MOLECULAR GENETICS OF BREAST AND OVARIAN
CANCER: RECENT ADVANCES AND CLINICAL IMPLICATIONS
Bogdanova N1,2, Dörk T2,*
*Corresponding Author: Thilo Dörk, Ph.D., Hannover Medical School, Gynaecology Research Unit (OE
6411), Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; Tel.: +49-511-532-6075; Fax: +49-511-532-
6081; E-mail: doerk.thilo@mh-hannover.de
page: 75
|
|
REVIEW
Epidemiological and genetic linkage studies
of mul-tiple-case families have guided the
identification of BRCA1 and BRCA2 as the first genes
in which mutations strongly predispose to breast
and ovarian cancer. However, hereditary breast and
ovarian cancer (HBOC) syndrome only represents the extreme end of a wide spectrum of genetically
influenced breast or ovarian carcinomas. During
the last few years, evidence has been accumulated
that several susceptibility genes exist [1-3]. Their
mutations have differential impact according to
the minor allele frequencies and the magnitude
of the allelic effect. We briefly summarize our
present knowledge about breast and ovarian cancer
susceptibility genes and discuss their implications
for risk prediction and therapy.
Rare Mutations With a High-to-Moderate
Penetrance. BRCA1 and BRCA2: The prototypic
BRCA1 and BRCA2 mutations confer a very
high lifetime risk for breast cancer in the range
of 55.0-85.0% for BRCA1 and 35.0-60.0% for
BRCA2, compared with an about 10.0% general
population risk. Mutations are usually truncating,
although pathogenic missense mutations have also
been described. Lifetime risk for ovarian cancer
is also high and may be up to 40.0% for BRCA1
mutation carriers. There seems to be allele-specific
expressivity as some of the mutations appear to
confer higher risks for ovarian cancer than others
[4-6]. Both the risks for breast and ovarian cancer
can also be modified by additional gene loci such as
single nucleotide polymorphisms (SNPs) in RAD51
or BNC2 [7,8] (see below).
The PALB2 Mutation. Subsequently, PALB2
has been identified as a breast cancer susceptibility
gene [9, 10]. The PALB2 protein bridges BRCA1 and BRCA2 and synergizes in their function in
recombinational DNA repair. Mutations in PALB2
predispose to breast cancer and gastric cancer, and
the penetrance for breast cancer in Finnish multiplecase
families has been found to be as high as for
BRCA2 mutations [11]. There is less evidence that
PALB2 mutations may also constitute ovarian cancer
susceptibility alleles. Although PALB2 founder
mutations have been identified in ovarian cancer
patients from Poland and Russia, they are still rare
in these populations [12,13].
The RAD51 Paralogs. Downstream of BRCA1,
BRCA2 and PALB2, the RAD51 protein is a key
mediator of homologous recombination, and a
regulatory variant c.–98G>C (also known as135G>C)
in RAD51 acts as a genetic modifier of BRCA2
mutations [7]. Mutation analyses in further genes
of RAD51 paralogs have subsequently uncovered
RAD51C and RAD51D as susceptibility genes
for breast and ovarian cancer [14-16]. The initial
data indicate that these mutations are specifically
associated with a family history of ovarian cancer.
However, mutations in RAD51C and RAD51D are
collectively very rare and their penetrance and tumor
spectrum remains to be fully explored.
Additional Fanconi Anemia Genes. Since
some breast and ovarian cancer susceptibility alleles,
e.g., in BRCA2, PALB2 or RAD51C, cause Fanconi
anemia (FA) in the homozygous state, it seemed
reasonable to assess further FA genes for their role
in breast and ovarian cancer. So far, mutations of the
BRIP1 gene have been associated with breast cancer
[17], although their precise risk estimates await
further studies. There is no evidence implicating the
FA core proteins in breast cancer, suggesting that
proteins at the heart of the downstream homologous
recombination machinery are the major factors for
breast and ovarian cancer susceptibility.
Familial Lobular Breast Cancer. Familial
lobular breast cancer has been associated with
rare germ-line mutations in CDH1, the gene for
E-cadherin [18,19]. While mutations in CDH1 are
also causative for diffuse gastric cancer, there is no
evidence to implicate CDH1 in ovarian cancer yet.
Rare Syndromes Including Breast Cancer.
Some rare syndromes include the occurrence of
breast cancer as part of the disease spectrum. These
include Li-Fraumeni (TP53), Muir-Torre Syndrome
(MSH2), Cowden’s Disease (PTEN), Peutz-Jeghers Syndrome (LKB1), and Ataxia-telangiectasia (ATM,
see below). Although these syndromes are generally
rare, they need to be kept in mind if a breast cancer
patient presents with a more complex disorder or
family history.
Ataxia-Telangiectasia. Twenty-five years ago,
it was shown that blood relatives of patients with the
neurode-generative disorder ataxia-telangiectasia
(A-T) face an increased breast cancer risk [20].
The gene mutated in ataxia-telangiectasia, ATM,
encodes a master protein kinase that orchestrates the
cellular response to DNA double-strand breaks and
controls, via phosphorylation, hundreds of proteins
involved in cell cycle control, repair and apoptosis,
among them BRCA1, BRCA2, TP53, CHEK2 and
many other tumor suppressors [21]. Truncating
mutations in ATM appear to confer an about 3-fold
increased breast cancer risk to heterozygous carriers
[22-24]. While the homozygous condition of A-T is
rare, heterozygotes may account for 0.5-1.0% of the
population.
MRE11A/RAD50/NBN. Chromosome breaks
are sensed and the ATM protein is activated via the
MRN complex consisting of the proteins MRE11A,
RAD50, and NBN. The NBN gene underlies
Nijmegen Breakage Syndrome (NBS), which is
most prevalent in Eastern Europe due to a Slavic
founder mutation. While biallelic mutations cause
NBS, heterozygous carriers face an about 3-5 fold
increased breast cancer risk [25-27]. Similarly,
biallelic mutations in RAD50 give rise to a NBSlike
disorder, whereas heterozygotes for a Finnish
founder mutation are predisposed towards breast
cancer [28]. MRE11A also is a gene for an A-Tlike
disorder, although there has been only one
study to associate MRE11A mutations with breast
cancer so far [29]. None of the three genes have
been extensively investigated in ovarian cancer, but
germ-line mutations in any of them were identified
in a recent large sequencing study [30].
CHEK2. Checkpoint kinase 2 is a major target
of ATM and itself phosphorylates further tumor
suppressor proteins, including p53 and BRCA1, in
response to DNA damage [31]. CHEK2 had initially
been found mutated in Li-Fraumeni patients and
one of these mutations, 1100 delC, has subsequently
been associated with familial breast cancer [32,33].
Heterozygous carriers for 1100delC have been
reported with a 2- to 3-fold increase in breast cancer risk [34], with rare homozygotes being found at
much higher risk [35]. In Eastern Europe, two
further truncating mutations IVS-II-1 (G>A) and
CHEK2dele9,10 (5 kb) have been associated with at
least similarly high breast cancer risks, whereas the
missense mutation p.I157T has a lower penetrance
[25,36,37]. There has not been conclusive evidence
for a strong association of CHEK2 mutations with
ovarian cancer, but their association with additional
malignancies suggests a more general role in cancer
predisposition [38].
Polymorphic Variants With Low Penetrance.
Several polymorphic loci are known today that
influence the risk of breast and/or ovarian cancer.
This has been achieved through genome-wide
association studies (GWAS) of SNPs by large
consortia during the past 5 years. The published
GWAS efforts have so far uncovered over 20
genomic loci for breast cancer [39-45] and six
loci for serous epithelial ovarian cancer [46-48] at
a genome-wide significance level. All these loci
harbor low-penetrance alleles with allelic odds ratios
of less than 1.5. As these loci still explain only a
small part of the heritable fraction and further largescale
studies are presently underway, it is likely that
these numbers will increase very rapidly. Most of
the hitherto identified loci appear to be specific for
either breast or ovarian carcinomas. For example, the
gene for fibroblast growth factor receptor 2, FGFR2
[39], harbors variants associated with breast but
not ovarian cancer, and the gene for basonuclin-2,
BNC2 [46], harbors variants associated with ovarian
but not breast cancer. Nevertheless, there is a minor
group of shared loci that appear to influence both
breast and ovarian cancer risk. Such genes include
BABAM1 (encoding a BRCA1 binding partner
also known as MERIT40), TERT (encoding a
component of telomerase), and the protooncogene
MYC on chromosome 8q24. Interestingly, a closer
inspection of the 8q24 locus indicated that the
associations with either breast or ovarian cancer
were caused by independent variants at the same
locus which may be explained by tissue-specific
regulation of gene expression [49]. As a caveat, a
GWAS roughly localizes but does not identify the
causal variant, and in several cases, there is more
than one candidate gene in the region spanned by
the associated linkage disequilibrium block or
under putative regulatory control of the identified locus. Fine-mapping approaches in different
ethnic populations and gene expression studies are
presently being used to further trace down the true
predisposing gene variants. Copy number variants
have also been investigated in a GWAS but this
did not detect a significant association for breast
cancer [50].
Implications for Risk Prediction and Therapy.
The identification of mutations in individuals from
families with HBOC makes it possible to predict
the age-dependent risk for different cancers,
including recurrence risks in the already affected,
and to appropriately counsel the patient and her
blood relatives. This may lead to an increased
surveillance or targeted prevention including
medication (such as tamoxifen) or preventive
surgery (such as prophylactic oophorectomy). In
many countries, this is available to patients with an
over 35.0% lifetime risk such as BRCA1 or BRCA2,
and possibly PALB2 mutation carriers, whereas a
more restrained position is taken for patients with
moderate-penetrance mutations conferring an about
3-fold increase in breast cancer risk such as ATM
or CHEK2. Although it might also be suggested
that for these mutations, the female carriers should
benefit from increased surveillance, large studies
on the efficacy of such measures are still lacking.
No further consequences are considered for patients
carrying common risk alleles at polymorphic loci, as
these risks are too small individually to be clinically
meaningful. With the identification of many more
low-risk loci, however, it may become possible to
calculate combinatorial risks that could be useful
in a stratified approach for cancer prevention in the
future [51,52].
Identifying the genetic basis of breast or
ovarian cancer in the individual patient might have
further prognostic and therapeutic implications. For
a long time, breast cancer therapy has been guided
by the presence or absence of gene products such
as hormone receptors or HER2/neu. Such gene
expression profiles are partly determined by germline
mutations such as BRCA1 mutations which are
frequently associated with triple-negative breast
cancers [53], but breast cancer pathology also
seems to be influenced by low-penetrance variants
such as in FGFR2, which is strongly associated with
estrogen-receptor positive disease [54]. Studies are
presently underway to investigate whether SNP profiling could thus be of prognostic value, and
there are new drugs being developed that target
additional breast cancer pathways such as those
mediated by fibroblast growth factor receptors [55].
Recent reports further indicate that the outcome of
ovarian cancer therapy is significantly influenced
by the BRCA1/BRCA2 mutational status. In these
multi-center studies, mutation carriers showed an
improved survival, probably due to a higher benefit
from the usually applied platinum-based therapy
that activates a DNA repair pathway defective in
BRCA1 or BRCA2 deficient tumors [56]. Another
recent approach to improve targeted therapy is
based on the concept of “synthetic lethality”
as exemplified by the introduction of PARP1
inhibitors into breast and ovarian cancer treatment
of patients with BRCA1 or BRCA2 mutations, and
probably beyond [57]. Here, the idea is to inhibit
a repair pathway that can still be compensated
by backup pathways in normal but not tumor
cells. The apparent success of this concept has
stimulated the targeting of other repair pathways
in parallel to those known to be defective in breast
or ovarian carcinomas. For example, inhibition of
ATR, which is a backup kinase of ATM, has been
reported to be particularly effective in tumors with
TP53 or ATM mutations [58]. Though promising,
such substances still need further development
until they can be tested in clinical practice. It is
the hope that with many more genes identified, a
deeper understanding of breast and ovarian cancer
development and progression, together with the
ability of gene-based stratification, will ultimately
lead to an improved and individually tailored
therapy for the benefit of each patient.
|
|
|
|
 |
Number 27
VOL. 27 (2), 2024 |
Number 27
VOL. 27 (1), 2024 |
Number 26
Number 26 VOL. 26(2), 2023 All in one |
Number 26
VOL. 26(2), 2023 |
Number 26
VOL. 26, 2023 Supplement |
Number 26
VOL. 26(1), 2023 |
Number 25
VOL. 25(2), 2022 |
Number 25
VOL. 25 (1), 2022 |
Number 24
VOL. 24(2), 2021 |
Number 24
VOL. 24(1), 2021 |
Number 23
VOL. 23(2), 2020 |
Number 22
VOL. 22(2), 2019 |
Number 22
VOL. 22(1), 2019 |
Number 22
VOL. 22, 2019 Supplement |
Number 21
VOL. 21(2), 2018 |
Number 21
VOL. 21 (1), 2018 |
Number 21
VOL. 21, 2018 Supplement |
Number 20
VOL. 20 (2), 2017 |
Number 20
VOL. 20 (1), 2017 |
Number 19
VOL. 19 (2), 2016 |
Number 19
VOL. 19 (1), 2016 |
Number 18
VOL. 18 (2), 2015 |
Number 18
VOL. 18 (1), 2015 |
Number 17
VOL. 17 (2), 2014 |
Number 17
VOL. 17 (1), 2014 |
Number 16
VOL. 16 (2), 2013 |
Number 16
VOL. 16 (1), 2013 |
Number 15
VOL. 15 (2), 2012 |
Number 15
VOL. 15, 2012 Supplement |
Number 15
Vol. 15 (1), 2012 |
Number 14
14 - Vol. 14 (2), 2011 |
Number 14
The 9th Balkan Congress of Medical Genetics |
Number 14
14 - Vol. 14 (1), 2011 |
Number 13
Vol. 13 (2), 2010 |
Number 13
Vol.13 (1), 2010 |
Number 12
Vol.12 (2), 2009 |
Number 12
Vol.12 (1), 2009 |
Number 11
Vol.11 (2),2008 |
Number 11
Vol.11 (1),2008 |
Number 10
Vol.10 (2), 2007 |
Number 10
10 (1),2007 |
Number 9
1&2, 2006 |
Number 9
3&4, 2006 |
Number 8
1&2, 2005 |
Number 8
3&4, 2004 |
Number 7
1&2, 2004 |
Number 6
3&4, 2003 |
Number 6
1&2, 2003 |
Number 5
3&4, 2002 |
Number 5
1&2, 2002 |
Number 4
Vol.3 (4), 2000 |
Number 4
Vol.2 (4), 1999 |
Number 4
Vol.1 (4), 1998 |
Number 4
3&4, 2001 |
Number 4
1&2, 2001 |
Number 3
Vol.3 (3), 2000 |
Number 3
Vol.2 (3), 1999 |
Number 3
Vol.1 (3), 1998 |
Number 2
Vol.3(2), 2000 |
Number 2
Vol.1 (2), 1998 |
Number 2
Vol.2 (2), 1999 |
Number 1
Vol.3 (1), 2000 |
Number 1
Vol.2 (1), 1999 |
Number 1
Vol.1 (1), 1998 |
|
|
