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. Author manuscript; available in PMC: 2016 Dec 1.
Published in final edited form as: Int J Cancer. 2015 Jul 14;137(11):2757–2761. doi: 10.1002/ijc.29641

Lynch Syndrome and Cervical Cancer

Yoland C Antill 1, James G Dowty 2, Aung Ko Win 2, Tina Thompson 3, Michael D Walsh 4, Margaret C Cummings 5, Steven Gallinger 6, Noralane M Lindor 7, Loïc Le Marchand 8, John L Hopper 2,9, Polly A Newcomb 10,11, Robert W Haile 12, James Church 13, Katherine M Tucker 14, Daniel D Buchanan 2,15, Joanne P Young 16,17,18, Ingrid M Winship 19,20, Mark A Jenkins 2,*
PMCID: PMC4573262  NIHMSID: NIHMS701514  PMID: 26077226

Abstract

Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6, and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA. Personal and family histories of cancer were obtained from participant interviews. Modified segregation analysis was used to estimate the hazard ratio (incidence rates for carriers relative to those for the general population), and age-specific cumulative risks of cervical cancer for carriers. A total of 65 cases of cervical cancer were reported (including 10 verified by pathology reports). The estimated incidence was 5.6–fold (95% CI: 2.3–13.8; p=0.001) higher for carriers than for the general population with a corresponding cumulative risk to 80 years of 4.5% (95% CI: 1.9–10.7%) compared with 0.8% for the general population. The mean age at diagnosis was 43.1 years (95% CI: 40.0–46.2), 3.9 years younger than the reported USA population mean of 47.0 years (p=0.02). Women with MMR gene mutations were found to have an increased risk of cervical cancer. Due to limited pathology verification we cannot be certain that a proportion of these cases were not lower uterine segment endometrial cancers involving the endocervix, a recognized cancer of Lynch syndrome.

BACKGROUND

Lynch syndrome, formerly known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is caused by a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2.1 MMR gene mutation carriers are at increased risk of colorectal (10–60% to age 70 years), endometrial (15–55% to age 70 years), and ovarian (12–24% to age 70 years) cancers.2–5 While there is some evidence that cervical cancer might be at increased risk of MMR gene mutation carriers, it is not currently recognized as a cancer associated with Lynch syndrome.

There have been several case reports of endocervical or cervical cancers in women suspected or known to carry mutations in MMR genes.5–9 Mongiat-Artus et al described a 48-year old woman with a germline nonsense mutation of the MSH2 gene who had developed a pT1b endocervical adenocarcinoma in addition to primary cancers of the ureter, colon and kidney.8 Tumoral microsatellite instability (MSI) (a hallmark of loss of MMR function) and loss of expression of both MSH2 and MSH6 proteins was observed in the cervical tumor as well as in the ureteric and colorectal tumors.8 MSI and loss of MMR protein expression in this cervical tumor suggest that its tumorigenesis could have been related to the inherent MMR defect along with the colorectal and ureteric tumors (already recognised as part of Lynch syndrome). Using a large resource of MMR gene mutation carrier families, we aimed to determine whether female carriers of a MMR gene mutation are at increased risk of cervical cancer.

MATERIALS AND METHODS

Ascertainment of families

Participants in this study were members of MLH1, MSH2, MSH6, and PMS2 mutation-carrying families recruited by the Colon Cancer Family Registry.10 Families were recruited between 1997 and 2012, and ascertained via incident cases of colorectal cancer (population-based probands) from population cancer registries in the USA (Washington, California, Arizona, Minnesota, Colorado, New Hampshire, North Carolina, and Hawaii), Australia (Victoria), and Canada (Ontario), or via patients (clinic-based probands) attending family cancer clinics in the USA (Mayo Clinic, Rochester, Minnesota and Cleveland), Australia (Melbourne, Adelaide, Perth, Brisbane, Sydney), New Zealand (Auckland), and Canada (Ontario). Probands were asked for permission to contact their relatives to seek their enrollment in the Colon Cancer Family Registry. Informed consent was obtained from all study participants, and the study protocols were approved at each recruitment center. Standardized instruments and protocols10 have been used to collect family history information, lifestyle and clinical data, and biological specimens (blood samples and tumor blocks).

Data collection

Information on personal and family history of cancer, including cancer site, age at diagnosis and cancer surgery, was obtained from all participants by interview, self-completed questionnaire or examination of clinical records. Participants were asked to consent to the release of tumor tissue, relevant medical records and provide a blood sample at the time of entry into the registry. Verification of all reported colorectal cancer diagnoses was attempted for all Colon Cancer Family Registry families, with some sites of the Colon Cancer Family Registry attempting to verify all reports of cancer recognized as part of Lynch syndrome using multiple sources, including reports from relatives, pathology reports, medical records, cancer registrations and death certificates. As cervical cancer is not a recognized Lynch associated cancer, no active verification was sought by the Colon Cancer Family Registry. Therefore, for this study, we attempted to obtain pathology reports for all reported cases of cervical cancer.

Mutation Screening and Testing

The Colon Cancer Family Registry tested for germline MLH1, MSH2, MSH6 and PMS2 mutations: all population-based probands who had a colorectal tumor displaying evidence of impaired MMR function by either MSI or by lack of MMR protein expression by immunohistochemistry; and the youngest-onset colorectal cancer case in each clinic-based family, regardless of MSI or MMR protein expression status. Details of germline testing methods have been described elsewhere.11 All participants who donated a blood sample, and who were relatives of probands with a pathogenic mutation,11 underwent testing for the same mutation identified in the proband.

Statistical Analysis

Hazard ratios (age-specific cancer incidence rates for carriers divided by the corresponding population rates) and corresponding 95% confidence intervals (CIs) were estimated from carrier families using modified segregation analysis. Models were fitted by maximum likelihood and all estimates were adjusted for ascertainment by conditioning the likelihood of each family on the proband’s phenotype and genotype (for population-based families) or on all of the family’s phenotypes and the proband’s genotype (for clinic-based families). Families were assumed to be independent so estimates were obtained by maximizing the sum of the conditional likelihoods over all families.

The hazard ratio for cervical cancer was estimated simultaneously with hazard ratios for colorectal, endometrial and other Lynch syndrome-associated cancers. This was necessary to correct for ascertainment and is likely to increase power (as these other cancers give probabilistic information about the carrier status of un-genotyped relatives). Hazard ratios were allowed to depend on age. Country-specific population cancer incidence rates were used as the incidences for non-carriers and were obtained from the Cancer in Five Continents 1998–2002,12 with this compilation chosen because its time-period is the closest to the median year of diagnosis of all cancers in the MMR gene mutation families. Individuals were censored at any cancer diagnosis (since the resultant treatment and surveillance might alter the risk of subsequent endometrial and cervical cancers) and at hysterectomy (since this is likely to remove the cervix).

Age-specific cumulative risk estimates were calculated from the estimated hazard ratios and population incidence rates as one minus the exponential of minus the cumulative incidences. Corresponding 95% CIs were calculated using a parametric bootstrap with 5000 replications, and were based on the joint distribution of the hazard ratio estimates known from asymptotic likelihood theory. We assumed Hardy-Weinberg equilibrium for each MMR gene and an allele frequency of 0.0001 for all MMR gene mutations combined.

All p-values were two-sided and were based on the likelihood ratio test (for the modified segregation analyses) or t-tests (for age comparisons). Modified segregation analyses were conducted using the statistical package MENDEL version 3.2,13 and all other calculations were performed using R version 2.11.1 (R development core team, 2010).

RESULTS

A total of 369 MMR gene mutation families were included in this analysis (distribution of the MMR gene mutation of the proband: 133 in MLH1, 174 in MSH2, 35 in MSH6 and 27 in PMS2). Data were available on 14,931 individuals within these families (7,119 females and 7,812 males). Mutation testing identified 1,073 carriers (including the probands) and 960 non-carriers.

A total of 65 cases of cervical cancer were self-reported or reported by a relative among the female relatives of the MMR gene mutation carrying probands (distribution of the MMR gene mutation of the proband: 23 MLH1, 35 MSH2, 3 MSH6 and 4 PMS2). Of these 65 reports of cervical cancer cases (included 2 in-situ cases) in the relatives: 16 (25%) cases were verified by either pathology report (n = 10), clinical record (n = 2) and/or cancer registry record (n = 4); with the remainder (n = 49; 75%) not clinically verified. None of the 65 reported cases were verified as not being a cervical cancer. Of the 10 cervical cancer cases verified by pathology reports, 7 were reported as being either adenocarcinoma or mixed histology with a predominance of adenocarcinoma, and 3 as squamous cell carcinomas.

Of the 65 females with reported cervical cancer, 11 were confirmed MMR mutation carriers, 13 were confirmed non-carriers, and the remaining 41 were untested but were genetically related to known carriers. The mean age at diagnosis was 43.1 years (95% CI: 40.0–46.2) (range 18–70), 3.9 years younger than the reported USA population mean of 47.0 years14 (p = 0.02). The incidence of cervical cancer was estimated to be 5.6–fold (95% CI: 2.3–13.8; p = 0.001) higher for MMR gene mutation carriers than for the general population. There was no evidence that the cervical cancer hazard ratios varied by MMR gene (p = 0.3 for heterogeneity). The corresponding estimated cumulative risks are given in Table 1 and, illustrated in Figure 1. The cumulative risk to age 80 years was 4.5% (95% CI: 1.9–10.7%) for MMR gene mutation carriers compared with 0.8% for the general population.12

Table 1.

Estimated cumulative risks (%) of cervical cancer to various ages by country and mismatch repair gene mutation carrier status (non-carriers assumed to have the population incidence).

Age (years) Carriers Non-carriers
USA Canada Australia USA Canada Australia
30 0.31 (0.13–0.76) 0.32 (0.13–0.79) 0.2 (0.08–0.48) 0.06 0.06 0.04
40 1.1 (0.44–2.6) 1.0 (0.42–2.5) 0.66 (0.27–1.6) 0.19 0.18 0.12
50 2.0 (0.82–4.8) 1.8 (0.75–4.4) 1.2 (0.51–3.0) 0.36 0.33 0.22
60 2.9 (1.2–6.8) 2.5 (1.0–6.1) 1.8 (0.74–4.4) 0.51 0.46 0.32
70 3.7 (1.5–8.9) 3.3 (1.4–7.9) 2.5 (1.0–6.1) 0.68 0.59 0.46
80 4.5 (1.9–10.7) 4.0 (1.7–9.5) 3.3 (1.4–7.9) 0.82 0.72 0.60
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Figure 1.

Figure 1

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Age-specific cumulative risk of cervical cancer for MMR gene mutation carriers (solid bold line) with corresponding 95% confidence intervals (shaded region) and for non-carriers (dashed bold line) from USA.

DISCUSSION

In this study, we estimated that female MMR gene mutation carriers have incidence rates of reported cervical cancer which are approximately six-times higher than those for the general population and that the reported cervical cancers of carriers are diagnosed an average of approximately four years earlier. Our findings are suggestive that cancer of the cervix may be an additional extracolonic cancer associated with germline MMR gene mutations. The very limited number of retrievable pathology reports importantly ruled out the ability for verification as to whether a proportion of these cases were in fact endometrial tumors arising from the lower uterine segment and involving the endocervix, a recognized phenomenon of MMR-deficient uterine tumors,15–17 either because of germline MMR gene mutations or MLH1 methylation. Based on our observation that all 10 pathology reports we could obtain, verified the reports as true cervical cancer, and assuming that the cases for which we could obtain these pathology reports were representative of all 65 reported cases, we estimate that the 95% CI for the true proportion of the 65 reported cases would be 74% to 100%.

A review of the literature revealed three reports including cervical cancers from registries of known or potential Lynch syndrome families; two supportive,18, 19 and one contrary to our findings.20 A study from the Hereditary Colorectal Cancer Registry of the AC Camargo Hospital in Brazil, observed that cervical cancer was the most frequently reported extracolonic tumor among known MMR gene mutation carriers.18 The authors, however, reported concern that without verification, most of the reported cancers were likely to be misreported endometrial cancers. Casey et al19 recently reviewed all gynaecological cancer records from the Creighton University Hereditary Cancer Registry for patients with known germline BRCA1/2 and MMR gene mutations. They reported cervical cancers in three known MMR gene carriers: one squamous cell carcinoma (in a MLH1 mutation carrier) and two adenocarcinomas (one in a MLH1 and one in a MSH2 mutation carrier). Contrary to our findings, Bermejo and colleagues reported that Swedish women in families that fulfilled the Amsterdam or Bethesda criteria for Lynch syndrome (N=5158; note: these were not tested for mutations in MMR genes) had a lower risk of cervical cancer compared with those in the population (relative risk = 0.76, 95% CI: 0.59–0.98, p=0.03).20 The authors postulated that this could have been because women in these families were undertaking regular screening for endometrial cancer, and the low cervical cancer risk estimate was due to serendipitous early detection and management of in situ lesions. Another explanation is that hysterectomies conducted as management of endometrial cancer or benign or precancerous conditions reduced risk due to removal of cervix.

The strengths of this study include: the large sample size and the use of statistical methods which utilize data on all subjects (whether genotyped or not), both of which increase the precision of risk estimates; the use of statistical methods which properly correct for ascertainment and so avoid ascertainment bias; the use of standardized questionnaires across recruitment sites, increasing the study’s validity and reliability; and the high-quality and sensitive testing for MMR gene mutations across all recruiting centers of Colon Cancer Family Registry. Though we included all female relatives in the analysis, even those not surveyed as participants, one limitation is that for women not surveyed, we do not know whether or not they had a hysterectomy, or the age at which this occurred. We had no hysterectomy data for 62% of women in this analysis. It is likely that a proportion of these women might have had a hysterectomy and therefore, in these women, the observation time in our analysis would have included time after a hysterectomy, thereby underestimating the actual risk. Therefore, our estimate of the increased risk of cervical cancer might be an underestimate of the true increased risk. A major limitation of this study was that most diagnoses of cervical cancers (75%) were self-reported or reported by relatives.

This novel finding highlights one of the current issues associated with understanding the breadth of cancer risk that may be associated with Lynch syndrome. While colorectal and endometrial cancers are the most frequent sites associated with Lynch syndrome, it is also recognized that other sites of cancer origin are reported more frequently in MMR gene mutation carriers than population rates.5, 21, 22 Ideally, future prospective collections of epidemiological data, tumor specimens, specimens from risk-reducing surgery from known MMR gene mutation carriers, regardless of the organ should be considered to assess for the likelihood of MMR deficiency. While it is conceivable that cervical cancer development in MMR gene mutation carriers is related to currently known tumorigenic pathways associated with the carcinogenic effects of human papilloma virus exposure, it is also important to establish with certainty the organs at increased risk of carcinogenesis in the setting of MMR deficiency not only for identifying individuals at risk of Lynch syndrome, but also for risk management (individual and familial) and potential future therapeutic options. We suggest that further studies are required to explore this finding.

Novelty & Impact Statements.

Women with a DNA mismatch repair gene mutation (Lynch syndrome) were found to have an increased risk of cervical cancer that is six-times higher than the general population. The reported cervical cancers of carriers were diagnosed an average of approximately four years earlier than the general population. Cervical cancer might be part of Lynch syndrome spectrum cancers.

Acknowledgments

The authors thank all study participants of the Colon Cancer Family Registry and staff for their contributions to this project

Funding

This work was supported by grant UM1 CA167551 from the National Cancer Institute, National Institutes of Health (NIH) and through cooperative agreements with members of the Colon Cancer Family Registry and Principal Investigators. Collaborating centers include Australasian Colorectal Cancer Family Registry (U01/U24 CA097735), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (U01/U24 CA074794), Stanford Consortium Colorectal Cancer Family Registry (U01/U24 CA074799), and University of Hawaii Colorectal Cancer Family Registry (U01/U24 CA074806). Yoland Antill has received salary support from the Royal Australasian College of Physicians, Servier Staff Scholarship, and a Victorian Cancer Agency Early Career Seed Grant. AKW is an Australian National Health and Medical Research Council (NHMRC) Early Career Fellow. MAJ is an NHMRC Senior Research Fellow. JLH is a NHMRC Senior Principal Research Fellow. DDB is a University of Melbourne Research at Melbourne Accelerator Program (R@MAP) Senior Research Fellow.

Footnotes

Disclaimer

The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Cancer Family Registries, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the Cancer Family Registry. Authors had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript.

Conflict of Interest

The authors have no conflict of interest to declare with respect to this manuscript.

References

  • 1.Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer. 2015;15:181–94. doi: 10.1038/nrc3878. [DOI] [PubMed] [Google Scholar]
  • 2.Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, Vriends AH, Cartwright NR, Barnetson RA, Farrington SM, Tenesa A, Hampel H, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102:193–201. doi: 10.1093/jnci/djp473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135:419–28. doi: 10.1053/j.gastro.2008.04.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Bonadona V, Bonaiti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Nogues C, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304–10. doi: 10.1001/jama.2011.743. [DOI] [PubMed] [Google Scholar]
  • 5.Dowty JG, Win AK, Buchanan DD, Lindor NM, Macrae FA, Clendenning M, Antill YC, Thibodeau SN, Casey G, Gallinger S, Marchand LL, Newcomb PA, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum Mutat. 2013;34:490–7. doi: 10.1002/humu.22262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Chen CH, Huang RL, Yu MS, Wong LJ, Chao TF, Chu TY. Hereditary nonpolyposis colorectal cancer with gynecologic malignancies: report of two families in Taiwan. J Formos Med Assoc. 2001;100:269–73. [PubMed] [Google Scholar]
  • 7.Lynch HT, Kriegler M, Christiansen TA, Smyrk T, Lynch JF, Watson P. Laryngeal carcinoma in a Lynch syndrome II kindred. Cancer. 1988;62:1007–13. doi: 10.1002/1097-0142(19880901)62:5<1007::aid-cncr2820620528>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  • 8.Mongiat-Artus P, Miquel C, Flejou JF, Coulet F, Verine J, Buhard O, Soliman H, Teillac P, Praz F. Spectrum of molecular alterations in colorectal, upper urinary tract, endocervical, and renal carcinomas arising in a patient with hereditary non-polyposis colorectal cancer. Virchows Arch. 2006;449:238–43. doi: 10.1007/s00428-006-0182-9. [DOI] [PubMed] [Google Scholar]
  • 9.Nair N, Curtin JP, Mittal K, Hiotis KL. Cervical adenocarcinoma in a patient with Lynch syndrome, Muir-Torre variant. J Clin Oncol. 2012;30:e5–6. doi: 10.1200/JCO.2011.36.3325. [DOI] [PubMed] [Google Scholar]
  • 10.Newcomb PA, Baron J, Cotterchio M, Gallinger S, Grove J, Haile R, Hall D, Hopper JL, Jass J, Le Marchand L, Limburg P, Lindor N, et al. Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:2331–43. doi: 10.1158/1055-9965.EPI-07-0648. [DOI] [PubMed] [Google Scholar]
  • 11.Win AK, Lindor NM, Young JP, Macrae FA, Young GP, Williamson E, Parry S, Goldblatt J, Lipton L, Winship I, Leggett B, Tucker K, et al. Risks of primary extracolonic cancers following colorectal cancer in Lynch syndrome. J Natl Cancer Inst. 2012;104:1363–72. doi: 10.1093/jnci/djs351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, Boyle P. Cancer Incidence in Five Continents. International Agency for the Research on Cancer; 2007. [Google Scholar]
  • 13.Lange K, Weeks D, Boehnke M. Programs for Pedigree Analysis: MENDEL, FISHER, and dGENE. Genet Epidemiol. 1988;5:471–2. doi: 10.1002/gepi.1370050611. [DOI] [PubMed] [Google Scholar]
  • 14.Gong G, Hannon N, Whittemore AS. Estimating gene penetrance from family data. Genet Epidemiol. 2010;34:373–81. doi: 10.1002/gepi.20493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Masuda K, Banno K, Hirasawa A, Yanokura M, Tsuji K, Kobayashi Y, Kisu I, Ueki A, Nomura H, Tominaga E, Susumu N, Aoki D. Relationship of lower uterine segment cancer with Lynch syndrome: a novel case with an hMLH1 germline mutation. Oncol Rep. 2012;28:1537–43. doi: 10.3892/or.2012.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Westin SN, Lacour RA, Urbauer DL, Luthra R, Bodurka DC, Lu KH, Broaddus RR. Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome. J Clin Oncol. 2008;26:5965–71. doi: 10.1200/JCO.2008.18.6296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Garg K, Leitao MM, Jr, Kauff ND, Hansen J, Kosarin K, Shia J, Soslow RA. Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age and tumor morphology enhances detection of mismatch repair abnormalities. Am J Surg Pathol. 2009;33:925–33. doi: 10.1097/PAS.0b013e318197a046. [DOI] [PubMed] [Google Scholar]
  • 18.da Silva FC, de Oliveira LP, Santos EM, Nakagawa WT, Aguiar S, Junior, Valentin MD, Rossi BM, de Oliveira Ferreira F. Frequency of extracolonic tumors in Brazilian families with Lynch syndrome: analysis of a hereditary colorectal cancer institutional registry. Fam Cancer. 2010;9:563–70. doi: 10.1007/s10689-010-9373-2. [DOI] [PubMed] [Google Scholar]
  • 19.Casey MJ, Bewtra C, Lynch HT, Snyder C, Stacy M, Watson P. Phenotypic heterogeneity of hereditary gynecologic cancers: a report from the Creighton hereditary cancer registry. Fam Cancer. 2013;12:719–40. doi: 10.1007/s10689-013-9651-x. [DOI] [PubMed] [Google Scholar]
  • 20.Bermejo JL, Eng C, Hemminki K. Cancer characteristics in Swedish families fulfilling criteria for hereditary nonpolyposis colorectal cancer. Gastroenterology. 2005;129:1889–99. doi: 10.1053/j.gastro.2005.09.012. [DOI] [PubMed] [Google Scholar]
  • 21.Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014;23:437–49. doi: 10.1158/1055-9965.EPI-13-1165. [DOI] [PubMed] [Google Scholar]
  • 22.Win AK, Lindor N, Jenkins M. Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Res. 2013;15:R27. doi: 10.1186/bcr3405. [DOI] [PMC free article] [PubMed] [Google Scholar]

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