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Broadening risk profile in familial colorectal cancer type X; increased risk for five cancer types in the national Danish cohort

BMC Cancer volume 20, Article number: 345 (2020) Cite this article

Abstract

Background

Familial colorectal cancer type X (FCCTX) is a phenotypically defined subset of hereditary colorectal cancer with unknown and potentially heterogeneous genetic aetiology. FCCTX has been characterized as a colorectal cancer-specific syndrome, which we herein challenge by estimating the risk for extra-colorectal cancer in the Danish FCCTX cohort.

Methods

Through the national hereditary non-polyposis colorectal cancer (HNPCC) register, 213 families fulfilling the Amsterdam I criteria and showing retained mismatch repair (MMR) function were identified. In here, sex and age-specific incidence rate ratios (IRR) were calculated for 30 extra-colorectal cancer types in comparison with the general Danish population.

Results

In total, 494 extra-colorectal cancers developed with significantly increased risks for cancers of the urinary tract, breast, stomach, pancreas, and eye tumours. The age groups at increased risks were 30–49 years for gastric cancer, 30–69 years for female breast cancer, 50–69 years for ocular melanoma and above age 70 for pancreatic cancer and urothelial cancer.

Conclusions

Danish FCCTX families show an increased risk of several extra-colorectal cancer types. This observation may indicate unidentified disease-predisposing genetic variants in this phenotypically defined subset of hereditary colorectal cancer and calls for awareness during genetic counselling and follow-up.

Peer Review reports

Background

Heredity is estimated to explain ~ 20% of the colorectal cancer diagnoses and covers a complex genetic landscape [35]. Though several rare high-risk alleles have been identified, a large fraction of families with seemingly inherited colorectal cancer diagnoses remains genetically undefined. In here families, who meet the Amsterdam I criteria for Lynch syndrome, but with no signs of mismatch repair (MMR) deficiency, i.e. a mismatch-repair stable phenotype and/or retained MMR protein expression, are referred to as familial colorectal cancer type X (FCCTX) [21, 38]. This subset constitutes 40% of the families that fulfil the Amsterdam I criteria and belong to the hereditary non-polyposis subgroup of hereditary cancer [34]. The genetic aetiology of FCCTX is most likely heterogenous and may include rare pathogenic germline variants in e.g. heterozygous MUTYH, CHEK2, BRCA2, POLE, POLD1, SEMA4A, BMPR1A, RPS20 or OGG1 or modifying single nucleotide polymorphisms in SEMA4A, EXO1, TGFBR1, or NUDT1 [1, 5, 9, 10, 12, 24, 25, 29, 40].

Besides the MMR proficient molecular phenotype, FCCTX-associated colorectal cancers have been distinguished from the genetically defined cancer syndrome, Lynch syndrome, by a predilection for tumour development in the distal colon and the rectum, a high adenoma/carcinoma rate and a lower risk of synchronous and metachronous colorectal cancer [6, 19, 22, 30]. The risk of colorectal cancer is lower than in Lynch syndrome with a relative risk (RR) of 0.5, but higher than the general population with a standardized incidence ratio of 2.3 [2, 21]. Current literature suggests that FCCTX is a colorectal cancer-only syndrome, which provide the basis for current recommendations of surveillance with regular colonoscopy starting 5–10 years prior to the youngest case in the family in families classified as FCCTX [2, 21, 22, 36].

We challenged this notion through risk assessment of 30 different extra-colorectal cancer types in the Danish FCCTX cohort compared to the Danish general population and to the national Lynch syndrome cohort and found increased risk of five extra-colorectal cancer types, i.e. urothelial cancer, female breast cancer, gastric cancer, pancreatic cancer, and ocular melanoma.

Methods

The national Danish hereditary non-polyposis colorectal cancer (HNPCC) register contains ~ 6000 families with suspected or verified hereditary colorectal cancer reported to the register by genetic counsellors, surgeons, pathologists, and genetic diagnostic laboratories. Families have been included based on a suspicious family history of colorectal cancer, fulfilment of the Amsterdam I or II criteria [38], or identification of disease-predisposing variants in genes linked to hereditary colorectal cancer. Based on family history, the register subclassifies families according to genotypic and phenotypic subsets [20]. The Danish HNPCC register identifies all family members in the Danish Civil Registration System, regardless of cancer history, based on data collected from clinical files and health care registers.

Patient selection

Families classified as FCCTX (n = 213) were eligible for the study. FCCTX was defined as fulfilment of the Amsterdam I criteria with no signs of MMR deficiency. The Amsterdam I criteria are defined as at least three relatives with histologically verified colorectal cancer in two generations with one individual being a first-degree relative of the other two and at least one individual diagnosed below the age of 50 [37]. MMR proficiency was characterized by retained MMR protein expression and/or a microsatellite stable phenotype and/or a gene test showing no MMR mutations in at least one of the three colorectal cancer patients included in the Amsterdam I triad.

A maximum of one tumour with MLH1/PMS2 protein loss in the family was accepted if this was in conjunction with a BRAF mutation and/or MLH1 promotor hypermethylation (N = 4) or normal MMR expression was found in ≥1 tumour from a family member (N = 16). Loss of MSH2/MSH6 protein expression was not allowed, while loss of MSH6 only was observed in two cases and allowed motivated by normal genetic test result in the same individual (N = 1) or normal MMR protein expression in another tumour in the same family (N = 1). Variants of unknown significance were included only when normal MMR protein expression was verified in a tumour from the same patient (N = 2). Of the 252 Amsterdam I positive families reviewed, 213 fulfilled the criteria for MMR proficiency. Individuals affected with colorectal cancer and their first- and second-degree relatives were eligible for the study.

Data processing

Data on primary extra-colorectal cancer diagnoses were obtained from the population-based Danish Cancer Registry. This registry has close to complete coverage based on mandatory double reporting from pathologists and clinicians [31, 32]. Benign tumours, carcinoma in situ/dysplasia, and basal cell carcinomas of the skin were excluded. Patients with more than one primary cancer in different organs were allowed to contribute to the tissue-specific risk estimates, while synchronous/metachronous cancer in the same organ or in the same side of paired organs were not allowed. Data on vital status were obtained from the Danish Civil Registration System.

To determine the risk relative to the general population, we used a population-based cohort obtained from the Nordcan database [8]. This cohort contains data on age-specific cancer events and person years at-risk in the Danish background population during the time period from January 1st, 1978 to December 31st, 2013 with stratification for year of diagnosis, sex, age, and disease. The Nordcan database classifies malignancies into 36 groups. The FCCTX-associated cancers could be matched to 30 of these after exclusion of cancer in the colon, rectum and anal canal, unspecified cancers, specified cancer (grouped by Nordcan), and 2 rare specified malignancies without cases in the FCCTX cohort. All cancers and person years at-risk identified in the Danish FCCTX cohort and the previously published Danish Lynch syndrome cohort were removed from the Nordcan data set [33]. To correct for potential ascertainment bias, we performed a subgroup analysis in a cohort surveilled for colorectal cancer, reflecting prospective data, with inclusion of cancers diagnosed following the first colonoscopic surveillance session in the family and exclusion of diagnoses and person years at-risk prior to this date. The study was granted acceptance from the Danish Data Protection Agency. According to Danish regulations, registry studies are not subject to ethical review.

Statistical analyses

Person years at-risk and cancer events in the FCCTX cohort and in the population-based Nordcan cohort were stratified and aggregated into 4 age groups (0–29 years, 30–49 years, 50–69 years and 70 years or above) using the %STRATIFY SAS macro, which removes individuals from the at-risk group if cancer is diagnosed within the study period, and SAS software, version 9.4 (SAS Institute Inc., Cary, NC, USA) [28]. Person years at-risk were determined as the period from date of birth or start of study period (January 1st, 1978), whichever came last, to date of diagnosis of any type of cancer, date of death or end of study period (December 31st, 2013), whichever came first.

Stratified and aggregated data were transferred into R 3.2.3 (R Core Team, 2019, A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing: URL https://www.R-project.org/). Incidence rates (IRs) were calculated as the number of events divided by person years at-risk in each age group. Incidence rate ratios (IRRs) were calculated as the ratio between the IRs in the FCCTX cohort and the population-based cohort. Since FCCTX is part of the HNPCC subgroup of hereditary colorectal cancer and are classified according to the same clinical criteria, i.e. the Amsterdam criteria, we also estimated IRs relative to the previous IRs published in the Danish Lynch syndrome cohort [33]. Confidence intervals (95% CI) and p values were calculated using the exact conditional Poisson test. All p values were two-sided and significance levels were adjusted for multiple testing using Bonferroni correction for estimation in the 4 age groups (i.e. significance was reached when p < 0.0125).

Results

The FCCTX cohort comprised 213 families, including 646 individuals with a colorectal cancer, 1982 first-degree relatives and 1044 second-degree relatives. These individuals contributed with 110,767 person-years at-risk and during this time 966 individuals developed 1078 cancers, including 493 extra-colorectal cancers and 585 colorectal cancers (Supplementary Table 1). The most prominent cancer types observed were breast cancer (N = 103), prostate cancer (N = 51), urothelial cancer (N = 45), and lung cancer (N = 40). Prospective analyses were based on 223 individuals in surveillance from 109 families, who contributed with 903,448 person years at-risk. In this subgroup that considered only cancers that developed after the initiation of surveillance in the family, 160 cancers, including 26 breast cancers, 21 urothelial cancers and 19 prostate cancers, were diagnosed (Supplementary Table 1).

Compared to a population-based cohort, the FCCTX cohort revealed significantly increased risks for five cancer types, i.e. breast cancer, urothelial cancer, pancreatic cancer, gastric cancer, and ocular melanoma with variable peak incidence ages identified in the different tumour types (Fig. 1, Table 1, Supplementary Table 2). Significantly increased IRRs were observed for breast cancer in the age groups from age 30 until 69 years (IRR for age 30–49: 1.71, 95% CI 1.02–2.68, p = 0.0070 and IRR for age 50–69: 1.54, 95% CI 1.06–2.14, p = 0.0030), while gastric cancer showed an IRR of 5.87 (95% CI 1.57–15.02, p = 0.0007) for the age group 30–49 years. Urothelial cancer and pancreatic cancer developed at significantly increased IRRs of 2.10 (95% CI 1.26–3.30, p = 0.0003) and 2.21 (95% CI 1.12–4.38, p = 0.0023), respectively, in the oldest age cohort, above age 70. In total, five eye tumours developed in age group 50–69 years, all of which were classified as ocular melanomas, giving an IRR of 7.73 (95% CI 1.76–21.45, p = 0.0006) (Fig. 1, Table 1).

Fig. 1
figure 1

Age-dependent incidence rates and 95% confidence intervals for five cancer types with significantly increased incidence rate ratios in at least one age group in FCCTX (dotted lines) compared to the general population (solid lines)

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Table 1 Age-dependent incidence rate ratios of different cancer types comparing the entire FCCTX cohort to the age and sex-matched population-based cohorts
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The increased risks of extra-colorectal cancers applied to all FCCTX individuals with similar risk levels in first-degree and second-degree relatives compared to the relatives affected with colorectal cancer (Supplementary Figure 1). In the prospective analysis, significantly increased risks applied to urothelial cancer and ocular melanoma with an IRR of 2.94 (95% CI 1.34–5.54, p = 0.0004) above age 70 for urothelial cancers and an IRR of 13.81 (95% CI 1.68–49.32, p = 0.0015) for ocular melanomas (Table 2).

Table 2 Age-dependent incidence rate ratios comparing the surveilled FCCTX cohort and the population-based cohorts
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At least one individual with breast cancer was observed in 85 FCCTX families. If the criteria for genetic testing for hereditary breast and ovarian cancer were considered, 35 of these families fulfilled at least one of the criteria previously described [41]. Likewise, gastric cancer was found in 18 FCCTX families, of which two families fulfilled the clinical criteria for genetic testing previously published [4, 26]. As we did not have genetic data on variants in the BRCA1/BRCA2 genes predisposing for hereditary breast and ovarian cancer or the CDH1 gene predisposing for hereditary diffuse gastric cancer, we excluded these families from the FCCTX cohort. The sensitivity analysis decreased the IRRs to non-significant levels for breast cancer, gastric, pancreatic and urothelial cancer, except for breast cancer age 30–49 where the IRR significantly decreased to 0.19 (95% CI: 0.02–0.67, p = 0.0002), from a previous increased IRR. Eye tumours remained significantly increased with similar IRR (Table 3).

Table 3 Age-dependent incidence rate ratios of specific cancer types in the FCCTX cohort without the 37 families that fulfilled the criteria for genetic testing for hereditary breast and ovarian cancer or hereditary gastric cancer conpared to the age and sex-matched population-based cohort
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Compared to Lynch syndrome, FCCTX families showed significantly lower risks in at least one age group for eight different tumour types, i.e. endometrial cancer, ovarian cancer, urothelial cancer, kidney cancer, gastric cancer, cancer of the small bowel, non-melanoma skin tumours and brain tumours (Table 4). For urothelial cancer and skin cancer this observation was consistent from age 30+. The risk of urothelial cancer in FCCTX showed IRRs of 0.06–0.31 (p-values < 0.0009) compared to Lynch syndrome and the risk of skin cancer showed IRRs of 0.11–0.24 (p < 0.005) (Table 4). For the other tumour types this difference particularly applied to the peak ages of these cancer types in Lynch syndrome, i.e. age 30–69 years (Table 4). No difference in risks of breast cancer, eye tumours and pancreatic cancer were found between the FCCTX and Lynch syndrome cohorts for all age groups (Supplementary Table 4.).

Table 4 Age-dependent incidence rate ratios of different cancer types comparing the entire FCCTX cohort with the Lynch syndrome cohort
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Discussion

Increased awareness of hereditary colorectal cancer and improved access to genetic diagnostics implies that a growing number of families with a phenotype suggesting hereditary cancer with an undefined genotype are identified. FCCTX represents one of these subsets where refined risk estimates are relevant to develop evidence-based surveillance recommendations. Lindor et al., described a standardized incidence ratio for colorectal cancer of 2.3 in a cohort of 71 FCCTX families and did not identify any significantly increased risk of extra-colorectal cancer [21]. Based on this observation, FCCTX is considered a colorectal cancer-only syndrome with surveillance generally recommended to be confined to colonoscopy with 5-year intervals starting 5–10 years prior to the first case in the family. Surveillance programs for colorectal cancer have been optimized with documentation of more efficient detection of precursor lesions and early-stage tumours (RR 0.2–0.3) [14]. Reduced risk of mortality from colorectal cancer and increased life expectancy implies that individuals with FCCTX may be at risk of extra-colorectal tumour types during this increased lifetime. Our data, based on all 213 FCCTX families in the national Danish HNPCC-register, challenges the present view on FCCTX as a colorectal cancer-only syndrome and demonstrate significantly increased incidence rates for five extra-colorectal cancer types with urothelial cancer remaining significant in the colorectal cancer-surveilled cohort (Fig. 1, Table 1, Table 2).

We demonstrate an increased risk of urothelial cancer from age 70 in FCCTX with IRRs of 2.1 in the entire FCCTX cohort and 2.9 in the surveilled subset compared to the risk in an age- and sex matched Danish population (Tables 1 and 2). The risk of urothelial cancer in FCCTX was significantly lower than in Lynch syndrome with IRRs of 0.1–0.3 (Table 4). Except for Lynch syndrome, urothelial cancer has not been linked to hereditary colorectal cancer [11]. One possibility would be undiagnosed Lynch syndrome cases e.g. MMR gene variants that allow for retained MMR function and normal MMR protein expression. Alternatively, a subset of FCCTX could harbour mutations in genes linked to urothelial cancer development, e.g. FGFR3, TP53 or HRAS [43]. To this point, 42/45 urothelial cancer in the FCCTX cohort developed in the urinary bladder, which stands in contrast to a predilection for tumours in the upper urinary tract in Lynch syndrome [17]. Unfortunately, it was not possible to discriminate between upper and lower urinary tract cancers in the population-based cohort since the Nordcan database does not differentiate between these sites.

The increased risk of gastric cancer with an IRR of 5.9 in the age group 30–49 years could potentially signify a genetic subset that confers heredity for this cancer type. About 10–20% of gastric cancer is caused by heredity with confirmed causes in 1–3%, predominantly linked to the hereditary diffuse gastric cancer caused by pathogenic variants in the CDH1 gene [27]. Only two of the 18 FCCTX families in our cohort in which gastric cancer developed fulfilled the criteria currently applied for genetic diagnostics due to early-onset cases in the families [4, 26]. When we excluded these families from the FCCTX cohort the risk was, as expected, reduced and was not significant. The co-occurrence of gastric and colorectal cancer in Amsterdam I positive families calls for further studies but may be explained by polygenetic defects resulting in a severe cancer phenotype in some FCCTX families. Addition of CDH1 in the genetic testing of FCCTX families might genetically classify a small fraction of the FCCTX families.

The increased risks of breast cancer with IRRs 1.5–1.7 in the age group 30–69 years and pancreatic cancer with an IRR of 2.2 after age 70 support the suggestion of disease-predisposing variants in BRCA2, causing the observed malignancies in a small subset of FCCTX families [10]. We also identified an IRR of 10.2 for early-onset ovarian cancer. Various guidelines exist for referring individuals to genetic diagnostics in hereditary breast and ovarian cancer [41]. In addition to fulfilling the Amsterdam I criteria, 35 out of the 213 FCCTX families also fulfilled the clinical genetic testing criteria for hereditary breast and ovarian cancer. Exclusion of these families from the FCCTX cohort decreased the risk of breast and pancreatic cancer to a nonsignificant level for the age groups 50–69 and 70+, and the risk for breast cancer flipped to a significantly decreased IRR when comparing to the population-based cohort for the age group 30–49 years (Table 3). Whether the increased risk of breast cancer and colorectal cancer in these families can be explained solely by BRCA2 germline mutations or by polygenetic defects or environmental factors remains to be elucidated. Though the families included in this study had not been systematically screened for hereditary breast and ovarian cancer, our data support a role for hereditary breast and pancreatic cancer in FCCTX, and application of broader diagnostic genetic panels that also cover the BRCA2 gene may, based on our data, have a potential to identify disease-predisposing mutations in some FCCTX families.

The five eye tumours identified in the Danish FCCTX cohort were all malignant melanomas. Uveal melanoma is predominantly sporadic but between 2 and 5% have been estimated to be caused by familial or hereditary predisposition. Autosomal dominant inheritance of pathogenic BAP1 gene variants have been observed in 47% of uveal melanomas, while pathogenic EIF1AX variants have been found in 14–20% of the cases [13, 15]. BAP1-associated uveal melanomas are diagnosed in the age of 30–59 years and are associated with cutaneous melanomas and renal cell carcinomas, while EIF1AX gene variants are associated with thyroid and ovarian cancer [13, 15]. In our cohort, uveal melanomas presented in the age span from 54 to 69 years and 2 of 5 cases occurred in patients with previous cutaneous melanomas. These data encourage awareness of family history during the genetic counselling and diagnostic testing.

Comparison between the risk of extra-colorectal cancer in the FCCTX cohort with the national Danish Lynch syndrome cohort, revealed differences as well as similarities. Urothelial cancer and skin cancer showed significantly lower risk levels in FCCTX compared to Lynch syndrome with IRRs of 0.06–0.31 and 0.11–0.24, respectively (Table 4). Increased risks and reminiscent risk profiles applied to breast cancer, gastric cancer and pancreatic cancer. These similarities are also supported by other studies on the risk of upper gastrointestinal cancer in Lynch syndrome [7, 18, 39]. Surveillance for cancer of the upper gastrointestinal tract is not recommended in FCCTX, but the increased risk observed may suggest awareness with consideration of Helicobacter Pyroli screening and eradication in FCCTX similarly to the recommendations in Lynch syndrome [16, 38, 39].

Studies have shown that compared to Lynch syndrome, FCCTX confers a lower risk for colorectal cancer (11–20% vs 58–75%), a higher age at onset (60 vs 45 years), a different predominant tumour locations (distal vs proximal) and a worse prognosis [3, 21, 23, 42]. In FCCTX, colonoscopic screening is generally recommended with 5-year intervals starting 5–10 years before the earliest colorectal cancer diagnosis in the family, though surveillance patterns are likely more variable in FCCTX than in Lynch syndrome. The recent demonstration of excess cancer-related deaths in FCCTX compared to Lynch syndrome and short intervals to second primary colorectal cancer suggests that clinical management in FCCTX needs to be optimized [3].

Conclusions

Our observation of increased risks with distinct and variable incidence patterns in relation to age for five extra-colorectal cancer types in FCCTX needs validation but challenges the present view of FCCTX as a colorectal cancer-only syndrome. The consistently increased risk of urothelial cancer motivates further investigation to obtain more detailed insights into risk profiles and tumour types with the aim to identify possible disease-predisposing genes. The demonstration of increased risks for breast cancer and pancreatic cancer could suggest that genetic variants in BRCA2 may explain some FCCTX families. The FCCTX cohort may be a suitable target for application of broader panels during genetic diagnostics. Further characterization and subdivision of FCCTX are needed to define discriminatory features, provide more robust risk estimates and recommend relevant and cost-effective surveillance to individuals at increased risk.

Abbreviations

FCCTX:

Familial colorectal cancer type X

HNPCC:

Hereditary non-polyposis colorectal cancer

IR:

Incidence rate

IRR:

Incidence rate ratio

MMR:

Mismatch repair

MLH1 :

MutL homolog 1

MSH2 :

MutS homolog 2

MSH6 :

MutS homolog 6

PMS2 :

PMS1 homolog 2

BRAF :

B-Raf protooncogene

MUTYH :

MutY DNA glucosylase

CHEK2 :

Checkpoint kinase 2

BRCA1 :

Breast cancer 1

BRCA2 :

Breast cancer 2

POLE :

DNA polymerase epsilon

POLD1 :

DNA polymerase delta 1

SEMA4A :

Semaphorin 4A

BMPR1A :

Bone morphogenetic protein receptor type 1A

RPS20 :

ribosomal protein S20

OGG1 :

8-oxoguanine DNA glycosylase

EXO1 :

Exonuclease 1

TGFBR1 :

Transforming growth factor beta receptor 1

NUDT1 :

Nudix hydrolase 1

CDH1 :

Cadherin 1

FGFR3 :

Fibroblast growth factor receptor 3

TP53 :

Tumour protein p53

HRAS :

H-Ras protooncogene

BAP1 :

BRCA1 associated protein 1

EIF1AX :

Eukaryotic translation initiation factor 1A X-linked

References

  1. Bellido F, Pineda M, Aiza G, Valdés-Mas R, Navarro M, Puente DA, Pons T, González S, Iglesias S, Darder E, et al. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med. 2016;18:325–32.

    Article  CAS  Google Scholar 

  2. Benatti P, Roncucci L, Ganazzi D, Percesepe A, Di Gregorio C, Pedroni M, Borghi F, Sala E, Scarselli A, Menigatti M, et al. Clinical and biologic heterogeneity of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2001;95:323–8.

    Article  CAS  Google Scholar 

  3. Choi Y-H, Lakhal-Chaieb L, Kröl A, Yu B, Buchanan D, Ahnen D, Le Marchand L, Newcomb PA, Win AK, Jenkins M, et al. Risks of colorectal Cancer and Cancer-related mortality in familial colorectal Cancer type X and Lynch syndrome families. J Natl Cancer Inst. 2019;111:675–83.

    Article  Google Scholar 

  4. Chun N, Ford JM. Genetic testing by Cancer site: stomach. Cancer J. 2012;18:355–63.

    Article  CAS  Google Scholar 

  5. Dominguez-Valentin M, Nakken S, Tubeuf H, Vodak D, Ekstrøm PO, Nissen AM, Morak M, Holinski-Feder E, Martins A, Møller P, et al. Identification of genetic variants for clinical management of familial colorectal tumors. BMC Med Genet. 2018;19.

  6. Dove-Edwin I, de Jong AE, Adams J, Mesher D, Lipton L, Sasieni P, Vasen HFA, Thomas HJW. Prospective results of surveillance colonoscopy in dominant familial colorectal cancer with and without Lynch syndrome. Gastroenterology. 2006;130:1995–2000.

    Article  Google Scholar 

  7. Engel C, Loeffler M, Steinke V, Rahner N, Holinski-Feder E, Dietmaier W, Schackert HK, Goergens H, von Knebel Doeberitz M, Goecke TO, et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:4409–15.

    Article  Google Scholar 

  8. Engel, G., Ferlay, J., Christensen, N., Kejs, A.M.T., Johannesen, T.B., Khan, S., Milter, M.C., Ólafsdóttir, E., Petersen, T., Pukkala, E., et al. (2016). NORDCAN: Cancer incidence, mortality, prevalence and survival in the Nordic countries, version 7.0 (17.12.2014). Available at: http:// www.ancr.nu Association of the Nordic Cancer Registries. Danish Cancer Society (accessed on 14 Apr 2016).

  9. Garre P, Briceño V, Xicola RM, Doyle BJ, de la Hoya M, Sanz J, Llovet P, Pescador P, Puente J, Díaz-Rubio E, et al. Analysis of the oxidative damage repair genes NUDT1, OGG1, and MUTYH in patients from mismatch repair proficient HNPCC families (MSS-HNPCC). Clin Cancer Res. 2011;17:1701–12.

    Article  CAS  Google Scholar 

  10. Garre P, Martín L, Sanz J, Romero A, Tosar A, Bando I, Llovet P, Diaque P, García-Paredes B, Díaz-Rubio E, et al. BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X. Clin Genet. 2015;87:582–7.

    Article  CAS  Google Scholar 

  11. Gu J, Wu X. Genetic susceptibility to bladder cancer risk and outcome. Pers Med. 2011;8:365–74.

    Article  CAS  Google Scholar 

  12. Hansen MF, Johansen J, Bjørnevoll I, Sylvander AE, Steinsbekk KS, Sætrom P, Sandvik AK, Drabløs F, Sjursen W. A novel POLE mutation associated with cancers of colon, pancreas, ovaries and small intestine. Familial Cancer. 2015;14:437–48.

    Article  CAS  Google Scholar 

  13. Harbour JW, Onken MD, Roberson EDO, Duan S, Cao L, Worley LA, Council, M.L., Matatall KA, Helms C, Bowcock AM. Frequent mutation of BAP1 in metastasizing Uveal melanomas. Science. 2010;330:1410–3.

    Article  CAS  Google Scholar 

  14. Hatfield E, Green JS, Woods MO, Warden G, Parfrey PS. Impact of colonoscopic screening in familial colorectal Cancer type X. Mol Genet Genomic Med. 2018;6:1021–30.

    Article  CAS  Google Scholar 

  15. Helgadottir H, Höiom V. The genetics of uveal melanoma: current insights. Appl Clin Genet. 2016;9:147–55.

    Article  CAS  Google Scholar 

  16. Ishaq S, Nunn L. Helicobacter pylori and gastric cancer: a state of the art review. Gastroenterol. Hepatol. Bed Bench. 2015;8:S6–S14.

    Google Scholar 

  17. Joost P, Therkildsen C, Dominguez-Valentin M, Jönsson M, Nilbert M. Urinary tract Cancer in Lynch syndrome; increased risk in carriers of MSH2 mutations. Urology. 2015;86:1212–7.

    Article  Google Scholar 

  18. Kastrinos F, Mukherjee B, Tayob N, Wang F, Sparr J, Raymond VM, Bandipalliam P, Stoffel EM, Gruber SB, Syngal S. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009;302:1790–5.

    Article  CAS  Google Scholar 

  19. Klarskov L, Holck S, Bernstein I, Nilbert M. Hereditary colorectal cancer diagnostics: morphological features of familial colorectal cancer type X versus Lynch syndrome. J Clin Pathol. 2012;65:352–6.

    Article  Google Scholar 

  20. Lindberg LJ, Ladelund S, Frederiksen BL, Smith-Hansen L, Bernstein I. Outcome of 24 years national surveillance in different hereditary colorectal cancer subgroups leading to more individualised surveillance. J Med Genet. 2017;54:297–304.

    Article  Google Scholar 

  21. Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005;293:1979–85.

    Article  CAS  Google Scholar 

  22. Mueller-Koch Y, Vogelsang H, Kopp R, Lohse P, Keller G, Aust D, Muders M, Gross M, Daum J, Schiemann U, et al. Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut. 2005;54:1733–40.

    Article  CAS  Google Scholar 

  23. Nejadtaghi M, Jafari H, Farrokhi E, Samani KG. Familial colorectal Cancer type X (FCCTX) and the correlation with various genes-A systematic review. Curr Probl Cancer. 2017;41:388–97.

    Article  Google Scholar 

  24. Nieminen TT, WM A-R, Ristimäki A, Lappalainen M, Lahermo P, Mecklin J, Järvinen HJ, Peltomäki P. BMPR1A mutations in hereditary nonpolyposis colorectal Cancer without mismatch repair deficiency. Gastroenterology. 2011;141:e23–6.

    Article  Google Scholar 

  25. Nieminen, T.T., O’Donohue, M.-F., Wu, Y., Lohi, H., Scherer, S.W., Paterson, A.D., Ellonen, P., Abdel-Rahman, W.M., Valo, S., Mecklin, J.-P., et al. (2014). Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency. Gastroenterology 147, 595-598.e5.

  26. van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N, Caldas C, Chelcun Schreiber KE, Hardwick RH, Ausems MGEM, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;52:361–74.

    Article  Google Scholar 

  27. van der Post RS, Oliveira C, Guilford P, Carneiro F. Hereditary gastric cancer: what’s new? Update 2013-2018. Familial Cancer. 2019;18:363–7.

    Article  Google Scholar 

  28. Rostgaard K. Methods for stratification of person-time and events - a prerequisite for Poisson regression and SIR estimation. Epidemiol Perspect Innov. 2008;5.

  29. Schulz E, Klampfl P, Holzapfel S, Janecke AR, Ulz P, Renner W, Kashofer K, Nojima S, Leitner A, Zebisch A, et al. Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X. Nat Commun. 2014;5:1–11.

    CAS  Google Scholar 

  30. Shiovitz S, Copeland WK, Passarelli MN, Burnett-Hartman AN, Grady WM, Potter JD, Gallinger S, Buchanan DD, Rosty C, Win AK, et al. Characterisation of familial colorectal cancer type X, Lynch syndrome, and non-familial colorectal cancer. Br J Cancer. 2014;111:598–602.

    Article  CAS  Google Scholar 

  31. Storm HH. Completeness of cancer registration in Denmark 1943-1966 and efficacy of record linkage procedures. Int J Epidemiol. 1988;17:44–9.

    Article  CAS  Google Scholar 

  32. Storm HH, Michelsen EV, Clemmensen IH, Pihl J. The Danish Cancer registry--history, content, quality and use. Dan Med Bull. 1997;44:535–9.

    CAS  PubMed  Google Scholar 

  33. Therkildsen C, Ladelund S, Smith-Hansen L, Lindberg LJ, Nilbert M. Towards gene- and gender-based risk estimates in Lynch syndrome; age-specific incidences for 13 extra-colorectal cancer types. Br J Cancer. 2017;117:1702–10.

    Article  Google Scholar 

  34. Valle L. Genetic predisposition to colorectal cancer: where we stand and future perspectives. World J Gastroenterol. 2014;20:9828–49.

    Article  CAS  Google Scholar 

  35. Valle L. Recent discoveries in the genetics of familial colorectal Cancer and polyposis. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2017;15:809–19.

    CAS  Google Scholar 

  36. Valle L, Perea J, Carbonell P, Fernandez V, Dotor AM, Benitez J, Urioste M. Clinicopathologic and pedigree differences in Amsterdam I-positive hereditary nonpolyposis colorectal cancer families according to tumor microsatellite instability status. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25:781–6.

    Article  CAS  Google Scholar 

  37. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The international collaborative group on hereditary non-polyposis colorectal Cancer (ICG-HNPCC). Dis. Colon rectum. 1991;34:424–5.

    Article  CAS  Google Scholar 

  38. Vasen HFA, Blanco I, Aktan-Collan K, Gopie JP, Alonso A, Aretz S, Bernstein I, Bertario L, Burn J, Capella G, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62:812–23.

    Article  CAS  Google Scholar 

  39. Win AK, Lindor NM, Young JP, Macrae FA, Young GP, Williamson E, Parry S, Goldblatt J, Lipton L, Winship I, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012;104:1363–72.

    Article  CAS  Google Scholar 

  40. Xicola RM, Bontu S, Doyle BJ, Rawson J, Garre P, Lee E, de la Hoya M, Bessa X, Clofent J, Bujanda L, et al. Association of a let-7 miRNA binding region of TGFBR1 with hereditary mismatch repair proficient colorectal cancer (MSS HNPCC). Carcinogenesis. 2016;37:751–8.

    Article  CAS  Google Scholar 

  41. Zeichner SB, Stanislaw C, Meisel JL. Prevention and screening in hereditary breast and ovarian Cancer. Oncol. Williston Park. 2016;30:896–904.

    Google Scholar 

  42. Zetner DB, Bisgaard ML. Familial colorectal Cancer type X. Curr Genomics. 2017;18:341–59.

    Article  CAS  Google Scholar 

  43. Zhang X, Zhang Y. Bladder Cancer and genetic mutations. Cell Biochem Biophys. 2015;73:65–9.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank all clinicians who have contributed with data to the Danish HNPCC Register.

Availability of data and material

Detailed data can be shared upon request for meta-analyses or other scientific purposes.

Funding

This work was funded by start-up funds from the Swedish Cancer Research Fund to M. Nilbert (2014/442), while salary to C. Therkildsen and M. Rasmussen was supported by the Danish Cancer Research Fund (R90-A6150 and R204-A12599, respectively). The funders did not have any influence in the study design, data collection, statistical analyses or interpretation of the results.

Author information

Authors and Affiliations

  1. HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Kettegård Allé 30, 2650, Hvidovre, Denmark

    Christina Therkildsen, Maria Rasmussen, Lars Smith-Hansen, Thomas Kallemose, Lars Joachim Lindberg & Mef Nilbert

  2. Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark

    Lars Joachim Lindberg

  3. Institute of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden

    Mef Nilbert

  4. Danish Cancer Society Research Center, the Danish Cancer Society, Copenhagen, Denmark

    Mef Nilbert

Authors
  1. Christina Therkildsen
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  2. Maria Rasmussen
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  3. Lars Smith-Hansen
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  4. Thomas Kallemose
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  5. Lars Joachim Lindberg
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  6. Mef Nilbert
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Contributions

MN and CT were responsible for the study design and wrote the first draft. LJL contributed to the concept and collected data from the Danish Cancer Society and verified all the tumour diagnoses in the cohort. LSH processed the data in SAS including the %STRATIFY macro analyses. CT and TK performed the statistical analyses in R. MR commented on the manuscript and assisted with the statistical analyses. All authors have approved the final version and agreed with submission to the BMC Cancer.

Corresponding author

Correspondence to Christina Therkildsen.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the Danish Data Protection Agency (AHH-2014-042). According to the Danish regulations, anonymized registry studies are not subjected to ethical review.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Supplementary information

Additional file 1 Table S1

Extracolonic cancers in the entire and the surveilled FCCTX cohort

Additional file 2 Table S2

Age-dependent incidence rates of different cancer types in the entire FCCTX cohort and in the age and sex-matched population-based cohorts.

Additional file 3 Figure S1

Impact from degree of relatedness in FCCTX families in the 6 extracolorectal cancer types that were significantly different from the population-based cohort. A) Table showing the number of cancers observed and the mean age at onset in individuals affected with colorectal cancer, their first-degree relatives and their second-degree relatives. B) Incidence rates calculated separately in individuals affected by colorectal cancer (red), first-degree relatives (blue) and second-degree relatives (green). No significant differences were observed. Incidence rates and p values are available upon request.

Additional file 4 Table S3

Age-dependent incidence rates of different cancer types in the surveilled FCCTX cohort and in the age and sex-matched population-based cohorts

Additional file 5 Table S4

. Age-dependent incidence rates for cancer types in the entire FCCTX cohort compared to the Danish Lynch syndrome cohort.

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Therkildsen, C., Rasmussen, M., Smith-Hansen, L. et al. Broadening risk profile in familial colorectal cancer type X; increased risk for five cancer types in the national Danish cohort. BMC Cancer 20, 345 (2020). https://doi.org/10.1186/s12885-020-06859-5

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BMC Cancer

ISSN: 1471-2407

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