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Original Article
Impact of gene-specific germline pathogenic variants on presentation of endometrial cancer in Lynch syndrome
  1. Giorgio Bogani1,
  2. Maria Teresa Ricci2,
  3. Marco Vitellaro2,
  4. Antonino Ditto1,
  5. Valentina Chiappa1 and
  6. Francesco Raspagliesi1
  1. 1 Department of Gynecologic Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy
  2. 2 Unit of Hereditary Digestive Tract Tumors, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Milano, Italy
  1. Correspondence to Dr Giorgio Bogani, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano 20100, Italy; giorgiobogani{at}yahoo.it

Abstract

Objective Lynch syndrome is a risk factor for developing endometrial carcinoma. Our aim was to evaluate the impact of gene-specific germline pathogenic variants on clinical features of patients affected by endometrial cancer.

Methods Patients with a diagnosis of endometrial cancer and with a germline pathogenic variant in mismatch repair genes were reviewed. Patients were classified on the basis of classes of risk according to the ESGO-ESGO-ESTRO (European Society of Medical Oncology/European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology) guidelines. One-way analysis of variance (ANOVA) and Kruskal-Wallis test were performed to compare three groups of continuous parametric and non-parametric variables, respectively. χ2 test was used to analyze proportions.

Results Overall, 68 patients with endometrial cancer and Lynch syndrome were evaluated. Ten (14.7%) patients were excluded because of absence of information about the gene involved in Lynch syndrome, thus leaving 58 (85.3%) patients available for the final analysis. MLH1, MSH2, and MSH6 pathogenic variants were observed in 19 (32.7%), 33 (56.9%), and six (10.3%) patients, respectively. Mean±SD age at endometrial cancer diagnosis was 51±6.4, 43.5±7.4, and 60.3±8.8 years (p=0.0002). Prevalence of non-endometrioid endometrial cancer was 15.7%, 24.2%, and 0% in the MLH1, MSH2, and MSH6 groups, respectively (p=0.345). According to the ESMO-ESGO-ESTRO classification, low, intermediate, and high risk endometrial cancer accounted for 47.3%, 10.5%, and 42.1% of the MLH1 group, 57.6%, 3%, and 39.4% of the MSH2 group, and 50%, 50%m and 0% of the MSH6 group (p=0.009).

Conclusions Patients with MLH1 and MSH2 pathogenic variants are at a higher risk of early onset of endometrial cancer than patients with MSH6 pathogenic variants.

  • lynch syndrome
  • endometrial cancer
  • MLH1
  • MSH2
  • MSH6

https://doi.org/10.1136/ijgc-2019-000277

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    HIGHLIGHTS

    • Women with Lynch syndrome have a substantial risk of developing endometrial cancer as their first tumor type.

    • Patients harboring an MLH1 and MSH2 mutation are at high risk of early onset of endometrial cancer.

    • MLH1 and MSH2 pathogenic variants are at higher risk of more aggressive disease than patients with the MSH6 variant.

    Introduction

    Lynch syndrome is an autosomal dominant inherited disorder caused by the presence a germline pathogenic variant in one of the four DNA mismatch-repair (MMR) genes: mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), or post-meiotoic segregation increased 2 (PMS2).1 2 Mutation carriers are at substantially increased risk of developing cancers of the colorectum and endometrium.1 2 In women with MLH1 and MSH2 pathogenic variants, the cumulative incidences at 75 years for colorectal cancer are 42% and 45%, respectively.1 2 Lower risks have been estimated in patients with MSH6 pathogenic variants (15%). Regarding endometrial cancer, the lifetime risks are estimated to be 43%, 57% and 46% for MLH1, MSH2, and MSH6 mutation carriers, respectively.3 Interestingly, for many patients, gynecological malignancies (ie, endometrial or ovarian cancers) are the sentinel cancers for Lynch syndrome, with a diagnosis before colonic cancer in approximately 50% of Lynch syndrome patients.4

    Several studies compared clinical features and natural history of sporadic versus Lynch syndrome-related endometrial cancer,5 6 thus highlighting that Lynch syndrome-related endometrial cancer are characterized by an early onset in comparison to sporadic endometrial cancer. Carcangiu et al, in one of the largest single series with endometrial cancer and genetically confirmed Lynch syndrome (23 cases), observed that Lynch syndrome-related endometrial cancer showed a wider variety of histological types, a higher frequency of non-endometrioid endometrial cancer despite the younger age of the patients, and a higher frequency of high grades among the endometrioid endometrial cancer.6 Other investigators evaluated how the genes involved and the type of mutation has an impact on age at presentation. Ryan et al observed that pathogenic variants in the MSH6 gene correlated with the onset of endometrial cancer in later ages in comparison to other mutations.7 Moreover, when they were stratified by variant type (ie, truncating, splicing, or large rearrangements), women with truncating MLH1 variants presented with endometrial cancer at later ages than those with non-truncating variants. In contrast, the type of variant did not have an impact on MSH2 or MSH6 mutations carriers.7

    We aimed to investigate how gene-specific pathogenic variants have an impact on the clinical features of endometrial cancer, the first such study to do so.

    Methods

    This study was approved by our institutional review board (IRB approval number: INT/MI/006812). We collected data on consecutive endometrial cancer patients with Lynch syndrome. All patients had undergone treatment at the National Cancer Institute (Milan, Italy) from January 1, 1973 to December 31, 2015. All patients who were still alive gave written consent for their clinical information to be used for research purposes. Patients who did not consent were excluded.

    Inclusion criteria were: (1) histologically-proven endometrial cancer; (2) detection of a germline pathogenic variant in one of the MMR genes. Exclusion criteria were: (1) consent withdrawn; (2) loss of MMR protein expression at immunohistochemistry testing in he absence of a documented germline mutation. They were identified over the years among members of the families enroled in the Registry of Hereditary Colorectal Tumors of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. The presence of mismatch-repair pathogenic variants was determined by Sanger sequencing and multiplex ligation dependent probe amplification assay. The sequence variant nomenclature followed the Human Genome Variation Society guidelines8 and the final classification was performed according to the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) criteria for the interpretation of MMR gene variants.9 EPCAM and MSH2 genes were tested together. Only carriers of pathogenic or likely pathogenic variants (ie, class 5 and 4 according to the InSiGHT classification) were included in the study.6

    Data were obtained from the computerized surgical database at our institution. This database is updated by trained residents, according to the American College of Surgeons' National Quality Improvement Program platform.10 Individual patients' records were reviewed in order to identify baseline patient and disease characteristics. Twenty-three patients included in our study were already included in a study published from our institution.6

    The diagnosis of endometrial cancer was performed by two gynecologic pathologists. Stage and architectural grade were reported in accord with the 2009 International Federation of Obstetrics and Gynecologists (FIGO).11 World Health Organization taxonomy was used in order to classify histological subtypes.11 Classes of risk were graded for the stratification system proposed by the ESMO-ESGO-ESTRO (European Society of Medical Oncology/European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology) consensus classification.10 Patients were classified as follows. Low-risk: FIGO stage I endometrioid endometrial cancer, grade 1 and 2 with myometrial invasion <50%, and without lymph-vascular space invasion. Intermediate-risk: FIGO stage I endometrioid endometrial cancer, grade 1 and 2 with myometrial invasion ≥50%, and lymph-vascular space invasion negative (intermediate-low); FIGO stage I endometrioid endometrial cancer, grade 1 and 2 with lymph-vascular space invasion (intermediate-high); FIGO stage I endometrioid endometrial cancer, grade 3 with myometrial invasion <50%, regardless of lymph-vascular space invasion status (intermediate-high). High-risk: FIGO stage I endometrioid endometrial cancer, grade 3 with myometrial invasion ≥50%; non-endometrioid endometrial cancer; FIGO stage >I. Figure 1 shows risk stratification according to the ESMO-ESGO-ESTRO criteria.12

    Figure 1
    Figure 1

    Risk stratification group according to the ESGO-ESMO-ESTRO (European Society of Medical Oncology/European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology) guidelines. FIGO, International Federation of Obstetrics and Gynecologists; LVSI, lymphovascular space invasion; MI, myometrial invasion.

    The primary endpoint measure was to investigate how gene-specific pathogenic variants impacted the clinical features of endometrial cancer, including age at presentation, histology, grade, and risk class. The secondary endpoint measure was to show characteristics of Lynch syndrome-related endometrial cancer. Owing to the relative small sample size of the study population, we did not perform an analysis on survival.

    Statistical analysis was performed with GraphPad Prism version 5.00 for Windows (GraphPad Software, San Diego, CA) and IBM-Microsoft SPSS version 20.0 for Mac. Normality testing (D’Agostino and Pearson test) was performed to determine whether data were sampled from a Gaussian distribution. One-way analysis of variance (ANOVA) and Kruskal-Wallis test were performed to compare three groups of continuous parametric and non-parametric variables, respectively. χ2 test was used to analyze proportions. The incidence of events between two groups was analyzed for statistical significance by using the Fisher exact test; 95% confidence intervals (CI) were calculated for each comparison. Values of p<0.05 were considered statistically significant.

    Results

    Overall, 68 patients with endometrial cancer and Lynch syndrome were evaluated. Table 1 presents the baseline patient characteristics. Ten (14.7%) patients were excluded because of absence of information about the gene involved in Lynch syndrome, leaving 58 (85.3%) patients available for analysis. MLH1, MSH2, and MSH6 pathogenic variants were observed in 19 (32.7%), 33 (56.9%), and six (10.3%) cases, respectively. Figure 2 shows the study design.

    Figure 2
    Figure 2

    Study design. MLH1, mutL homolog 1; MSH2, mutS homolog 2; MSH6, mutS homolog 6.

    View this table:
    Table 1

    Baseline patient characteristics

    Mean+SD age at endometrial cancer diagnosis was 51±6.4, 43.5±7.4, and 60.3±8.8 years (p=0.0002). Patients carrying a germline pathogenic variant in MLH1, MSH2, and MSH6 had endometrial cancer arising in the isthmus in 10.5%, 12%, and 0% of cases, respectively (p=0.67). Similarly, the prevalence of non-endometrioid endometrial cancer was 15.7%, 24.4%, and 0% in the MLH1, MSH2, and MSH6 groups, respectively (p=0.34). FIGO stage at presentation included: stage I, II and III in 15 (79%), two (10.5%), and two (10.5%) patients with an MLH1 pathogenic variant; 27 (81.8%), four (12.1%), and two (6.1%) patients with an MSH2 pathogenic variant; and six (100%), 0 (0%), and 0 (0%) patients with an MSH6 pathogenic variant, respectively (p=0.77). Details about baseline difference according to which gene is mutated are reported in Table 2.

    View this table:
    Table 2

    Patients’ details according to the gene-specific germline pathogenic variants

    When we focus on class of risk, we observed a trend toward a higher proportion of more aggressive endometrial cancer in patients harboring an MLH1 or an MSH2 pathogenic variant than in patients with an MSH6 mutation. In fact, according to the ESMO-ESGO-ESTRO classification, low-risk, intermediate-, and high-risk endometrial cancer accounted or 47.3%, 10.5%, and 42.1% of the MLH1 group, 57.6%, 3%, and 39.4% of the MSH2 group, and 50%, 50%, and 0% of the MSH6 group (p=0.009). Table 3 reports risk stratification of the entire cohort of patients.

    View this table:
    Table 3

    Risk stratification according to the gene-specific germline pathogenic variants

    Discussion

    We found that patients harboring an MSH6 pathogenic variant are characterized by low aggressive disease in comparison to carriers of pathogenic variants in the MLH1 or MSH2 genes. Patients harboring pathogenic variants in the MLH1 or MSH2 gene are characterized by a younger age at presentation in comparison to patients with a pathogenic variant in the MSH6 gene. Overall, 2.9%, 16%, and 52.9% of Lynch syndrome patients were diagnosed with endometrial cancer before the age of 35, 40, and 50 years, respectively. We also noted that Lynch syndrome-related endometrial cancers are characterized by aggressive histological features, with approximately a quarter diagnosed with non-endometrioid endometrial cancer and a third with high-risk endometrial cancer.

    Historically, Lynch syndrome-related endometrial cancers are considered to occur at a young age (about two decades earlier than sporadic endometrial cancer) and most are characterized by endometrioid histology.13 14 There are limited data reported on outcomes of patients affected by Lynch syndrome-related endometrial cancer.5 6 12–14 Boks et al, reported data from the registry of the Netherlands Foundation for Hereditary Tumors, including 50 patients with Lynch syndrome-related endometrial cancer from 46 families (not all harboring a germline mutation). They observed that 92% of the Lynch syndrome-related endometrial cancers were endometrioid endometrial cancer, as compared with 88% in the control group.13 Similarly, van den Bos and colleagues reported a series of six cases of endometrial cancer harboring Lynch syndrome-mutation carriers. All six cases were endometrioid endometrial cancer.13 Rossi et al performed a French multicenter retrospective study, collecting data from 49 Lynch syndrome-related endometrial cancers in five centers from 1977 to 2013.5 They observed that Lynch syndrome-related endometrial cancers are characterized by young age at onset, high prevalence of lower uterine segment involvement, and synchronous ovarian cancers. The prognosis for these cancers does not appear to be different from sporadic tumors.

    There is increasing evidence that Lynch syndrome-related endometrial cancers are characterized by more aggressive features in comparison with the sporadic counterpart.6 15 The aforementioned research by Carcangiu et al reported data from 23 Lynch syndrome-related endometrial cancer patients, and compared these data with an age-adjusted control group of 46 sporadic endometrial cancer patients (control group had a personal and family history of Lynch syndrome-associated cancers). The authors observed that among Lynch syndrome-related endometrial cancers there were 13 (56.5%) endometrioid and 10 (43.5%) non-endometrioid endometrial cancers, while among the control group there were 44 (95.7%) endometrioid and two (4.3%) non-endometrioid endometrial cancers (p=0.001). Similarly, Lynch syndrome-related endometrial cancers are characterized by higher FIGO grade and more frequent vascular invasion. Broaddus et al analyzed data from 50 Lynch syndrome-related endometrial cancers. Nearly one in four of the Lynch syndrome-related endometrial cancers had pathologic features requiring adjuvant therapy after surgery. Moreover, the authors showed that women diagnosed with Lynch syndrome had a high tendency to be diagnosed with non-endometrioid endometrial cancer, in particular patients with MSH2 pathogenic variants.15 The present study corroborated these results, suggesting that Lynch syndrome-related endometrial cancers are characterized by high-risk features that include those with non-endometrioid histology.

    Recently, Ring et al aimed to determine the prevalence of cancer predisposition gene mutations in an unselected cohort of 381 endometrial cancer patients having tumor testing to screen for Lynch syndrome, using a next-generation sequencing-based panel.16 Twenty-two (5.8%) patients had mutations in genes involved in Lynch syndrome (three MLH1, five MSH2, two EPCAM-MSH2, six MSH6, and six PMS2) and 13 (3.4%) in 10 non-Lynch syndrome genes (four CHEK2, one each in APC, ATM, BARD1, BRCA1&2, BRIP1, NBN, PTEN, and RAD51C). The author observed that patients with deleterious mutations in non-Lynch syndrome genes were more likely to have non-endometrioid endometrial cancer in comparison to patients with mutations in Lynch syndrome genes (23.1% vs 6.4%, p=0.02).16 Another interesting point is the relatively high prevalence of tumors arising from the lower uterine segment, especially for patients with mutations of the MLH1 and MSH2 genes. These data are in agreement with those presented by Westin et al, who reported a high prevalence of endometrial cancer arising in the lower uterine segment among patients with Lynch syndrome in comparison to sporadic cases (29% vs 1.8%).17

    To date, our investigation is the first study to highlight an association between the mutated gene and clinical features of endometrial cancer. Recently, Ryan et al evaluated how the types of variants influence presentation of Lynch syndrome-related cancer, analyzing data included in the clinical database of a large quaternary referral center for genomic medicine in the northwest of England. They evaluated 1063 individuals with cancer and proven Lynch syndrome, of whom 162 women had endometrial cancer.7 They observed that women with MSH6 pathogenic variants presented with endometrial cancer at later ages than women with other mutations (median difference from MLH1 mutation carriers, 3.9 years, 95% CI 0.9 to 6.5 years; median difference from MSH2 mutation carriers, 5.7 years, 95% CI 2.4 to 8.5 years). The authors stratified their results for variant type, thus observing that women with truncating MLH1 pathogenic variants presented with endometrial cancer at later ages than those with non-truncating pathogenic variants (median difference, 6.6 years, 95% CI 2.7 to 10.4 years). The same was not true for MSH2 and MSH6 mutation carriers.7

    The inherent biases of the single center study design represent the main weaknesses of the present study. Although the relatively small sample size did not allow us to investigate survival outcomes, we consider this study represents the largest single center investigation on Lynch syndrome-related endometrial cancer. The sample size and the inclusion of proven Lynch syndrome-related endometrial cancers are the strength of our investigation. Our data would be useful for patient counseling and to help physicians in planning surveillance or timing of prophylactic surgery. In fact, accumulating data underlined that prophylactic hysterectomy with bilateral salpingo-oophorectomy is an effective strategy for preventing endometrial and ovarian cancer in women with Lynch syndrome.18 Schmeler et al, comparing data from women with Lynch syndrome having prophylactic surgery versus surveillance alone, observed that prophylactic hysterectomy reduces the risk of developing endometrial cancer (density was 0.000 per woman-year for those who underwent prophylactic hysterectomy and 0.045 per woman-year for those who did not (p<0.001)).18

    In conclusion, our data underline the high prevalence of high-risk endometrial cancer in carriers of MMR mutations. MSH6 pathogenic variants correlate with the onset of endometrial cancer in later ages compared to pathogenic variants in the MLH1 or MSH2 genes. More importantly, patients harboring a pathogenic variant in the MSH6 gene are characterized by less aggressive disease compared with patients harboring pathogenic variants in the MLH1 or MSH2 genes. Further studies are warranted in order to provide a clear insight into genotype–phenotype correlations.

    Acknowledgments

    We thank Maria Luisa Carcangiu for her help in the pathology review.

    References

    1. 1.↵
      2. Gruber SB ,
      3. Thompson WD
      . A population-based study of endometrial cancer and familial risk in younger women. Cancer and Steroid Hormone Study Group. Cancer Epidemiol Biomarkers Prev1996;5:411–7.
      OpenUrlAbstract
    2. 2.↵
      2. Adar T ,
      3. Rodgers LH ,
      4. Shannon KM , et al
      . Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome. Cancer2018;124:3145–53.doi:10.1002/cncr.31534
      OpenUrl
    3. 3.↵
      2. Møller P ,
      3. Seppälä TT ,
      4. Bernstein I , et al
      . Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut2018;67:1306–16.doi:10.1136/gutjnl-2017-314057
      OpenUrlAbstract/FREE Full Text
    4. 4.↵
      2. Lu KH ,
      3. Dinh M ,
      4. Kohlmann W , et al
      . Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol2005;105:569–74.doi:10.1097/01.AOG.0000154885.44002.ae
      OpenUrlCrossRefPubMedWeb of Science
    5. 5.↵
      2. Rossi L ,
      3. Le Frere-Belda M-A ,
      4. Laurent-Puig P , et al
      . Clinicopathologic characteristics of endometrial cancer in Lynch syndrome: a French multicenter study. Int J Gynecol Cancer2017;27:953–60.doi:10.1097/IGC.0000000000000985
      OpenUrlAbstract/FREE Full Text
    6. 6.↵
      2. Carcangiu ML ,
      3. Radice P ,
      4. Casalini P , et al
      . Lynch syndrome--related endometrial carcinomas show a high frequency of nonendometrioid types and of high FIGO grade endometrioid types. Int J Surg Pathol2010;18:21–6.doi:10.1177/1066896909332117
      OpenUrlCrossRefPubMed
    7. 7.↵
      2. Ryan NAJ ,
      3. Morris J ,
      4. Green K , et al
      . Association of mismatch repair mutation with age at cancer onset in Lynch syndrome: implications for stratified surveillance strategies. JAMA Oncol2017;3:1702–6.doi:10.1001/jamaoncol.2017.0619
      OpenUrl
    8. 8.↵
      2. den Dunnen JT ,
      3. Dalgleish R ,
      4. Maglott DR , et al
      . HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat2016;37:564–9.doi:10.1002/humu.22981
      OpenUrlCrossRefPubMed
    9. 9.↵
      2. Thompson BA ,
      3. Spurdle AB ,
      4. Plazzer J-P , et al
      . Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the INSIGHT locus-specific database. Nat Genet2014;46:107–15.doi:10.1038/ng.2854
      OpenUrlPubMed
    10. 10.↵
      2. Hutter MM ,
      3. Rowell KS ,
      4. Devaney LA , et al
      . Identification of surgical complications and deaths: an assessment of the Traditional Surgical Morbidity and Mortality Conference compared with the American College of Surgeons-National Surgical Quality Improvement Program. J Am Coll Surg2006;203:618–24.doi:10.1016/j.jamcollsurg.2006.07.010
      OpenUrlCrossRefPubMedWeb of Science
    11. 11.↵
      2. Bogani G ,
      3. Multinu F ,
      4. Dowdy SC , et al
      . Incorporating robotic-assisted surgery for endometrial cancer staging: analysis of morbidity and costs. Gynecol Oncol2016;141:218–24.doi:10.1016/j.ygyno.2016.02.016
      OpenUrl
    12. 12.↵
      2. Colombo N ,
      3. Creutzberg C ,
      4. Amant F , et al
      . ESMO-ESGO-ESTRO Consensus Conference on endometrial cancer: diagnosis, treatment and follow-up. Int J Gynecol Cancer2016;26:2–3.doi:10.1097/IGC.0000000000000609
      OpenUrlAbstract/FREE Full Text
    13. 13.↵
      2. Boks DES ,
      3. Trujillo AP ,
      4. Voogd AC , et al
      . Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer2002;102:198–200.doi:10.1002/ijc.10667
      OpenUrlCrossRefPubMedWeb of Science
    14. 14.↵
      2. van den Bos M ,
      3. van den Hoven M ,
      4. Jongejan E , et al
      . More differences between HNPCC-related and sporadic carcinomas from the endometrium as compared to the colon. Am J Surg Pathol2004;28:706–11.doi:10.1097/01.pas.0000126720.49083.11
      OpenUrlCrossRefPubMedWeb of Science
    15. 15.↵
      2. Broaddus RR ,
      3. Lynch HT ,
      4. Chen L-M , et al
      . Pathologic features of endometrial carcinoma associated with HNPCC: a comparison with sporadic endometrial carcinoma. Cancer2006;106:87–94.doi:10.1002/cncr.21560
      OpenUrlCrossRefPubMedWeb of Science
    16. 16.↵
      2. Ring KL ,
      3. Bruegl AS ,
      4. Allen BA , et al
      . Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. Mod Pathol2016;29:1381–9.doi:10.1038/modpathol.2016.135
      OpenUrl
    17. 17.↵
      2. Westin SN ,
      3. Lacour RA ,
      4. Urbauer DL , et al
      . Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome. J Clin Oncol2008;26:5965–71.doi:10.1200/JCO.2008.18.6296
      OpenUrlAbstract/FREE Full Text
    18. 18.↵
      2. Schmeler KM ,
      3. Lynch HT ,
      4. Chen L-may , et al
      . Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med2006;354:261–9.doi:10.1056/NEJMoa052627
      OpenUrlCrossRefPubMedWeb of Science

    Footnotes

    • Contributors GB: manuscript preparation; data analysis; statistical analysis. MTR: data collection; data analysis; reviewing the manuscript. MV: data collection; data analysis; reviewing the manuscript. AD: data collection; data analysis; reviewing the manuscript. VC: data collection; data analysis; reviewing the manuscript. FR: data collection; data analysis; reviewing the manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent for publication Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.