University of Groningen Gynaecological malignancies in Lynch syndrome Woolderink, Jorien Maria

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Gynaecological malignancies in Lynch syndrome

Woolderink, Jorien Maria

DOI:

10.33612/diss.84185340

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Publication date:

2019

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Woolderink, J. M. (2019). Gynaecological malignancies in Lynch syndrome: surveillance and cancer

characteristics. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.84185340

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Ovarian cancer in

Lynch syndrome;

a systematic review

Helder-Woolderink JM

1

_{, Blok EA}

1

_{, Vasen HFA}

2

_{, Hollema H}

3

_,

Mourits MJ

1

_{, De Bock GH}

4

1_{Department of Gynaecologic Oncology, University Medical Center Groningen} 2_{Department of Gastroenterology & Hepatology, Leiden University Medical Centre} 3_{Department of Pathology, University Medical Center Groningen}

4_{Department of Epidemiology, University Medical Center Groningen}

Eur J Cancer. 2016;55:65-73

5

MLH1 M MLH1 MSH2 MSH6 PMS2 M SH2 MSH6 PMS2 EpCAM MLH1 PMS2 EpCAM MLH1 MSH2 MSH6 PM M M MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 SH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 MS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 M M M MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH P LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpC SH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH CAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 SH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM ML 2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH H1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM H6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH AM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 Ep 2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 S2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 M LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 SH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM ML CAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MS SH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpC SH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM ML pCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MS

pCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH H1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 Ep MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MS EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 E

M H1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1

SH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 P pCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM ML

P MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6

MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM

M 2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 M

LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 Ep 6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 M

2 EpCA MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 Ep SH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 pCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM ML

M PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MS

M MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpC 2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH 2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH

M H6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 P

CAM MLH1 MSH2 MSH6 P EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM

ML SH2 MSH6 PMS2 EpCAM MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 S2 EpCAM MLH1 MSH2 M

M MS2 EpCAM MLH1 MSH PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCA LH1 MSH2 MSH6 PMS2 Ep

Ep MLH1 MSH2 MSH6 PM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MS H6 PMS2 EpCAM MLH1

SH6 PMS2 EpCAM M MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS M MLH1 MSH2 MSH6 PM

pCAM MLH1 MSH2 M EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM ML 2 MSH6 PMS2 EpCAM M

SH2 MSH6 PMS2 Ep MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MS

MS2 EpCAM MLH1 6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 Ep

MLH1 MSH2 MSH6 AM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1

H6 PMS2 EpCAM SH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 P

CAM MLH1 MSH PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM

SH2 MSH6 PMS2 M MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2

MS2 EpCAM MLH1 H2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6

MLH1 MSH2 MSH6 MS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 SH6 PMS2 EpCAM LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 Ep CAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 M SH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS

2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH

LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MS PMS2 EpCAM MLH1 MSH2 MSH6 PM

M PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCA MLH1 MSH2 MSH6 PMS2 EpCAM M

M MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 M

2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCM MLH1 MSH2 MSH6 PMS2 EpCA

EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MS M MLH1 M

H1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2EpCAM MLH1 MSH2 MSH6 PMS

6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 M

P CAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6

H2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM

S2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2

LH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 P

PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM MLH1 MSH2 MSH6 PMS2 EpCAM ML

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Objective

The aim was to systematically review the characteristics of ovarian cancer in women with Lynch Syndrome (LS) and to evaluate the role of surveillance in detection of ovarian cancer in LS.

Methods

All studies between 1979-2015 of women with ovarian cancer and LS or at 50% risk of LS were evaluated. Two reviewers independently evaluated eligible studies and extracted data on age at diagnosis, histological type, FIGO stage and way of detection according to pre-specified criteria. The studies were assessed for quality using the Newcastle-Ottawa Quality Assessment Scales (NOS).

Results

The quality score of the 49 identified studies was at least 6 out of 8 and provide clinical information on 747 LS women with ovarian cancer. The mean age at diagnosis was 45.3 (range 19-82) years. Most frequent mutations were MSH2 (47%) and MLH1 (38%). Histopathological data were available for 445 women. The most frequently reported histological type was mixed type (mucinous/endometrioid/clearcell carcinomas) (n=136; 31%). Most tumours (281, 65%) were diagnosed at an early stage (FIGO I/II). Six studies evaluating the effect of surveillance of ovarian cancer, reported that seven of 22 (32%) ovarian cancers were found during surveillance, 6/22 (27%) were detected at an early stage.

Conclusion

This systematic review describes that ovarian cancer in women with LS has a wide age-range of onset, is often diagnosed at an early stage with frequently endometrioid/ clearcell histology. Data about the role of surveillance in detection of ovarian cancer in women with LS are scarce however detection at an early stage seems possible.

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5 INTRODUCTION

Lynch Syndrome (LS) is an autosomal dominant predisposition to develop cancer characterized by germ line mutations in one of four DNA mismatch repair (MMR) genes,

MLH1, MSH2, MSH6 and PMS2. (1,2) MLH1 and MSH2 predominate in LS with mutations

in one or the other found in between 80-90% of affected Lynch syndrome families, with

MSH6 and PMS2 mutation causing the remaining 10-20%. (3-5) In female carriers with

LS, endometrial cancer is after colon cancer the most common tumour type (6,7), with a cumulative lifetime risk of 21-71%, depending on which gene is mutated. Women with MSH6 mutation have a risk of 40-70% to develop endometrial cancer. (7-11) For women with LS, there is a 24%-63% cumulative lifetime risk of developing colorectal cancer. (7,12-16) The cumulative lifetime risk of ovarian cancer varies between 6-12%. (7-9,13,16-18)

Due to these high cancer risks, women with LS are regularly surveyed with the aim of early detection of these cancers. Endometrial cancer surveillance could be effective. (19-21) However the value of surveillance for ovarian cancer is under debate. (19,22) In general, ovarian cancer surveillance has not been proven effective in the general population and among women with BRCA 1/2 mutations. Most ovarian cancers are found in an advanced stage and interval ovarian cancers develop between two surveillance visits. (23-28) As in most studies only a small number of LS women are included, the information about clinical and histopathological characteristics of the screen detected versus the clinically detected ovarian cancer in women with LS or their first-degree relatives is scattered.

The aim of this systematic review was to analyze all published studies on ovarian cancer in women with LS, regarding the age of onset of ovarian cancer, the histopathological type and FIGO stage and to evaluate the role of surveillance in the detection of (early stage) ovarian cancer in LS.

METHODS

This systematic review was performed following the PRISMA statement guidelines (http://www.prisma-statement.org/stagement.htm). We conducted a systematic search in the Medline database from January 1979 until April 2015. The following search terms were used; ”ovarian cancer”, ”ovarian carcinoma”, ”HNPCC”, ”Lynch Syndrome”,

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is shown in Figure 1. After reading the titles and abstracts of all potentially relevant articles, the full texts were assessed for eligibility by two independent reviewers (JHW and EB). In addition, the references of the included publications were screened to evaluate if relevant articles might have been missed. If there was disagreement about inclusion or exclusion of an article a consensus meeting was organized between the reviewers (JHW and EB) and if indicated with the other authors of this review.

Inclusion criteria

Studies were included if they contained information on ovarian cancer patients that carry a LS mutation or patients who are a first degree relative of a family member with LS or patients that fulfilled the Amsterdam II criteria (see Figure 2) and if they presented data on the women’s age of onset of ovarian cancer and/or the histopathology and/ or FIGO stage. Excluded were studies describing ovarian cancer in women without FIGURE 1 literature search

Literature search

362 studies

49 studies

included

125 reviews & guidelines excluded

42 studies excluded for other reasons

44/49 studies for mean/median age

at ovarian cancer diagnosis

27/49 studies for

histopathology 24/49 studies for FIGO stage

6/49 studies for surveillance 122 studies excluded

(no ovarian cancer)

24 studies no LS or first degree relatives

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5

LS mutation or first degree relatives. Also excluded were studies with ovarian cancer in women with LS or first degree relatives without information on any of the following items: age of onset, histopathology or FIGO stage. A total of 50 studies were included in this systematic review (see Table 1). As data on the same patients were reported in two studies (29,30), the study of Crijnen et al. (29) was excluded and finally 49 studies were included.

Data extraction

For all 49 studies the following data was extracted: design of study (cohort, case control, case report); the number of patients and the number of ovarian cancers (Table 1). In addition, the following information was retrieved for women with LS or their first degree relatives and their ovarian cancer: type of mutation, the age of onset (mean or median and standard deviation or range), the FIGO stage of the ovarian cancer (Table 1) and the histopathology report (Table 2). For the studies that evaluated the role of surveillance in the detection of ovarian cancer the following was retrieved: the number of women in surveillance; the number of ovarian cancers found during surveillance, the number of interval ovarian cancers, the surveillance interval (in years); the FIGO stage of the ovarian cancer found during surveillance and in interval and the related survival time (in years). All data were extracted independently by two reviewers (JHW and EB). Quality assessment

The quality of the included studies was assessed using the Newcastle-Ottawa Scale as recommended by the Cochrane Non-Randomized Studies Methods Working Group in which a study is judged on three areas; the selection of the study groups, the comparability of the groups and the ascertainment of either the exposure or the outcome of interest for case-control or cohort studies, respectively. In this systematic review 31 cohort studies and 11 case control studies were evaluated. The other seven studies were case reports and could not been scored with the Newcastle-Ottawa Scale.

At least three relatives with a Lynch-associated cancer (cancer of the colorectum, endometrium, small bowel, ureter or renal pelvis) and

• one should be a first-degree relative to the other two • at least two successive generations should be affected, • at least one should be diagnosed before age 50, • familial adenomatous polyposis should be excluded • tumours should be verified by pathological examination

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TABLE 1

Overview of studies pr

esenting data on ovarian cancer in women with L

ynch Syndr ome (LS) (2,6,7,11,13-15,18-20,22,30-35,37,40,42-71) Design of study Patients with LS (N) Ovarian cancer Mutation FIGO stage A verage age at diagnosis (range) 1 Aarnio (1999) Cohort 869 13 MLH 1:12 MSH2: 1 -49.2 (26-76) 2 A ysal (2012) Cohort 71 7 MLH1 :5 MSH2 :1 PMS2 :1 I:7 -3 Baglietto (2009) Cohort 113 families* 12 MSH6 :12 -48.4 (27-72) 4 Barr ow (2009) Cohort 839 24 Unknown:24 -43.3 (38.4-48.2) 5 Bats (2013) Case r eport 1 1 MLH1 :1 I:1 45 6 Bewtra (1992) Case Contr ol 37 4 Unknown:4 I:1 III:3 41 7 Blokhuis (2008) Cohort 87 1 MLH1 :1 -3 4 8 Bonadona (2011) Cohort 537 82 MLH1 :31 MSH2 :44 MSH6 :7 -44 ( 20-58)** 9 Br own (2001) Case contr ol 120 families* 24 Unknown:24 -48.3 (29-74) 10 Casey (2013) Cohort 174 18 MLH1 :9 MSH2 :8 MSH6 :1 --11 Cohn (2000) Cohort 19 2 MSH2 :2 II:1 III:1 71 (50-92) 12 Domanska (2007) Case contr ol 98 6 MSH1 :2 MSH2 :1 MSH6 :3 -38.3 (34-40) 13 Domanska (2010) Case contr ol 44 8 MLH1 :1 MSH2 :3 MSH6 :4

I:3 II:3 III:1 IV:1

-14 Engel (2012) Cohort 1107 49 Unknown:49 -44 (26-58)** 15 Gerritzen (2009) Cohort 100 1 MSH2 1 III:1 50 16 Goldber g (2009) Family 19 1 MSH6 :1 -5 7 17 Grindedal (2009) * Cohort 144 144 MLH1 :51 MSH2: 78 MSH6 :15 I/II:110 III/IV : 25 Unknown:9 44.7 (20.1-82) 18 Hampel (2005) Cohort 183 12 Unknown:12 -54.1 19 Hendriks (2004) Cohort 146 4 MSH6 :4 -49 (45-51) 20 Huang (2004) Case r eport 5 1 MSH2 :1 I:1 42 21 Jager (1997) Cohort 26 1 MSH1 :1 -3 6 22 Järvinen (2009) Case contr ol 242 6 Unknown:6 I/II:5 III:1 -23 Jensen (2008) Cohort 52 5 Unknown :5 I/II:3 III/IV :2 36 24 Karamurzin (2013) Cohort 25 1 MSH2 :1 I:1 44 25 Ketabi (2011) Cohort 63 63 MLH1 :11 MSH2 :31 MSH6 :21

I:20 II:6 III:10 IV:4 Unknown:23

47.7 (30-79) 26 Ketabi (2014) Cohort 676 4 MLH1 :1 MSH2 :3

I:2 II:1 III:1

41 (37-42) 27 Lavie (2008) Cohort 122 2 MSH2 :2 -59 (38-80) 28 Lu (2005) Cohort 117 6 Unknown:6 -39.5 (29-65)** 29 Lu (2012) Cohort 290 9 Unknown:9

I:2 II:3 III:3 IV:1

54.5 (42-59) 30 L ynch (1991) Family 24 3 Unknown:3 -41.3 ( 38-46) 31 L ynch (1991) Case-contr ol 347 15 Unknown:15 -44.9 ( 28-65) 32 Malander (2006) Cohort 128 3 MLH1 :2 MSH6 :1 I:2 IV:1 45.3 (40-49) 33 Mar celis (2001) Case r eport 2 2 MSH2:2 I:1 II:1 46.5 (45-48) 34 Niskakoski (2013) Case contr ol 107 20 MLH1 :16 MSH2 :4

I:11 II:5 III:4

45.7 (36-63)

35 Niskakoski (2015)

Cohort

104

19 MLH1

:15

MSH2

:4

I/II:15

III/IV

:4

-36 Pal (2012)

Cohort

1893

9 MLH1

:2

MSH2

:2

MSH6

:5

-47.1

37 Par

c (2003)

Cohort

348

7 MLH1

:3

MSH2

:4

-40 (35-53)

38 Paspatis (1994)

Case r

eport

6

1 Unknown:1

-5

0 39 Phippen (2011)

Case r

eport

1

1 MLH1

:1

I:1

-40 Renkonen (2006)

Cohort

175

4 Unknown:4

I:3

III:1

44.5 (41-50)

41 Rubin (1998)

Cohort

116

2 MLH1

:1

MSH2

:1

-55 (46-64)

42 Schmeler (2006)

Case contr

ol

315

12 MLH1

:5

MSH2

:7

I:5

II:3

III:

2 Unknown:2

42 (31-48)**

43 South (2009)

Cohort

77

2 MSH2:

2-38 (37-39)

44 Stratton (1999)

Cohort

313

2 MLH1

:2

-26 (25-27)

45 Stuckless (2013)

Case contr

ol

174

22 MSH2

:22

I:1

II:3

Unknown:18

44 (37-50)

46 To

moda (1998)

Case contr

ol

1170

1 Unknown:1

-3

8 47 V

asen (2001)

Cohort

3222

24 MLH:

6 MSH2

:13

MSH6

:5

-46 (19-75)

48 Vierkoetter (2014)

Cohort

90

7 MLH1

:2

MSH2

:2

MSH6

:3

I:5

II:1

III:1

47 (39-53)

49 W

atson (2001)

Cohort

80

80 MLH1

:27

MSH2

:17

Unknown:36

I:39

II:15

III:9

IV

:1

Unknown:16

42.7 (19-76)

Overall

49 studies

14785***

747 MLH1

:208

MSH2

:257

MSH6

:82

PMS1

:1

Unknown:199

I/II: 281

III/IV

:77

Unknown:68

45.3 (19-

92)****

* T

otal number of patients unknown

** Median age instead of average age *** The two studies pr

esenting only the number of families ar

e not included in this overall number of patients.

**** The averaged mean ages (median ages ar

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5

TABLE 1

I:3 II:3 III:1 IV:1

I:2 II:1 III:1

I:2 II:3 III:3 IV:1

I:11 II:5 III:4

45.7 (36-63)

35 Niskakoski (2015)

Cohort

104

19 MLH1

:15

MSH2

:4

I/II:15

III/IV

:4

-36 Pal (2012)

Cohort

1893

9 MLH1

:2

MSH2

:2

MSH6

:5

-47.1

37 Par

c (2003)

Cohort

348

7 MLH1

:3

MSH2

:4

-40 (35-53)

38 Paspatis (1994)

Case r

eport

6

1 Unknown:1

-5

0 39 Phippen (2011)

Case r

eport

1

1 MLH1

:1

I:1

-40 Renkonen (2006)

Cohort

175

4 Unknown:4

I:3

III:1

44.5 (41-50)

41 Rubin (1998)

Cohort

116

2 MLH1

:1

MSH2

:1

-55 (46-64)

42 Schmeler (2006)

Case contr

ol

315

12 MLH1

:5

MSH2

:7

I:5

II:3

III:

2 Unknown:2

42 (31-48)**

43 South (2009)

Cohort

77

2 MSH2:

2-38 (37-39)

44 Stratton (1999)

Cohort

313

2 MLH1

:2

-26 (25-27)

45 Stuckless (2013)

Case contr

ol

174

22 MSH2

:22

I:1

II:3

Unknown:18

44 (37-50)

46 To

moda (1998)

Case contr

ol

1170

1 Unknown:1

-3

8 47 V

asen (2001)

Cohort

3222

24 MLH:

6 MSH2

:13

MSH6

:5

-46 (19-75)

48 Vierkoetter (2014)

Cohort

90

7 MLH1

:2

MSH2

:2

MSH6

:3

I:5

II:1

III:1

47 (39-53)

49 W

atson (2001)

Cohort

80

80 MLH1

:27

MSH2

:17

Unknown:36

I:39

II:15

III:9

IV

:1

Unknown:16

42.7 (19-76)

Overall

49 studies

14785***

747 MLH1

:208

MSH2

:257

MSH6

:82

PMS1

:1

Unknown:199

I/II: 281

III/IV

:77

Unknown:68

45.3 (19-

92)****

* T

e excluded)

TABLE 1

I:3 II:3 III:1 IV:1

I:2 II:1 III:1

I:2 II:3 III:3 IV:1

I:11 II:5 III:4

45.7 (36-63)

35 Niskakoski (2015)

Cohort

104

19 MLH1

:15

MSH2

:4

I/II:15

III/IV

:4

-36 Pal (2012)

Cohort

1893

9 MLH1

:2

MSH2

:2

MSH6

:5

-47.1

37 Par

c (2003)

Cohort

348

7 MLH1

:3

MSH2

:4

-40 (35-53)

38 Paspatis (1994)

Case r

eport

6

1 Unknown:1

-5

0 39 Phippen (2011)

Case r

eport

1

1 MLH1

:1

I:1

-40 Renkonen (2006)

Cohort

175

4 Unknown:4

I:3

III:1

44.5 (41-50)

41 Rubin (1998)

Cohort

116

2 MLH1

:1

MSH2

:1

-55 (46-64)

42 Schmeler (2006)

Case contr

ol

315

12 MLH1

:5

MSH2

:7

I:5

II:3

III:

2 Unknown:2

42 (31-48)**

43 South (2009)

Cohort

77

2 MSH2:

2-38 (37-39)

44 Stratton (1999)

Cohort

313

2 MLH1

:2

-26 (25-27)

45 Stuckless (2013)

Case contr

ol

174

22 MSH2

:22

I:1

II:3

Unknown:18

44 (37-50)

46 To

moda (1998)

Case contr

ol

1170

1 Unknown:1

-3

8 47 V

asen (2001)

Cohort

3222

24 MLH:

6 MSH2

:13

MSH6

:5

-46 (19-75)

48 Vierkoetter (2014)

Cohort

90

7 MLH1

:2

MSH2

:2

MSH6

:3

I:5

II:1

III:1

47 (39-53)

49 W

atson (2001)

Cohort

80

80 MLH1

:27

MSH2

:17

Unknown:36

I:39

II:15

III:9

IV

:1

Unknown:16

42.7 (19-76)

Overall

49 studies

14785***

747 MLH1

:208

MSH2

:257

MSH6

:82

PMS1

:1

Unknown:199

I/II: 281

III/IV

:77

Unknown:68

45.3 (19-

92)****

* T

(9)

TABLE 1

I:3 II:3 III:1 IV:1

I:2 II:1 III:1

I:2 II:3 III:3 IV:1

I:11 II:5 III:4

45.7 (36-63)

35 Niskakoski (2015)

Cohort

104

19 MLH1

:15

MSH2

:4

I/II:15

III/IV

:4

-36 Pal (2012)

Cohort

1893

9 MLH1

:2

MSH2

:2

MSH6

:5

-47.1

37 Par

c (2003)

Cohort

348

7 MLH1

:3

MSH2

:4

-40 (35-53)

38 Paspatis (1994)

Case r

eport

6

1 Unknown:1

-5

0 39 Phippen (2011)

Case r

eport

1

1 MLH1

:1

I:1

-40 Renkonen (2006)

Cohort

175

4 Unknown:4

I:3

III:1

44.5 (41-50)

41 Rubin (1998)

Cohort

116

2 MLH1

:1

MSH2

:1

-55 (46-64)

42 Schmeler (2006)

Case contr

ol

315

12 MLH1

:5

MSH2

:7

I:5

II:3

III:

2 Unknown:2

42 (31-48)**

43 South (2009)

Cohort

77

2 MSH2:

2-38 (37-39)

44 Stratton (1999)

Cohort

313

2 MLH1

:2

-26 (25-27)

45 Stuckless (2013)

Case contr

ol

174

22 MSH2

:22

I:1

II:3

Unknown:18

44 (37-50)

46 To

moda (1998)

Case contr

ol

1170

1 Unknown:1

-3

8 47 V

asen (2001)

Cohort

3222

24 MLH:

6 MSH2

:13

MSH6

:5

-46 (19-75)

48 Vierkoetter (2014)

Cohort

90

7 MLH1

:2

MSH2

:2

MSH6

:3

I:5

II:1

III:1

47 (39-53)

49 W

atson (2001)

Cohort

80

80 MLH1

:27

MSH2

:17

Unknown:36

I:39

II:15

III:9

IV

:1

Unknown:16

42.7 (19-76)

Overall

49 studies

14785***

747 MLH1

:208

MSH2

:257

MSH6

:82

PMS1

:1

Unknown:199

I/II: 281

III/IV

:77

Unknown:68

45.3 (19-

92)****

* T

e excluded)

TABLE 1

I:3 II:3 III:1 IV:1

I:2 II:1 III:1

I:2 II:3 III:3 IV:1

I:11 II:5 III:4

45.7 (36-63)

35 Niskakoski (2015)

Cohort

104

19 MLH1

:15

MSH2

:4

I/II:15

III/IV

:4

-36 Pal (2012)

Cohort

1893

9 MLH1

:2

MSH2

:2

MSH6

:5

-47.1

37 Par

c (2003)

Cohort

348

7 MLH1

:3

MSH2

:4

-40 (35-53)

38 Paspatis (1994)

Case r

eport

6

1 Unknown:1

-5

0 39 Phippen (2011)

Case r

eport

1

1 MLH1

:1

I:1

-40 Renkonen (2006)

Cohort

175

4 Unknown:4

I:3

III:1

44.5 (41-50)

41 Rubin (1998)

Cohort

116

2 MLH1

:1

MSH2

:1

-55 (46-64)

42 Schmeler (2006)

Case contr

ol

315

12 MLH1

:5

MSH2

:7

I:5

II:3

III:

2 Unknown:2

42 (31-48)**

43 South (2009)

Cohort

77

2 MSH2:

2-38 (37-39)

44 Stratton (1999)

Cohort

313

2 MLH1

:2

-26 (25-27)

45 Stuckless (2013)

Case contr

ol

174

22 MSH2

:22

I:1

II:3

Unknown:18

44 (37-50)

46 To

moda (1998)

Case contr

ol

1170

1 Unknown:1

-3

8 47 V

asen (2001)

Cohort

3222

24 MLH:

6 MSH2

:13

MSH6

:5

-46 (19-75)

48 Vierkoetter (2014)

Cohort

90

7 MLH1

:2

MSH2

:2

MSH6

:3

I:5

II:1

III:1

47 (39-53)

49 W

atson (2001)

Cohort

80

80 MLH1

:27

MSH2

:17

Unknown:36

I:39

II:15

III:9

IV

:1

Unknown:16

42.7 (19-76)

Overall

49 studies

14785***

747 MLH1

:208

MSH2

:257

MSH6

:82

PMS1

:1

Unknown:199

I/II: 281

III/IV

:77

Unknown:68

45.3 (19-

92)****

* T

(10)

5

TABLE 1

I:3 II:3 III:1 IV:1

I:2 II:1 III:1

I:2 II:3 III:3 IV:1

I:11 II:5 III:4

45.7 (36-63)

35 Niskakoski (2015)

Cohort

104

19 MLH1

:15

MSH2

:4

I/II:15

III/IV

:4

-36 Pal (2012)

Cohort

1893

9 MLH1

:2

MSH2

:2

MSH6

:5

-47.1

37 Par

c (2003)

Cohort

348

7 MLH1

:3

MSH2

:4

-40 (35-53)

38 Paspatis (1994)

Case r

eport

6

1 Unknown:1

-5

0 39 Phippen (2011)

Case r

eport

1

1 MLH1

:1

I:1

-40 Renkonen (2006)

Cohort

175

4 Unknown:4

I:3

III:1

44.5 (41-50)

41 Rubin (1998)

Cohort

116

2 MLH1

:1

MSH2

:1

-55 (46-64)

42 Schmeler (2006)

Case contr

ol

315

12 MLH1

:5

MSH2

:7

I:5

II:3

III:

2 Unknown:2

42 (31-48)**

43 South (2009)

Cohort

77

2 MSH2:

2-38 (37-39)

44 Stratton (1999)

Cohort

313

2 MLH1

:2

-26 (25-27)

45 Stuckless (2013)

Case contr

ol

174

22 MSH2

:22

I:1

II:3

Unknown:18

44 (37-50)

46 To

moda (1998)

Case contr

ol

1170

1 Unknown:1

-3

8 47 V

asen (2001)

Cohort

3222

24 MLH:

6 MSH2

:13

MSH6

:5

-46 (19-75)

48 Vierkoetter (2014)

Cohort

90

7 MLH1

:2

MSH2

:2

MSH6

:3

I:5

II:1

III:1

47 (39-53)

49 W

atson (2001)

Cohort

80

80 MLH1

:27

MSH2

:17

Unknown:36

I:39

II:15

III:9

IV

:1

Unknown:16

42.7 (19-76)

Overall

49 studies

14785***

747 MLH1

:208

MSH2

:257

MSH6

:82

PMS1

:1

Unknown:199

I/II: 281

III/IV

:77

Unknown:68

45.3 (19-

92)****

* T

e excluded)

TABLE 1

I:3 II:3 III:1 IV:1

I:2 II:1 III:1

I:2 II:3 III:3 IV:1

I:11 II:5 III:4

45.7 (36-63)

35 Niskakoski (2015)

Cohort

104

19 MLH1

:15

MSH2

:4

I/II:15

III/IV

:4

-36 Pal (2012)

Cohort

1893

9 MLH1

:2

MSH2

:2

MSH6

:5

-47.1

37 Par

c (2003)

Cohort

348

7 MLH1

:3

MSH2

:4

-40 (35-53)

38 Paspatis (1994)

Case r

eport

6

1 Unknown:1

-5

0 39 Phippen (2011)

Case r

eport

1

1 MLH1

:1

I:1

-40 Renkonen (2006)

Cohort

175

4 Unknown:4

I:3

III:1

44.5 (41-50)

41 Rubin (1998)

Cohort

116

2 MLH1

:1

MSH2

:1

-55 (46-64)

42 Schmeler (2006)

Case contr

ol

315

12 MLH1

:5

MSH2

:7

I:5

II:3

III:

2 Unknown:2

42 (31-48)**

43 South (2009)

Cohort

77

2 MSH2:

2-38 (37-39)

44 Stratton (1999)

Cohort

313

2 MLH1

:2

-26 (25-27)

45 Stuckless (2013)

Case contr

ol

174

22 MSH2

:22

I:1

II:3

Unknown:18

44 (37-50)

46 To

moda (1998)

Case contr

ol

1170

1 Unknown:1

-3

8 47 V

asen (2001)

Cohort

3222

24 MLH:

6 MSH2

:13

MSH6

:5

-46 (19-75)

48 Vierkoetter (2014)

Cohort

90

7 MLH1

:2

MSH2

:2

MSH6

:3

I:5

II:1

III:1

47 (39-53)

49 W

atson (2001)

Cohort

80

80 MLH1

:27

MSH2

:17

Unknown:36

I:39

II:15

III:9

IV

:1

Unknown:16

42.7 (19-76)

Overall

49 studies

14785***

747 MLH1

:208

MSH2

:257

MSH6

:82

PMS1

:1

Unknown:199

I/II: 281

III/IV

:77

Unknown:68

45.3 (19-

92)****

* T

(11)

TABLE 1

I:3 II:3 III:1 IV:1

I:2 II:1 III:1

I:2 II:3 III:3 IV:1

I:11 II:5 III:4

45.7 (36-63)

35 Niskakoski (2015)

Cohort

104

19 MLH1

:15

MSH2

:4

I/II:15

III/IV

:4

-36 Pal (2012)

Cohort

1893

9 MLH1

:2

MSH2

:2

MSH6

:5

-47.1

37 Par

c (2003)

Cohort

348

7 MLH1

:3

MSH2

:4

-40 (35-53)

38 Paspatis (1994)

Case r

eport

6

1 Unknown:1

-5

0 39 Phippen (2011)

Case r

eport

1

1 MLH1

:1

I:1

-40 Renkonen (2006)

Cohort

175

4 Unknown:4

I:3

III:1

44.5 (41-50)

41 Rubin (1998)

Cohort

116

2 MLH1

:1

MSH2

:1

-55 (46-64)

42 Schmeler (2006)

Case contr

ol

315

12 MLH1

:5

MSH2

:7

I:5

II:3

III:

2 Unknown:2

42 (31-48)**

43 South (2009)

Cohort

77

2 MSH2:

2-38 (37-39)

44 Stratton (1999)

Cohort

313

2 MLH1

:2

-26 (25-27)

45 Stuckless (2013)

Case contr

ol

174

22 MSH2

:22

I:1

II:3

Unknown:18

44 (37-50)

46 To

moda (1998)

Case contr

ol

1170

1 Unknown:1

-3

8 47 V

asen (2001)

Cohort

3222

24 MLH:

6 MSH2

:13

MSH6

:5

-46 (19-75)

48 Vierkoetter (2014)

Cohort

90

7 MLH1

:2

MSH2

:2

MSH6

:3

I:5

II:1

III:1

47 (39-53)

49 W

atson (2001)

Cohort

80

80 MLH1

:27

MSH2

:17

Unknown:36

I:39

II:15

III:9

IV

:1

Unknown:16

42.7 (19-76)

Overall

49 studies

14785***

747 MLH1

:208

MSH2

:257

MSH6

:82

PMS1

:1

Unknown:199

I/II: 281

III/IV

:77

Unknown:68

45.3 (19-

92)****

* T

e excluded)

TABLE 1

I:3 II:3 III:1 IV:1

I:2 II:1 III:1

I:2 II:3 III:3 IV:1

I:11 II:5 III:4

45.7 (36-63)

35 Niskakoski (2015)

Cohort

104

19 MLH1

:15

MSH2

:4

I/II:15

III/IV

:4

-36 Pal (2012)

Cohort

1893

9 MLH1

:2

MSH2

:2

MSH6

:5

-47.1

37 Par

c (2003)

Cohort

348

7 MLH1

:3

MSH2

:4

-40 (35-53)

38 Paspatis (1994)

Case r

eport

6

1 Unknown:1

-5

0 39 Phippen (2011)

Case r

eport

1

1 MLH1

:1

I:1

-40 Renkonen (2006)

Cohort

175

4 Unknown:4

I:3

III:1

44.5 (41-50)

41 Rubin (1998)

Cohort

116

2 MLH1

:1

MSH2

:1

-55 (46-64)

42 Schmeler (2006)

Case contr

ol

315

12 MLH1

:5

MSH2

:7

I:5

II:3

III:

2 Unknown:2

42 (31-48)**

43 South (2009)

Cohort

77

2 MSH2:

2-38 (37-39)

44 Stratton (1999)

Cohort

313

2 MLH1

:2

-26 (25-27)

45 Stuckless (2013)

Case contr

ol

174

22 MSH2

:22

I:1

II:3

Unknown:18

44 (37-50)

46 To

moda (1998)

Case contr

ol

1170

1 Unknown:1

-3

8 47 V

asen (2001)

Cohort

3222

24 MLH:

6 MSH2

:13

MSH6

:5

-46 (19-75)

48 Vierkoetter (2014)

Cohort

90

7 MLH1

:2

MSH2

:2

MSH6

:3

I:5

II:1

III:1

47 (39-53)

49 W

atson (2001)

Cohort

80

80 MLH1

:27

MSH2

:17

Unknown:36

I:39

II:15

III:9

IV

:1

Unknown:16

42.7 (19-76)

Overall

49 studies

14785***

747 MLH1

:208

MSH2

:257

MSH6

:82

PMS1

:1

Unknown:199

I/II: 281

III/IV

:77

Unknown:68

45.3 (19-

92)****

* T