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1
BORDERLINE OVARIAN TUMORS SHARE FAMILIAL
RISKS WITH ITSELF AND INVASIVE CANCERS
Guoqiao Zheng1,2
, Hongyao Yu1,2
, Anna Kanerva3,4
, Asta Försti1,5
, Kristina Sundquist
5 and Kari Hemminki
1,5
1Division of Molecular Genetic Epidemiology, German Cancer Research Center
(DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany
2 Faculty of Medicine, University of Heidelberg, Heidelberg, Germany
3 Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Finland
4 Deparment of Obstetrics and Gynecology, Helsinki University Hospital, Finland
5 Center for Primary Health Care Research, Lund University, Sweden
Correspondence to: Guoqiao Zheng
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580
69120 Heidelberg, Germany
Phone: +49-6221-421805
Fax: +49-6221-421810
Email: [email protected]
Running title: Borderline ovarian tumors
Key words: familial cancer, in situ cancer, genetic association, familial aggregation,
Swedish Family-Cancer database
Financial support
This work was funded by the German Cancer Aid, the EU Transcan funding by the
German Federal Ministry of Education and Research, and the Swedish Research
Council for Health, Working Life and Welfare (in Swedish: FORTE; Reg. no. 2013-
1836), and FORTE (Reg. no. 2014-0804) and the Swedish Research Council (2012-
2378 and 2014-10134), ALF funding from Region Skåne as well as by the China
Scholarship Council (201606100057, for doctoral student G.Z.).
Conflicts of Interest Statement
All authors declared no conflicts of interest.
Word count: 248 (abstract), 2264 (text), 3 (tables), 1 (figure)
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Abstract
Background: Borderline ovarian tumors (BOTs) are a subgroup of ovarian
malignancies with low malignant potential. Very limited earlier data are available on
familial clustering of BOTs with other cancers. We aim to explore histology-specific
familial associations among BOTs and associations between BOT and any invasive
cancers.
Methods: Based on 16.1 million individuals in the Swedish Family-Cancer Database,
we estimated familial risks for overall or histology-specific BOT patients considering
both BOT and any invasive cancers in first-degree relatives (parents or siblings), as
well as familial risks for invasive cancers considering family history of BOTs.
Results: A total of 4199 BOT cases were found in the offspring generation; among
them, 34 (0.8%) cases had first-degree relatives diagnosed with any BOT, and 2489
(59.3%) cases with any invasive cancers. A family history of BOT was associated
with risks for all BOTs (RR=2.20, p<0.001). Papillary BOT in first-degree relatives
was associated with the increased risk of having the same type of BOT (RR=10.10,
p<0.001). BOTs showed familial associations with some invasive cancers, most
consistently with colorectal, ovarian, pancreatic, lung and bone cancers, and with
leukemia. In histological analyses, associations of BOT with even rare cancers of the
anus, thyroid and endocrine glands were noted.
Conclusions: BOTs may share susceptibility with itself and a number of invasive
cancers.
Impact: These results provide insight into familial associations of BOT for the first
time which may help with the etiologic mechanism and preventive strategy of BOTs
as well as the genetic counseling for BOT patients.
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INTRODUCTION
Borderline ovarian tumors (BOTs) are a subgroup of ovarian malignancies with low
malignant potential (1). The common histological types of BOTs are serous and
mucinous BOT; papillary type has been considered as a distinctive variant of serous
BOTs (2). In the 2014 WHO Classification of Tumours of the Female Genital Organs
the main refinements concerned serous BOT which was described to share molecular
and genetic alterations with low-grade serous carcinomas, specifically for
micropapillary variant of serous BOT (2). BOTs display epithelial proliferation higher
than that seen in benign tissue and variable nuclear atypia. Compared to ovarian
carcinomas, BOTs usually occur in young women, have no destructive stromal
invasion, and have better prognosis (3). However, the treatment for BOT is usually
surgery, which may affect the fertility of women (4).
Risk factors for BOTs are largely similar to those reported for invasive ovarian
tumors, including protective effects of pregnancy and lactation (5,6). However, some
studies on reproductive and hormone‐related factors showed distinct risks between
BOTs and ovarian cancer (7-9). For example, risks for BOTs were less reduced
among women who had used oral contraceptives and more elevated among women
with a history of infertility compared to women with ovarian cancer (7). In agreement
with ovarian cancer, smoking is a risk for mucinous BOT (relative risk 2.25) but not
for serous BOT (10). Pelvic inflammatory disease has been reported as a modest risk
factor (11).
Family history of ovarian cancer is one of the strongest known risk factors for ovarian
cancer (12). Yet family history data on BOTs are sparse. No significant risk was
observed for concordant BOTs, i.e., BOT in two family members; however, an
association of BOT with invasive ovarian cancer was found among sisters but not
among mother-sister pairs (13,14). Very few study reported BOTs are related to
germline mutations in BRCA1/2 (15,16), MSH2 (15), CHEK2 (17). Low-risk genetic
loci were described for serous BOT alone or in combination with serous low-grade
ovarian cancer in a large genome-wide association study (GWAS) (18). We examine
here familial risks for BOT patients considering both BOT and any invasive cancers
in family members based on the nation-wide Swedish Family-Cancer Database, the
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largest dataset of its kind in the world, in order to resolve whether BOT share familial
risk with itself and invasive cancers.
METHODS
Swedish Family-Cancer Database (FCD) includes all Swedish people born since 1932
(offspring generation) with their biological parents (parental generation) (19). The
recently updated version of FCD contains 16.1 million individuals among which
almost 2.0 million were cancer patients recorded to the end of 2015. The 3-digital
codes of 7th revision of the International Classification of Diseases (ICD-7) were used
to identify BOTs, 35 most common primary cancers and cancer of unknown primary
(CUP). BOTs are classified as in situ tumors in the Swedish Cancer Registry.
Histological subtypes of BOTs were classified according to Systemized Nomenclature
of Medicine (SNOMED) codes since 1993, into serous, papillary and mucinous types.
The follow-up for cancer in the offspring generation was started from the beginning
of 1958 (for histological analysis it began from 1993), the birth year, or the
immigration year, whichever came latest. The follow-up was terminated when a
person was diagnosed with BOT or cancer, or when he emigrated or died, or at the
end of 2015, whichever came first. Having first-degree relatives (including parents
and/or siblings) who were affected with cancer was considered as family history.
For familial risk analysis, the incidence in those with a family history of BOTs or
cancer (affected relatives) was compared to the incidence in persons (reference group)
without a family history (unaffected relatives). A two-way comparison was employed
to estimate familial relative risks (RRs) for (a histology-specific) BOTs in daughters
when a first-degree relative was diagnosed with any invasive cancer, for example,
brother with cancer X (Figure 1, left part), and conversely familial risk for invasive
cancer X in offspring when mother or sisters were diagnosed with (a histology-
specific) BOT (Figure 1, right part). For parents and offspring relation (large majority
of familial cases), the two comparisons are independent but for siblings the pairs of
cases are the same.
The Poisson regression model was employed to estimate RRs and corresponding
confidence intervals (CIs) for 5%, 1% and 0.1% significance levels. We use here
different significance levels in order to differentiate the likely true associations from
likely chance findings and a single 95%CI is not very informative in the context of
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multiple comparisons. Potential confounders, including age group (17 groups with 5-
year gap), sex, calendar period, residential area and socioeconomic status, were added
to the model as covariates. SAS version 9.4 was used to perform the statistical
analysis.
The study was approved by the Ethical Committee of Lund University and the study
was conducted in accordance with the approved guidelines.
RESULTS
A total of 4729 BOT cases were found in our database and of these 4199 cases were
in the offspring generation diagnosed at ages 0-83 years, for which RRs were
calculated. Among all BOT cases in the offspring generation, there were 34 (0.8%)
cases with a first-degree relative affected by BOT, of which seven cases were serous,
seven were papillary, and nine were mucinous (Table 1). Individuals have increased
risk of being diagnosed with BOT when first-degree relatives were affected by any
histological type of BOTs (N=34, RR 2.20, p <0.001), and papillary BOT (N=7, RR
4.02, p <0.001). Risk for papillary BOT was elevated with a family history of any
histological type of BOTs (N=7, RR 2.40) and papillary BOT (N=4, RR 10.10, p <
0.001) in first-degree relatives. Increased risk for mucinous BOT was observed in
families with any histological type of BOT patients (N=9, RR 2.06).
Among all BOT cases in the offspring generation, a total of 2489 (59.3%) cases had
first-degree relatives diagnosed with invasive cancers. Significant familial
associations of all BOTs with invasive cancers were found for pancreatic (1.39, p
<0.01), lung (1.20, p <0.01) and bone (2.27, p <0.01) cancers and leukemia (1.23)
(Table 2). In the reverse order, RRs for colorectal and ovarian cancers were 1.18 and
1.59 (p <0.01) when a family member was diagnosed with BOT. The relative risks of
BOT were 1.14 in families with cancer patients diagnosed with any cancer including
or excluding ovarian cancer. On the contrary, a family history of BOT was associated
with the increased risk of any cancers (1.06, p <0.01) and the risk slightly decreased
(1.05) when only considering any cancers other than ovarian cancer. Only cancer
sites with at least 10 familial cases (column N) in either of the two-way comparison
were included in Table 2.
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Results from detailed analyses of familial risks in histology-specific BOT with
invasive cancers are shown in Table 3. However included are only invasive cancers
with at least one significant association with histology-specific BOT; additionally
ovarian cancer was included although it showed no significant associations. The risk
for serous BOT was not associated with a family of invasive cancers. Increased risk of
papillary BOT was associated with family history of lung (1.39) and endocrine gland
(1.68) cancers and with all cancers (1.25, p <0.01). Mucinous BOT risk was elevated
when first-degree relatives were diagnosed with anal (2.69) and pancreatic (3.30, p
<0.01) cancers. In the reverse analysis elevated risks for pancreatic (3.03, p <0.001)
and kidney (2.87, p <0.001) cancers were found in family of papillary BOT patients,
thyroid gland cancer in family of serous patients.
DISCUSSION
BOTs are one subset of epithelial neoplasms with low malignant potential that affect
women in the reproductive age group and show excellent prognosis with 5-year
survival rates of 95–97% (20). The present study on the relation between BOT and
invasive cancers is mainly about the personal risk of invasive cancer after diagnosis of
BOT, especially risk of ovarian cancer, as the histopathological findings strongly
suggest a continuum from benign presentation to borderline and to invasive ovarian
tumors (21). The vast majority of serous carcinoma arise de novo, while only 5% to
10% of them derived from the precursor lesion serous BOT (22). High heterogeneity
(benign, borderline, intraepithelial carcinoma, microinvasion, and invasive
carcinoma) are presented in mucinous tumor (23). There are a few studies focusing on
the familial association of BOT with invasive cancers (24). The present and the
previous studies provide insight into the etiology of BOT which helps management of
BOT patients and counselling of their family members.
Based on the Swedish Family-Cancer Database, we found the familial risk of BOT
with a family history of BOT was 2.20, higher than the risk with a family history of
any invasive cancers (1.14).However, BOT cases with a family history of BOT only
accounted for a small proportion (0.8%) of all the BOT patients compared to the large
amount of the BOT patients with the first-degree relative diagnosed with invasive
cancers (59.3%). The familial risk for BOT (RR=2.20) was also higher than the
association of BOT with ovarian cancer (RRs 1.17 and 1.59) in two-way analyses of
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which only the latter was significant. These data probably suggest that some risk
factors responsible for development of familial BOTs do not predispose to
development of invasive ovarian cancer, even though the two diseases have common
risk factors such as parity and sex hormone levels (7,9-11,25). As far as we know, risk
of BOT with a family history of BOT has never been reported before. Furthermore, in
histology-specific analysis, only concordant family history of papillary BOT was
significant which may suggest that this histology has a unique pathophysiology,
probably in accordance with the recent WHO classification in which papillary variant
of serous BOT is mentioned as a distinct subtype of serous BOT (2). Of cautionary
note, all the results of the familial associations of BOT were based on small numbers
of cases.
We used two-way comparisons in the search of familial associations of BOT with
invasive cancers in order to find internal support to the findings. However, incidence
rates and diagnostic age ranges differ between BOT and many cancers, thus a lacking
two-way association is no strong evidence against an association. We found
significant results including or excluding ovarian cancer. We did this because ovarian
cancer shares many common risk factors with BOT, which can drive the associations
between BOT and other cancers. However, the magnitude of effect remained similar
after excluding ovarian cancer, indicating that BOT shares common risk factors with
other cancers.
RRs for BOT were found to be increased in families with pancreatic, lung and bone
cancers and leukemia. In the reverse analyses, RRs for colorectal and ovarian cancers
were increased in families with BOT. No associations were significant in both of the
two-way analyses although for lung and ovarian cancer one RR was significant at 5%
level and the other one was of borderline significance. The association with pancreatic
cancer was earlier reported from a population-based study in Finland (24). The
associations between BOT with invasive cancers found here may be related to shared
common genetic or environmental factors. The association of BOT with ovarian may
be contributed by germline mutations in BRCA1/2 and MSH2 as well as by some
reproductive and hormone‐related factors. Association with pancreatic cancer may
probably be due to germline mutations in BRCA1/2 (26), colorectal cancers due to
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MSH2 (27) and bone cancer due to CHEK2 (28). Furthermore, smoking may
contribute to the associations with lung and pancreatic cancers.
The analyses of familial risk of BOTs stratified by histology revealed associations
with some cancers, although those associations were only significant in the one-way
analysis. Smoking is a risk factor for mucinous BOT and we found familial
associations of mucinous BOT with smoking-related cancers, including anal,
pancreatic and lung cancers, although the latter was marginally significant (10,29,30).
Serous BOT is thought to be a precursor to low grade serous ovarian carcinoma (18);
no familial associations between these two were observed in the two-way comparison,
yet the results were both moderately significant. Papillary BOT was associated with
most number of cancers, including pancreatic, lung, kidney and endocrine glands
cancers. Papillary BOT is characterized by a frequent association with extraovarian
implants (particularly invasive implants), which confer prognostic information of
increased risk (31).
To the best of our knowledge, this is so far the largest study focusing on familial
aggregation of BOTs. As the Family-Cancer Database is based on registered resources
with practically complete nationwide coverage of medically diagnosed cancers, it
provides a reliable estimation of familial risks. However, there are limitations in our
study. Firstly, identifiable histology was diagnosed only after 1993 when the ICD-O/2
classification was taken to use in the cancer registry. A 22 year follow-up, although
the longest yet reported, is still short for intergenerational study considering risks of
both the parental and offspring generations. Information on possible confounders,
such as smoking and use of oral contraceptive use, were not available; yet we adjusted
for socio-economic and demographic factors in order to reduced possibility of
confounding.
In summary, we report for the first time that family history contributes to the risk of
concordant BOT. BOTs showed familial associations with some invasive cancers,
most consistently with colorectal, pancreatic, ovarian and bone cancers as well as with
leukemia. These results provide insight into familial associations of BOT which may
also help in surveillance and genetic counseling of BOT patients. Furthermore, the
familial clustering of BOT with invasive cancers suggests that some preventive
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counselling for invasive cancer, such as smoking cessation, can also be applied to
BOT. However, due to small numbers of cases in this study, larger studies with
detailed lifestyle information are needed to validate the present familial associations
between BOT and invasive cancers.
Data Availability Statement
The data that support the findings of this study are available from Lund University but
restrictions apply to the availability of these data, which were used under license for
the current study, and so are not publicly available.
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Fig. 1 Flowchart of calculating the RRs for borderline ovarian tumor (BOT) and cancer X
in a two-way analysis. On the left side, relative risk (RR) was calculated for BOT when
family history was cancer X; person-years at risk were calculated for all offspring;
probands were all first-degree relatives. On the right side, RR was calculated for cancer X
when family history was BOT.
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Table 1 Familial associations among borderline ovarian tumors
Histology of borderline ovarian tumors Cases with any affected FDRs
Offspring First-degree relative N RR 95%CI
Lower Upper
All any
Any 34 2.20 1.57 3.09
Serous 2 0.87 0.22 3.46
Papillary 7 4.02 1.91 8.44
Mucinous 3 1.08 0.35 3.34
All serous Any 7 2.00 0.95 4.22
Papillary 1 2.36 0.33 16.74
All papillary
Any 7 2.40 1.14 5.05
Serous 1 2.12 0.30 15.07
Papillary 4 10.10 3.78 26.98
Mucinous 1 1.75 0.25 12.47
All mucinous
Any 9 2.06 1.07 3.97
Serous 1 1.31 0.18 9.32
Papillary 2 3.62 0.90 14.49
Mucinous 1 1.09 0.15 7.77
FDR: first-degree relative;
Bolding, italic and underlining indicate that the 95% CI, 99% CI and 99.9% CI did not overlap with 1.00
respectively;
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Table 2 Risk of borderline ovarian tumor with a family history of other cancer and risk of other cancer
with a family history of borderline ovarian tumor
Cancer site Risk of borderline ovarian tumor Risk of invasive cancer
N RR 95% CI N RR 95% CI
Upper aerodigestive
tract 64 0.83 0.65-1.07 34 0.86 0.61-1.21
Esophagus 24 0.95 0.64-1.42 7 0.58 0.28-1.22
Stomach 109 1.05 0.87-1.27 29 1.31 0.91-1.89
Small intestine 16 1.15 0.70-1.88 9 1.18 0.62-2.28
Colorectum 342 1.00 0.89-1.11 173 1.18 1.01-1.37
Anus 12 1.75 0.99-3.08 5 1.07 0.44-2.58
Liver 77 0.99 0.79-1.24 29 1.13 0.78-1.63
Pancreas 111 1.39 1.15-1.68 36 1.21 0.87-1.68
Lung 271 1.20 1.06-1.36 118 1.13 0.94-1.35
Breast 421 1.03 0.94-1.14 290 0.96 0.85-1.08
Cervix 59 1.07 0.83-1.38 40 1.22 0.9-1.67
Endometrium 102 1.16 0.95-1.41 55 1.22 0.93-1.59
Ovary 81 1.17 0.94-1.46 60 1.59 1.24-2.05
Prostate 521 1.07 0.97-1.17 294 1.07 0.96-1.20
Testis 14 1.12 0.66-1.89 31 1.27 0.89-1.80
Kidney 105 1.19 0.98-1.45 43 1.14 0.84-1.53
Bladder 141 0.96 0.81-1.13 58 1.00 0.78-1.30
Melanoma 125 1.07 0.90-1.28 109 0.96 0.8-1.16
Skin 113 0.82 0.68-0.99 45 0.86 0.64-1.15
Nervous system 103 1.08 0.89-1.32 89 1.17 0.95-1.44
Thyroid gland 26 0.99 0.67-1.45 29 1.38 0.96-1.99
Endocrine gland 67 1.21 0.95-1.54 45 1.21 0.9-1.62
Bone 12 2.27 1.29-4.01 5 0.91 0.38-2.19
Connective tissue 20 0.99 0.64-1.53 13 1.01 0.58-1.74
Non-Hodgkin
lymphoma 103 1.05 0.86-1.28 49 0.89 0.67-1.17
Hodgkin lymphoma 16 1.10 0.67-1.79 17 1.23 0.76-1.98
Myeloma 43 0.97 0.72-1.31 18 1.04 0.66-1.66
Leukemia 109 1.23 1.01-1.48 45 0.9 0.67-1.20
CUP 104 1.07 0.88-1.30 37 0.99 0.72-1.37
All cancersa 2489 1.14 1.07-1.22 1830 1.06 1.02-1.11
All cancersb 2457 1.14 1.07-1.22 1770 1.05 1.00-1.10
CUP: cancer of unknown primary
Bolding, italic and underlining indicate that the 95% CI, 99% CI and 99.9% CI did not overlap with 1.00
respectively;
a: all cancers include ovarian cancers and all other cancers;
b: all cancers include all other cancers except ovarian cancer.
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Table 3 Familial associations of borderline ovarian tumors with invasive cancers according to histology of
borderline ovarian tumor
Histology of
borderline
ovarian tumor
Invasive
cancer
site
Risk of borderline ovarian
tumor Risk of invasive cancer
N RR 95% CI N RR 95% CI
Serous
Anus
2 1.30 0.33-5.22 0 - -
Papillary 1 0.74 0.10-5.29 1 1.75 0.25-12.43
Mucinous 5 2.69 1.12-6.48 2 2.21 0.55-8.84
Serous
Pancreas
20 1.11 0.72-1.74 1 0.20 0.03-1.40
Papillary 19 1.29 0.82-2.04 10 3.03 1.63-5.62
Mucinous 33 1.58 1.11-2.23 9 1.43 0.74-2.75
Serous
Lung
54 1.08 0.82-1.42 19 1.09 0.69-1.70
Papillary 60 1.39 1.07-1.81 11 0.94 0.52-1.69
Mucinous 62 1.01 0.78-1.31 30 1.38 0.96-1.97
Serous
Ovary
23 1.49 0.98-2.25 9 1.72 0.89-3.30
Papillary 19 1.46 0.93-2.30 5 1.29 0.53-3.09
Mucinous 14 0.75 0.44-1.27 8 1.23 0.62-2.46
Serous
Kidney
20 1.01 0.65-1.57 3 0.51 0.16-1.57
Papillary 23 1.42 0.94-2.15 12 2.87 1.63-5.05
Mucinous 29 1.23 0.85-1.78 6 0.83 0.37-1.86
Serous Thyroid
gland
8 1.35 0.67-2.71 9 3.35 1.74-6.43
Papillary 7 1.41 0.67-2.96 3 1.41 0.45-4.36
Mucinous 5 0.68 0.28-1.64 2 0.61 0.15-2.45
Serous Endocrine
gland
16 1.29 0.79-2.12 8 1.50 0.75-3.01
Papillary 18 1.68 1.05-2.68 5 1.22 0.51-2.94
Mucinous 13 0.86 0.50-1.48 8 1.24 0.62-2.47
Serous All
cancersa
544 1.08 0.95-1.24 279 1.05 0.93-1.18
Papillary 497 1.26 1.09-1.46 212 1.06 0.93-1.22
Mucinous 658 1.06 0.94-1.19 314 0.96 0.86-1.07
Serous All
cancersb
536 1.08 0.95-1.23 270 1.03 0.92-1.16
Papillary 489 1.25 1.08-1.45 207 1.06 0.92-1.21
Mucinous 651 1.07 0.95-1.20 306 0.95 0.85-1.07
Bolding, italic and underlining indicate that the 95% CI, 99% CI and 99.9% CI did not overlap with 1.00
respectively;
a: all cancers include ovarian cancers and all other cancers;
b: all cancers include all other cancers except ovarian cancer.
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Published OnlineFirst July 17, 2018.Cancer Epidemiol Biomarkers Prev Guoqiao Zheng, Hongyao Yu, Anna Kanerva, et al. WITH ITSELF AND INVASIVE CANCERSBORDERLINE OVARIAN TUMORS SHARE FAMILIAL RISKS
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