Cancer Characteristics in Swedish Families Fulfilling Criteria for Hereditary Nonpolyposis Colorectal Cancer
2005; Elsevier BV; Volume: 129; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2005.09.012
ISSN1528-0012
AutoresJusto Lorenzo Bermejo, Charis Eng, Kari Hemminki,
Tópico(s)BRCA gene mutations in cancer
ResumoBackground & Aims: The present study quantified the prevalence of families that fulfill the Amsterdam or Bethesda criteria for hereditary nonpolyposis colorectal cancer (HNPCC) in the whole Swedish population and investigated the extent to which tumors in the classified families are HNPCC-related. Methods: The families of the Swedish Family-Cancer Database with at least 4 generations (N = 566,877) were classified according to the Amsterdam and the Bethesda criteria. Survival methods were used to assess the risk of cancer in the classified families, the prognosis of cancer patients, and the risk of subsequent malignancies after colorectal adenomas and after colorectal/endometrial adenocarcinomas. Results: The Bethesda criteria identified 0.9% of all Swedish families and 11.2% of patients with colorectal cancer. Families that fulfilled the Bethesda criteria showed increased risks of cancer in the colorectum, endometrium, small bowel, ovary, stomach, bile ducts, renal pelvis, and ureter; members of Bethesda criteria families were at decreased risks of lung and cervical cancers. The prognosis of cancer in the ureter, renal pelvis, stomach, ovary, and colorectum, but not in the endometrium, was better in Bethesda criteria than in nonclassified families. Conclusions: Most malignancies in the classified families reflect typical features of HNPCC (association with subsequent malignancies, accelerated adenoma-carcinoma sequence, and better survival). The data presented in this study should help to define surveillance strategies for members of families that fulfill the criteria for HNPCC testing. Background & Aims: The present study quantified the prevalence of families that fulfill the Amsterdam or Bethesda criteria for hereditary nonpolyposis colorectal cancer (HNPCC) in the whole Swedish population and investigated the extent to which tumors in the classified families are HNPCC-related. Methods: The families of the Swedish Family-Cancer Database with at least 4 generations (N = 566,877) were classified according to the Amsterdam and the Bethesda criteria. Survival methods were used to assess the risk of cancer in the classified families, the prognosis of cancer patients, and the risk of subsequent malignancies after colorectal adenomas and after colorectal/endometrial adenocarcinomas. Results: The Bethesda criteria identified 0.9% of all Swedish families and 11.2% of patients with colorectal cancer. Families that fulfilled the Bethesda criteria showed increased risks of cancer in the colorectum, endometrium, small bowel, ovary, stomach, bile ducts, renal pelvis, and ureter; members of Bethesda criteria families were at decreased risks of lung and cervical cancers. The prognosis of cancer in the ureter, renal pelvis, stomach, ovary, and colorectum, but not in the endometrium, was better in Bethesda criteria than in nonclassified families. Conclusions: Most malignancies in the classified families reflect typical features of HNPCC (association with subsequent malignancies, accelerated adenoma-carcinoma sequence, and better survival). The data presented in this study should help to define surveillance strategies for members of families that fulfill the criteria for HNPCC testing. Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant syndrome that accounts for 1%–5% of colorectal cancer.1Lynch H.T. de la Chapelle A. 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Nystrom-Lahti M. et al.Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer.Cell. 1993; 75: 1215-1225Abstract Full Text PDF PubMed Scopus (2109) Google Scholar Defective mismatch repair may lead to expansion or contraction of short repeat sequences of DNA, a phenomenon known as microsatellite instability (MSI), which also characterizes HNPCC.16Aaltonen L.A. Peltomaki P. Leach F.S. Sistonen P. Pylkkanen L. Mecklin J.P. Jarvinen H. Powell S.M. Jen J. Hamilton S.R. et al.Clues to the pathogenesis of familial colorectal cancer.Science. 1993; 260: 812-816Crossref PubMed Scopus (2589) Google Scholar, 17Thibodeau S.N. Bren G. Schaid D. Microsatellite instability in cancer of the proximal colon.Science. 1993; 260: 816-819Crossref PubMed Scopus (2821) Google Scholar, 18Popat S. Hubner R. Houlston R.S. Systematic review of microsatellite instability and colorectal cancer prognosis.J Clin Oncol. 2005; 23: 609-618Crossref PubMed Scopus (1471) Google Scholar Because screening for colorectal cancer can largely reduce morbidity and mortality in HNPCC patients and their relatives, several clinical criteria have been proposed to identify HNPCC.19Salovaara R. Loukola A. Kristo P. Kaariainen H. Ahtola H. Eskelinen M. Harkonen N. Julkunen R. Kangas E. Ojala S. Tulikoura J. Valkamo E. Jarvinen H. Mecklin J.P. Aaltonen L.A. de la Chapelle A. Population-based molecular detection of hereditary nonpolyposis colorectal cancer.J Clin Oncol. 2000; 18: 2193-2200Crossref PubMed Scopus (450) Google Scholar, 20Aaltonen L.A. Salovaara R. Kristo P. Canzian F. Hemminki A. Peltomaki P. Chadwick R.B. Kaariainen H. Eskelinen M. Jarvinen H. Mecklin J.P. de la Chapelle A. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease.N Engl J Med. 1998; 338: 1481-1487Crossref PubMed Scopus (991) Google Scholar The International Collaborative Group on HNPCC defined the Amsterdam I and II criteria3Vasen H.F. Mecklin J.P. Khan P.M. Lynch H.T. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC).Dis Colon Rectum. 1991; 34: 424-425Crossref PubMed Scopus (1759) Google Scholar, 21Vasen H.F. Watson P. Mecklin J.P. Lynch H.T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.Gastroenterology. 1999; 116: 1453-1456Abstract Full Text Full Text PDF PubMed Scopus (2121) Google Scholar; the Bethesda criteria for selection of patients who should undergo MSI analysis have been revised recently2Umar A. Risinger J.I. Hawk E.T. Barrett J.C. Testing guidelines for hereditary non-polyposis colorectal cancer.Nat Rev Cancer. 2004; 4: 153-158Crossref PubMed Scopus (149) Google Scholar, 22Rodriguez-Bigas M.A. Boland C.R. Hamilton S.R. Henson D.E. Jass J.R. Khan P.M. Lynch H. Perucho M. Smyrk T. Sobin L. Srivastava S. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome meeting highlights and Bethesda guidelines.J Natl Cancer Inst. 1997; 89: 1758-1762Crossref PubMed Scopus (952) Google Scholar (see Table 1). Other countries have developed their own clinical criteria, according to population-specific gene mutations, clinical phenotype, and clinical outcomes.23Park Y.J. Shin K.H. Park J.G. Risk of gastric cancer in hereditary nonpolyposis colorectal cancer in Korea.Clin Cancer Res. 2000; 6: 2994-2998PubMed Google Scholar, 24Song Y.M. Zheng S. Analysis for phenotype of HNPCC in China.World J Gastroenterol. 2002; 8: 837-840PubMed Google Scholar, 25Fujita S. Moriya Y. Sugihara K. Akasu T. Ushio K. Prognosis of hereditary nonpolyposis colorectal cancer (HNPCC) and the role of Japanese criteria for HNPCC.Jpn J Clin Oncol. 1996; 26: 351-355Crossref PubMed Scopus (54) Google ScholarTable 1Testing Guidelines for HNPCCShort nameCriteriaReferenceAmsterdam Amsterdam IaEach condition must be fulfilled. Three relatives with colorectal cancer, 1 of which is a first-degree relative of the other 2Colorectal cancer affecting more than 1 generationAt least 1 colorectal cancer diagnosed before age 50 yearsVasen et al (1991)3Vasen H.F. Mecklin J.P. Khan P.M. Lynch H.T. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC).Dis Colon Rectum. 1991; 34: 424-425Crossref PubMed Scopus (1759) Google Scholar Amsterdam IIaEach condition must be fulfilled.Three relatives with HNPCCbIncludes colorectum, endometrium, small bowel, ureter, and renal pelvis.-related cancer, 1 of which is a first-degree relative of the other 2Vasen et al (1999)21Vasen H.F. Watson P. Mecklin J.P. Lynch H.T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.Gastroenterology. 1999; 116: 1453-1456Abstract Full Text Full Text PDF PubMed Scopus (2121) Google ScholarHNPCCbIncludes colorectum, endometrium, small bowel, ureter, and renal pelvis.-related cancer affecting more than 1 generationAt least 1 HNPCCcIncludes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary.-related cancer diagnosed before age 50 yearsBethesdaUmar et al (2004)2Umar A. Risinger J.I. Hawk E.T. Barrett J.C. Testing guidelines for hereditary non-polyposis colorectal cancer.Nat Rev Cancer. 2004; 4: 153-158Crossref PubMed Scopus (149) Google Scholar Set 1Colorectal cancer diagnosed in a patient who is less than 50 years of age Set 2Presence of synchronous, metachronous colorectal, or other HNPCCcIncludes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary.-associated tumors, regardless of age Set 3dInformation about the MSI-H histology of the tumors (presence of tumor-infiltrating lymphocytes, Crohn’s disease-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern) was not available in the present study.Colorectal cancer with the MSI-H histology diagnosed in a patient who is less than 60 years of age Set 4Colorectal cancer or HNPCCcIncludes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary.-associated tumor diagnosed under age 50 years in at least 1 first-degree relative Set 5Colorectal cancer or HNPCCcIncludes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary.-associated tumor diagnosed at any age in 2 first- or second-degree relativesa Each condition must be fulfilled.b Includes colorectum, endometrium, small bowel, ureter, and renal pelvis.c Includes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary.d Information about the MSI-H histology of the tumors (presence of tumor-infiltrating lymphocytes, Crohn’s disease-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern) was not available in the present study. Open table in a new tab In the present study, the families of the nationwide Swedish Family-Cancer Database were classified according to the Amsterdam and the revised Bethesda criteria. The objective was to analyze the prevalence of the classified families in the Swedish population and to investigate the extent to which tumors in Amsterdam or Bethesda criteria families reflect HNPCC features. The Swedish Family-Cancer Database offers unique possibilities for reliable estimation at the national level because the data on family relationships and cancers were obtained from registered sources of practically complete coverage and free from bias.26Hemminki K. Vaittinen P. National database of familial cancer in Sweden.Genet Epidemiol. 1998; 15: 225-236Crossref PubMed Scopus (71) Google Scholar The Swedish Family-Cancer Database was created in the middle of the 1990s by linking census information, death notifications, and the administrative family register at Statistics Sweden to the Swedish Cancer Registry.26Hemminki K. Vaittinen P. National database of familial cancer in Sweden.Genet Epidemiol. 1998; 15: 225-236Crossref PubMed Scopus (71) Google Scholar, 27Hemminki K. Li X. Plna K. Granstrom C. Vaittinen P. The nation-wide Swedish family-cancer database—updated structure and familial rates.Acta Oncol. 2001; 40: 772-777Crossref PubMed Scopus (215) Google Scholar The Database includes persons who were born in Sweden after 1931 along with their biologic parents. The 2004 update of the Database includes more than 10.5 million individuals.28Hemminki K. Granstrom C. Chen B. The Swedish Family-Cancer Database update, application to colorectal cancer and clinical relevance.Hereditary Cancer Clin Pract. 2005; 3: 7-18Crossref PubMed Scopus (23) Google Scholar The Swedish Cancer Registry relies on separate compulsory notifications of cases from clinicians who diagnosed a neoplasm and pathologists/cytologists.29The National Board of Health and Welfare, Centre for Epidemiology. Cancer incidence in Sweden, Stockholm2002Google Scholar A 4-digit diagnostic code according to the 7th revision of the International Classification of Diseases (ICD-7) and subsequent ICD classifications are available. In this study, colorectal, endometrial, ovarian, stomach, and small bowel cancers included only the adenocarcinoma histology. Rectal cancers did not include anal malignancies. ICD-7 codes were also used for classification of colorectal adenomas. Only families belonging to the Database with at least 4 generations were considered in the present study. If a founder parent of the family was missing or if they had married several times, the family was excluded. Overlap between families was possible, eg, individuals in the fourth generation could belong to 4 different families. The ages of the parents were unlimited, but the maximum age in the second generation was 70 years. Families were classified according to the Amsterdam and Bethesda criteria as described in Table 1. The median number of individuals and the median number of individuals older than 50 years were used to summarize the size of the families. In the present study, “HNPCC-related” cancer sites included the colon, rectum, endometrium, ovary, stomach, small bowel, ureter, renal pelvis, and biliary tract. The relevance of the classified families in the population burden of cancer was assessed by the percentage of colorectal/all HNPCC-related cancers within those families. The familial relationship of colorectal/all HNPCC-related cancer patients in families eligible for MSI testing was also investigated. The possible association between risk of cancer and fulfillment of Amsterdam/Bethesda criteria was explored by survival methods. This approach has been applied before to analyze the familial aggregation of cancer, and details can be found elsewhere.30Pfeiffer R.M. Goldin L.R. Chatterjee N. Daugherty S. Hemminki K. Pee D. X L.I. Gail M.H. Methods for testing familial aggregation of diseases in population-based samples application to Hodgkin lymphoma in Swedish registry data.Ann Hum Genet. 2004; 68: 498-508Crossref PubMed Scopus (28) Google Scholar, 31Liang K.Y. Estimating effects of probands’ characteristics on familial risk: I. Adjustment for censoring and correlated ages at onset.Genet Epidemiol. 1991; 8: 329-338Crossref PubMed Scopus (38) Google Scholar In brief, the marginal proportional hazards model λ(tij/Xij, Zij) = λ0(tij)exp(βXij + γZij) was used to analyze the age at onset of cancer or the censoring age (tij) for member j of family i. The term λ0 represents the arbitrary baseline hazard function, Xij denotes covariates for a given individual (in the present study, sex and calendar year treated as a time-dependent covariate), and Zij indicates whether the individual belongs to a classified family. Individuals entered the risk period at birth, immigration date, or first year of the study (1961), whichever came latest. Censoring events were death, emigration, December 31, 2002, and diagnosis of a malignancy at cancer site other than the site under consideration. Testing for increased cancer risk in families that fulfilled HNPCC criteria corresponds to testing the null hypothesis H0: γ = 0 (ie, hazard ratio = 1). The parameters β and γ were estimated under a working independence assumption (PROC PHREG; SAS Version 9.2; SAS Institute, Cary, NC). The data were also analyzed using the robust sandwich covariance matrix to account for dependence of family members; if an individual belonged to several families, those families were linked together in the same cluster.30Pfeiffer R.M. Goldin L.R. Chatterjee N. Daugherty S. Hemminki K. Pee D. X L.I. Gail M.H. Methods for testing familial aggregation of diseases in population-based samples application to Hodgkin lymphoma in Swedish registry data.Ann Hum Genet. 2004; 68: 498-508Crossref PubMed Scopus (28) Google Scholar The term “relative risk” (RR) denotes the hazard ratios defined above. In addition, the Kaplan–Meier method was used to estimate the cumulative risk of cancer in the classified families (PROC LIFETEST; SAS Version 9.2; SAS Institute). Estimates from the marginal proportional hazards models and the Kaplan–Meier method were also used to compare the prognosis of patients in the classified families with the prognosis in nonclassified families. To test the possible association between prognosis and fulfillment of classification criteria, the event analyzed was the time from diagnosis of cancer to death. The individual covariates included age at cancer diagnosis, sex, and calendar year. Individuals entered the risk period the year of cancer diagnosis, and censoring events were the emigration date or December 31, 2002, whichever occurred first. The term “relative survival” (RS) refers to the previous hazard ratio. Survival methods were also applied to explore the adenoma-carcinoma sequence in Bethesda criteria families and to test the hypothesis that members of Amsterdam criteria families are at increased risk of developing subsequent malignancies after the first colorectal/endometrial cancer. To answer this question, the event of interest was the time between first and second cancer diagnoses. The individual covariates included the age at first diagnosis, sex, and calendar year. Individuals entered the risk period 1 month after detection of the first tumor. Censoring events were death, emigration, December 31, 2002, and diagnosis of second tumors at other than the cancer site under consideration, whichever came first. Table 2 shows the number and size of the families that fulfilled the classification criteria. The “general population” analyzed in this study (N = 566,877 families) had a median family size of 12 persons; the median number of family members who reached the minimum age of 50 years was 4. Twenty-one families fulfilled the Amsterdam I criteria, and 42 families fulfilled the Amsterdam II criteria. The Bethesda criteria identified 5095 families, ie, approximately 0.9% of the Swedish families fulfilled any of the 4 sets of the Bethesda criteria. Families that fulfilled the classification criteria were larger than families from the general population. The percentage of colorectal cancer patients in Amsterdam I criteria families was 0.15%; 0.21% of the colorectal cases belonged to Amsterdam II criteria families. In contrast, families that fulfilled the Bethesda criteria included 11.2% of the colorectal cancer patients. Among the 87,960 patients in the general population affected by cancer at any HNPCC-related site, 6.9% of the cases were members of families that fulfilled the Bethesda criteria.Table 2Number and Size of Families That Fulfilled Amsterdam or Bethesda Criteria and Number of Patients Affected by Colorectal Cancer/Cancer at HNPCC-Related Sites in the Classified FamiliesCriteriaNo. of families‰ of familiesFamily sizeColorectal cancerHNPCCaIncludes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary. cancerAll individualsIndividuals >50 yearsNo.%No.%Median(5th and 95th percentiles)Median(5th and 95th percentiles)General population566,87710001263043646,22310087,960100Amsterdam I210.04171035537690.15700.08Amsterdam II420.07171037537970.211370.16Bethesda50958.9913734437515911.1660686.90a Includes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary. Open table in a new tab The 21 families that fulfilled the Amsterdam I criteria could also be classified as Bethesda criteria families. Three Amsterdam II criteria families included multiple cases of endometrial cancer, and they did not fulfill any Bethesda criteria (results not shown). The relationship among patients in families eligible for MSI testing is presented in Table 3. Among the 21 Amsterdam I criteria families, 12 families (57%) included 1 parent and 2 siblings with colorectal cancer. Thirty-one percent (13 of 42) of the Amsterdam II criteria families had a parent and 2 siblings with colorectal cancer. In contrast, 85.7% (4365 of 5095) of the Bethesda criteria families included only 1 colorectal cancer patient.Table 3Familial Relationship of Patients Affected by Colorectal Cancer/Cancer at HNPCC-Related Sites in Families That Fulfilled Amsterdam or Bethesda CriteriaCriteriaNo. of patients in the family and relationship among them1 patient2 patients3 patients4 patients or moreTotal No. of familiesOtherOtherAmsterdam ICRC1231521HNPCCaIncludes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary1236Amsterdam IICRC76121331542HNPCCaIncludes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary2679BethesdaCRC436529234382233155095HNPCCaIncludes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary4285592566170114313CRC, colorectal cancer.a Includes colorectum, endometrium, small bowel, ureter, renal pelvis, biliary tract, stomach, and ovary Open table in a new tab CRC, colorectal cancer. The Kaplan–Meier estimates of the cumulative risk of colorectal cancer for members of the classified families are represented in Figure 1. By age 75 years, the cumulative risk of colorectal cancer in Amsterdam I criteria families was 57.1% (95% CI: 46.0%–68.8%), and it was 41.2% (95% CI: 33.3%–50.1%) in Amsterdam II criteria families. The cumulative risk of colorectal cancer by age 75 years in Bethesda criteria families was 41.7% (95% CI: 39.4%–44.1%) for men and 23.3% (95% CI: 22.2%–24.4%) for women (results not shown). Figure 2 shows the estimated cumulative risks of endometrial cancer for women in Amsterdam II and Bethesda criteria families. The cumulative risk of endometrial cancer by age 75 years was 45.4% (95% CI: 34.1%–58.5%) in Amsterdam II criteria families, and it was 8.7% (95% CI: 8.0%–9.5%) in Bethesda criteria families. For ovarian cancer, the cumulative risk by age 75 years in Bethesda criteria families was 4.7% (95% CI: 4.2%–5.3%); for gastric cancer, it was 2.3% (95% CI: 2.0%–2.7%, results not shown).Figure 2Cumulative risk of endometrial cancer for women in the general population and in families that fulfilled Amsterdam/Bethesda criteria.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Table 4 shows the number of cases and the RR of cancer for Amsterdam and Bethesda criteria families. Members of Amsterdam I criteria families showed increased RRs for colorectal, endometrial, cervical, and bladder cancers. Individuals in Amsterdam II criteria families were at increased risk of endometrial, ureter, colorectal, small intestine, and renal pelvis cancers. Bethesda criteria families showed increased RRs of cancer in the colon, rectum, endometrium, small bowel, ovary, and stomach. The RRs of colorectal adenomas were also increased in Bethesda criteria families. Members of Bethesda criteria families were at increased risk for cancer of the bile ducts (P = .05), the renal pelvis (P < .0001), and the ureter (P < .0001). In contrast, the RRs of cancer for the liver as a primary site, the renal parenchyma, and the bladder were not significantly increased in Bethesda criteria families. Families that fulfilled Bethesda criteria presented with a paucity of cervical and lung cancers. The RR of in situ cervical cancer in Bethesda criteria families was 1.02 (849 cases, 95% CI: 0.95–1.09, P = .67). RRs presented in Table 4 were calculated without considering the clustered family structure of the data, but the results were practically identical when the robust sandwich covariance matrix was used, eg, after adjusting for family dependence, Bethesda criteria families showed an RR for cervical cancer of 0.76 (95% CI: 0.59–0.98, P = .03) and an RR for lung cancer of 0.84 (95% CI: 0.72–0.98, P = .02).Table 4Relative risk of Cancer for Members of Families That Fulfilled Amsterdam/Bethesda CriteriaCancer siteICD-7Amsterdam IAmsterdam IIBethesdaNo. casesRR (95% CI)No. casesRR (95% CI)No. casesRR (95% CI)Oral140-1,143-8520.94 (0.71–1.23)Salivary gland14240.42 (0.16–1.13)Esophagus150241.07 (0.72–1.60)Stomach1512762.57 (2.28–2.89)a95% Cl does not include 1.00.Small bowel152136.11 (5.09–256.1)a95% Cl does not include 1.00.225.75 (3.75–8.81)a95% Cl does not include 1.00.Colon1533966.00 (48.21–90.35)a95% Cl does not include 1.00.5540.18 (30.84–52.35)a95% Cl does not include 1.00.280015.72 (15.11–16.35)a95% Cl does not include 1.00. Adenoma153235.03 (8.79–139.5)a95% Cl does not include 1.00.216.61 (4.18–66.07)a95% Cl does not include 1.00.1136.72 (5.56–8.12)a95% Cl does not include 1.00.Rectum154 (except 1541)1849.12 (30.94–77.99)a95% Cl does not include 1.00.2328.02 (18.62–42.17)a95% Cl does not include 1.00.138512.83 (12.14–13.56)a95% Cl does not include 1.00. Adenoma153562.72 (2.09–3.54)a95% Cl does not include 1.00.Liver155-6461.12 (0.84–1.50) Liver primary155051.17 (0.49–2.82) Gallbladder1551210.97 (0.63–1.48) Bile ducts1552111.83 (1.01–3.32)a95% Cl does not include 1.00.Pancreas157750.96 (0.77–1.21)Nose16040.69 (0.26–1.83)Larynx161160.92 (0.56–1.50)Lung162–1631710.84 (0.72–0.98)a95% Cl does not include 1.00.Breast17032.47 (0.80–7.63)51.61 (0.67–3.86)4160.96 (0.87–1.06)Cervix17127.19 (1.81–28.67)a95% Cl does not include 1.00.22.93 (0.73–11.70)600.76 (0.59–0.98)a95% Cl does not include 1.00.Endometrium172313.16 (4.25–40.71)a95% Cl does not include 1.00.3356.76 (40.34–79.87)a95% Cl doe
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