and similar to breast
cancer, mutations in BRCA2 or PALB2/FANCN have
been identified in a subset of these patients.
168
e
171
Further, genetic mutations in FA components, such as
FANCC
and
FANCG
, have been identified in pancreatic
cancer cell lines and human tumors.
172
e
174
Importantly,
germ line mutations can seemingly be found in patients
without an obvious family history of pancreatic cancer,
perhaps suggesting low penetrance.
175,176
While it
seems logical to expect that components of the BRCA/
FA pathways are inactivated by somatic mutations or
epigenetic events in truly sporadic pancreatic cancers,
this remains to be established.
Non-Small Cell Lung Cancer (NSCLC)
In NSCLC, reduced expression of FA/BRCA compo-
nents at the mRNA or protein level has been obser-
ved.
177
e
182
For example,
FANCF
and
BRCA1
promoter
hypermethylation was found in 14% and 4% of tumors,
respectively.
179
Interestingly, a history of smoking and
alcohol use was associated with inactivation of the FA/
BRCA pathway. In another report, low BRCA1/2 expres-
sion was found in ~23% of NSCLC.
180
Whether reduced
FA/BRCA expression in any of these studies is associ-
ated with reduced HRR has been poorly studied. In
Ovarian Cancer
Similar to breast cancer, BRCA1 promoter hyperme-
thylation is also found in approximately 5
e
30% of
sporadic ovarian cancers while BRCA2 hypermethyla-
tion is rarely seen.
143,145,159
e
161
Interestingly, in approxi-
mately 10
e
20% of ovarian cancer cell lines and tumors
there was an association between cisplatin sensitivity
and hypermethylation of the FANCF promoter.
162
However, even though FANCF deficiency causes
cisplatin sensitivity,
it
is unclear whether
this
