BORDERLINE OVARIAN TUMORS SHARE FAMILIAL RISKS WITH …€¦ · Borderline ovarian tumors (BOTs)...

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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)

on June 23, 2020. © 2018 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on July 17, 2018; DOI: 10.1158/1055-9965.EPI-18-0503

http://cebp.aacrjournals.org/

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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.




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;




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


respectively;

a: all cancers include ovarian cancers and all other cancers;

b: all cancers include all other cancers except ovarian cancer.




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


respectively;

a: all cancers include ovarian cancers and all other cancers;

b: all cancers include all other cancers except ovarian cancer.




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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