Invasive breast carcinoma - IARC

family cancer database {715}, a slightly
higher risk of 1.93 (1.52-2.42) in mothers
of invasive cervical cancer cases and
2.39 (1.59-3.46) in sisters. Unlike many
other cancers, there did not appear to be
a significant effect of age at diagnosis in
familial risk of cervical cancer, although
the risks to mothers did depend on the
number of affected daughters. In this
s t u d y, significant familial aggre g a t i o n
was also found for in situ carcinoma of
the cervix (FRR 1.79, (1.75-1.84).
Multiple cancer sites
In most but not all studies, a familial
association between cancers of the
breast and ovary have been found, particularly
when the breast cancer cases
have been diagnosed at a young age.
Undoubtedly, the majority of the association
between breast and ovarian cancer
detected in these population studies is
due to the BRCA1 gene, which is known
to be involved in a large proportion of
extended kindreds with clearly inherited
susceptibility to breast and ovarian cancer.
It is likely that some of the discrepant
results are linked to the frequency of
BRCA1 deleterious alleles in the respective
populations in these studies.
For breast cancer, the most consistent
finding has been a small (FRR/SIR ~ 1.2)
but highly significant familial association
with prostate cancer. Other sites found to
be associated in at least two studies with
breast cancer in the familial context have
been thyroid cancer and other endocrine-related
tumours.
For endometrial cancer, there is a familial
association with colorectal cancer which
is consistently found in a number of studies
with statistically significant OR/SIRs
ranging from from 1.3 to 1.9. Some, but
not all studies have also reported associations
with ovarian cancer, particularly
among relatives of younger patients.
The strongest and most consistent familial
association between cervical and
other sites is for lung cancer with statistically
significant SIRs of 1.8 and 1.64
found in the Swedish FCDB and the Utah
UPDB, respectively. Other cancers with
possible associations in both studies are
Table 8.01
Specific inherited syndromes involving cancers of the breast and female genital organs.
Syndrome MIM Gene Location Associated sites / tumours
BRCA1 syndrome 113705 BRCA1 17q Breast, ovary, colon, liver,
endometrium, cervix,
fallopian tube, peritoneum
BRCA2 syndrome 600185 BRCA2 13q Breast (female and male), ovary, fallopian
tube, prostate, pancreas, gallbladder,
stomach, melanoma
Li-Fraumeni 151623 TP53 17p Breast, sarcoma, brain,
adrenal, leukaemia
Cowden 158350 PTEN 10q Skin, thyroid, breast, cerebellum, colon
HNPCC 114500 MLH1 3p Colon, endometrium, small intestine,
MSH2 2p ovary, ureter/renal pelvis,
MSH6 2p hepatobiliary tract, brain, skin
Muir Torre 158320 MLH1 3p HNPCC sites plus sebaceous glands
MSH2 2p
Peutz-Jeghers 175200 STK11 19p Small intestine, ovary, cervix, testis,
pancreas, breast
Ataxia Telangiectasia 208900 ATM 11q Breast (heterozygotes)
lip/skin (SIR 2.4 and 1.83) and bladder
cancer (SIR=1.6), though the latter was
not statistically significant in the UPDB
study.
In addition to this statistical and observational
evidence for the role of genetic factors
in the development of these cancers,
a number of specific genes have been
identified. Of these, the most important in
terms of both risk and frequency are the
breast cancer susceptibility loci BRCA1
and BRCA2, and the mismatch repair
genes MSH2, MLH1, and MSH6 in the
context of the hereditary non-polyposis
colorectal cancer (HNPCC).
Search for additional genes
While some of the familial clustering may
be due to shared environmental factors,
it seems likely that a number of additional
loci remain to be identified for cancers of
the breast and female genital tract. Some
studies have shown that only about onefifth
of the familial aggregation of breast
cancer is attributable to the BRCA1 and
BRCA2 genes {107,592,2230} and that
these genes only explain less than half of
all high risk site-specific breast cancer
families {898,2631}. Whether the remaining
familial aggregation is due to additional
moderate to high risk loci or to the
combined effects of a number of more
common, but lower risk, susceptibility
alleles is unknown {2236}. In contrast, it
appears that almost all of the familial
clustering in ovarian cancer can be
ascribed to the effects of the BRCA1/2
and HNPCC loci {2802}. Although no
systematic studies have been done for
endometrial cancer, it is also likely that
the HNPCC loci account for a substantial
fraction of familial aggregation in this
cancer as well.
Familial aggregation of cancers of the breast and female genital organs 337