Importance of Family History of Colorectal Carcinoma In Situ Versus Invasive Colorectal Cancer: A Nationwide Cohort Study

Authors: Yu Tian PhD1,2,3, Elham Kharazmi MD, PhD1,4,5, Hermann Brenner MD, PhD1,6,7, Xing Xu PhD1,2, Kristina Sundquist MD, PhD4,8,9, Jan Sundquist MD, PhD4,8,9, and Mahdi Fallah MD, PhD1,4,10
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  • 1 Division of Preventive Oncology, German Cancer Research Center (DKFZ), and National Center for Tumor Diseases (NCT), and
  • | 2 Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany;
  • | 3 School of Public Health, Capital Medical University, Beijing, China;
  • | 4 Center for Primary Health Care Research, Lund University, Malmö, Sweden;
  • | 5 Statistical Genetics Group, Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany;
  • | 6 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany;
  • | 7 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany;
  • | 8 Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York;
  • | 9 Center for Community-based Healthcare Research and Education, Department of Functional Pathology, School of Medicine, Shimane University, Japan; and
  • | 10 Department of Global Public Health and Primary Care, Faculty of Medicine, University of Bergen, Norway.

Background: The aim of this study was to explore the risk of invasive colorectal cancer (CRC) in relatives of patients with colorectal carcinoma in situ (CCIS), which is lacking in the literature. Patients and Methods: We collected data from Swedish family-cancer datasets and calculated standardized incidence ratio (SIR) and cumulative risk of CRC in family histories of CCIS in first- and second-degree relatives. Family history was defined as a dynamic (time-dependent) variable allowing for changes during the follow-up period from 1958 to 2015. Of 12,829,251 individuals with available genealogical data, 173,796 were diagnosed with CRC and 40,558 with CCIS. Results: The lifetime (0–79 years) cumulative risk of CRC in first-degree relatives of patients with CCIS was 6.5%, which represents a 1.6-fold (95% CI, 1.5–1.7; n=752) increased risk. A similarly increased lifetime cumulative risk (6.7%) was found among first-degree relatives of patients with CRC (SIR, 1.6; 95% CI, 1.6–1.7; n=6,965). An increased risk of CRC was also found in half-siblings of patients with CCIS (SIR, 1.9; 95% CI, 1.1–3.0; n=18) and also in half-siblings of patients with CRC (SIR, 1.7; 95% CI, 1.3–2.1; n=78). Moreover, the increased risk of CRC was higher for younger age at diagnosis of CCIS in the affected first-degree relative and for younger age at diagnosis of CRC in the index person. Conclusions: Results of this study show that first-degree relatives and half-siblings of patients with CCIS have an increased risk of CRC, which is comparable in magnitude to the risk of those with a family history of invasive CRC. These findings extend available evidence on familial risk of CRC and may help to refine guidelines and recommendations for CRC screening.

Background

Colorectal cancer (CRC) has become the third most common cancer and the second leading cause of cancer death globally.1 Colorectal carcinoma in situ (CCIS), which is defined as abnormal cells in the mucosa (innermost layer) of the colon/rectum wall, is the earliest stage of CRC.2 These abnormal cells may become cancerous and spread into nearby normal tissue, and are usually focal and situated on the superficial portion of the polyp.3,4

It is well-known that a family history of invasive CRC is associated with increased risk of invasive CRC57; however, there is less clarity regarding whether and to what extent family history of CCIS is associated with an increased risk of developing invasive CRC. Invasive CRC incidence in young adults below the age of screening (50 years) is increasing, and the discovery of any new risk factor that helps identify such young high-risk individuals would be of great importance.8,9 The highest familial risk of invasive CRC is seen in relatives of those who are diagnosed with early-onset invasive CRC.7,10

We aimed to explore and quantify the association between family history of CCIS and risk of invasive CRC in first- and second-degree relatives, using the world’s largest record linkage of nationwide cancer registry and genealogical datasets from Sweden. We also intended to investigate whether the diagnosis of CCIS in a family should raise concern in other family members and prompt them to seek early medical advice about preventive measures, such as screening.

Patients and Methods

Swedish Family-Cancer Datasets

This study used the 2017 update of the Swedish Family-Cancer Datasets. In this update, information from the Multigeneration Register, national censuses, death notifications, and the Swedish Cancer Registry (started in 1958) were linked using unique personal national registration number.11 This record linkage study of multiple nationwide datasets included all individuals residing in Sweden and born since 1932 (offspring generation) and their parents (parental generation), totaling more than 12.8 million individuals with available genealogical information. During the follow-up of these individuals by the end of 2015, approximately 1.7 million primary invasive cancer diagnoses and approximately 0.5 million carcinoma in situ diagnoses were recorded. The completeness of the registry has been estimated to be >96%.12

Study Population

All 12,829,251 individuals with available genealogical information who were living in Sweden from January 1, 1958, to December 31, 2015, were included in this study. The follow-up period started for each individual from the beginning of 1958, the birth year, or the immigration year, whichever was latest. The follow-up period ended when the individual was diagnosed with CRC, emigrated, died, or at the end of 2015, whichever was first. The datasets did not contain real national identification numbers. Instead, pseudonymized data with technical serial numbers were used. The study protocol was approved by the Lund Regional Ethics Committee (ref 2012/795).

Family History Ascertainment

Detailed information on family history of colorectal tumors for each subject during the follow-up period was obtained from our record linkage between the Multigeneration Register and the Swedish Cancer Registry. Therefore, we were able to acquire not only the final family history status of individuals at the end of study follow-up but also dynamic family history status reflecting changes during follow-up of the index person whenever a new relative was diagnosed with colorectal tumor.13 These 2 definitions of family history assessment are explained in supplemental eAppendix 1 (available with this article at JNCCN.org).

Colorectal Tumors Ascertainment

Data from the Swedish Cancer Registry (from 1958 to 2015) were used to identify CCIS and primary CRC. The diagnoses of CRC were classified according to a 4-digit diagnostic code of the International Classification of Diseases, Seventh Revision (ICD-7), and subsequent revisions in Sweden. The following ICD-7 codes were used to extract information on patients with CRC: 153, 153.0, 153.1, 153.2, 153.3, 153.4, 153.8, 153.9, 154, 154.0, and 154.8. Two kinds of codes for histopathologic type were available: ICD codes for oncology (ICD-O-2 or ICD-O-3 since 1993) and WHO/HS/CANC/24.1 Histology Code (pathoanatomic diagnosis [PAD] since 1958), by which invasive and in situ colorectal tumors in the study were identified. Behavior code “2” as the fifth digit of the ICD-O-2/3 morphology code and value “4” as the third digit of PAD code were used to identify patients with CCIS. We regarded the pathologically verified CCIS as a synonym for adenoma with high-grade dysplasia.14 In this study, by the term (invasive) CRC we mean primary invasive CRC. Both types of colorectal tumors in family histories reported in our results are exclusive, unless otherwise specified; for example, the risk reported for family history of CCIS did not include those with both family history of CCIS and family history of CRC.

Statistical Analyses

Standardized incidence ratios (SIRs) were calculated to measure the risk of cancer in family members of patients with CCIS or CRC, as the ratio of observed to expected number of cases. The expected numbers were calculated from strata-specific person-years in those with a certain family history of colorectal tumor multiplied by strata-specific incidence rates in those without history of colorectal tumor in their first- and second-degree relatives. For stratification and adjustment, we used sex, 5-year age group, time period (1958–1964, 1965–1969, 1970–1974, 1975–1979, 1980–1984, 1985–1989, 1990–1994, 1995–1999, 2000–2004, 2005–2009, or 2010–2015), residential area (small cities in south Sweden, small cities in north Sweden, or large cities), and socioeconomic status (white-collar worker, blue-collar worker, professional, farmer, private, or other/unspecified). We also included information on hospital admission for obesity, alcoholism, and chronic obstructive pulmonary disease, a surrogate measure of heavy smoking in our adjustment models.

The age-specific cumulative risks were calculated for each family history group based on the following equations: age-specific annual incidence rate = number of cases for each age divided by person-years for that age; cumulative incidence rate = sum of each age-specific annual incidence rates from age 0 to certain ages (ie, sum of incidence rates from age 0–30 years was reported as cumulative incidence for age 30, 0–40 for age 40, etc); cumulative risk = 1 − exp[− cumulative incidence rate]. Similarly, the lifetime cumulative risk (LCR; with lifetime assumed to be 0–79 years based on the average life expectancy in Europe in 2015 of 78 years)15 was calculated. The 95% confidence intervals of SIR, LCR, and age-specific cumulative risk were calculated using Poisson approximation. All analyses were performed using SAS 9.4 (SAS Institute Inc).

Results

A total of 12,829,251 individuals with available genealogy information (with at least 1 known first-degree relative in our datasets) were included in this study (6,527,022 [50.9%] were men), of which 173,796 were diagnosed with CRC and 40,558 with CCIS. Follow-up was up to 58 years (median, 35 years). Only 1,738 (4.3%) of patients with CCIS were later diagnosed with CRC after an average interval of 6.3 years (median, 4 years). In total, at the time of their diagnosis, 164,242 patients with CRC had no family history of CCIS or CRC (94.5%), 861 had a family history of only CCIS (0.5%), and 8,458 had a family history of only invasive CRC (4.9%).

Individuals with a CCIS diagnosis in a first-degree relative (and no such diagnosis in a second-degree relative) had a 1.6-fold (95% CI, 1.5–1.7) increased risk of invasive CRC, and individuals with CCIS diagnosed in a second-degree relative (and no such diagnosis in a first-degree relative) had a 1.2-fold (95% CI, 1.0–1.5) increased risk (Table 1). These risks were similar to those in individuals with corresponding family history of CRC (one first-degree relative: SIR, 1.6; 95% CI, 1.6–1.7; one second-degree relative: SIR, 1.2; 95% CI, 1.1–1.3). Even the LCRs of these 2 categories of family history of CCIS were rather similar to risks in individuals with corresponding family history of invasive CRC (one first-degree relative: 6.5% CCIS vs 6.7% invasive CRC; one second-degree relative: 4.6% CCIS vs 5.1% invasive CRC), and so were cumulative risks by age of both groups, with similar curves with overlapping confidence intervals (Figure 1).

Table 1.

Risk of Invasive CRC by Family History of In Situ or Invasive Colorectal Tumor

Table 1.
Figure 1.
Figure 1.

Cumulative risk of invasive colorectal cancer by age in those with an affected FDR with in situ or invasive colorectal tumor. Orange and blue shaded areas represent 95% confidence intervals for family history of invasive and in situ colorectal tumor, respectively.

Abbreviation: FDR, first-degree relative.

Citation: Journal of the National Comprehensive Cancer Network 2021; 10.6004/jnccn.2021.7004

After further stratification by detailed type of relationship, the similarity of invasive CRC risk between family history of CCIS and family history of invasive CRC still existed in each stratum. For example, individuals whose father was diagnosed with CCIS had similar invasive CRC risk (SIR, 1.6; LCR, 6.8%) to those whose father had invasive CRC (SIR, 1.6; LCR, 6.6%) (Table 1).

Results of further stratification by type of relationship of affected family members showed that the invasive CRC risk in those with one half-sibling affected with CCIS was highly increased (SIR, 1.9; 95% CI, 1.1–3.0), similar to the risk in those with one sibling affected with CCIS (SIR, 1.8; 95% CI, 1.6–2.1) (Table 1). This similarity was also found in those with a history of invasive CRC in a half-sibling (SIR, 1.7; 95% CI, 1.3–2.1) or a sibling (SIR, 1.7; 95% CI, 1.6–1.8). However, we did not find any significant increase in risk of invasive CRC in those with one second-degree relative affected with CCIS other than a half-sibling (without any affected first-degree relatives), such as a grandparent (SIR, 1.2; 95% CI, 0.9–1.7; data not shown), or an uncle/aunt (SIR, 1.0; 95% CI, 0.6–1.5; data not shown).

After further stratification by sex, age at diagnosis of invasive CRC in the index person, and age at diagnosis of CCIS or invasive CRC in the affected first-degree relative, the similarity of increased risk of invasive CRC between those with family history of CCIS and those with family history of invasive CRC was consistently observed in each stratum (Table 2). The highest relative risk was observed for invasive CRC diagnosed before age 60 years when the first-degree relative was also diagnosed with CCIS before age 60 years (SIR, 2.8; 95% CI, 2.1–3.7). After exclusion of likely cases of hereditary nonpolyposis CRC according to the Amsterdam II criteria, the CRC risk remained unchanged (supplemental eAppendix 1).

Table 2.

Relative Risk of Invasive CRC by Sex, Age at Diagnosis, and Tumor Type

Table 2.

Discussion

Using the world’s largest nationwide datasets of its kind, we found that family history of CCIS in a first-degree relative or in a half-sibling is associated with an increased risk of invasive CRC. The magnitude of the risk increase is similar to that of having a family history of invasive CRC in corresponding family relationships. Interestingly, the risk of invasive CRC further significantly increased when one more first-degree relative (even one second-degree relative) was affected with CCIS. Furthermore, risk of early-onset invasive CRC was higher when first-degree relatives were diagnosed with CCIS at earlier ages.

Many studies have suggested the increased familial CRC risk in first-degree relatives (to the best of our knowledge excluding CCIS from their familial risk estimates),5,16 but to date there is limited research on risk of invasive CRC in those with a family history of CCIS. Only one study, published in 1998, has examined the association of having a family history of colon or rectum carcinoma in situ and risk of invasive CRC in parents and offspring, and found an increase in relative risk of invasive CRC.17 Limitations of that study were limited inclusion of information on relatives (siblings were not included), the fact that the risks could not be evaluated in detail because of a small number of cases, and the static definition of family history; that is, not taking into account the changes in family history status of individuals during follow-up. Nevertheless, our current results were consistent with these results from the pre-CRC screening era in Sweden, supporting our hypothesis that family history of CCIS is as important as family history of invasive CRC for risk of invasive CRC. In our study, we found almost identical risk of invasive CRC associated with family history of CCIS and with family history of invasive CRC in different combinations of family history, type of relationship, sex, age at diagnosis of index person, and age at diagnosis of the affected first-degree relative. These subgroup analyses could be considered as internal validation of our findings, and the consistency of results across subgroups underlines the robustness of the findings for potential use in clinical practice and consulting of family members of patients with either CCIS or invasive CRC.

A potential association between increased risk of invasive CRC and family history of advanced adenoma (adenoma ≥1 cm or high-grade dysplasia or tubulovillous/villous histology)18 or advanced colorectal polyps (advanced adenoma or sessile serrated polyp ≥1 cm or sessile serrated polyp with cytologic dysplasia, or traditional serrated adenoma of any size) has been reported. The National Colorectal Cancer Roundtable has accordingly created sample letters to help endoscopists and clinicians identify patients with advanced colorectal polyps, understand risk factors, and even be mindful of the increased risk to patients and their family members.19 Similar to individuals with family history of invasive CRC, family members of patients with advanced polyps are also critical screening targets for the prevention of early-onset CRC. In some existing screening guidelines, individuals who have first-degree relatives with advanced colorectal polyps are recommended to start screening at younger ages in the same way as those who have first-degree relatives with invasive CRC.2023 Our nationwide cohort study, using high-quality register-based data with long-term follow-up, and pathologically verified CCIS and invasive CRC, responded to the call from experts to “take the bull by the horns” with regard to methodology,24 which could overcome methodologic shortcomings of previous studies21 and provide novel findings of great importance. Studies on precursor lesions may increase the understanding of cancer etiology and cancer progression and can provide rationales for its molecular basis and genetic links, given that the progression of genetic alteration in invasive CRC has been extensively studied.25,26

Our study was based on data from latest available versions of several nationwide Swedish registers, which resulted in the world’s largest study of its kind, assuring a high level of accuracy and completeness of the analyzed data. Using the data linkage between genealogy dataset and cancer registry to retrieve family history could mitigate several common biases, such as selection bias (exempted in a nationwide study), recall bias, and information bias (all required information was retrieved from record linkage, not self-reported during interviews); thus the study avoided biased estimates resulting from self-reports.27 Furthermore, this long-term cohort study allowed us to track CRC incidence over the lifetime with age-specific cumulative risk, which is an effect measure tangible for patients, their relatives, clinicians, researchers, and health policymakers. In addition, benefiting from large subgroup sample sizes, the study allowed precise quantification and comparison of the risk associated with the different categories of family history of colorectal tumors. However, some results in subgroup analyses (eg, for multiple first-degree relatives affected with CCIS) were still based on relatively small sample sizes, and therefore some of risk estimates could be due to random variation. Nevertheless, the trend of risk by number of family members affected with CCIS was quite logical in these groups and was in line with that in multiple relatives affected with invasive CRC using a much larger sample size.

Although CCIS tumors in the Swedish Cancer Registry were 100% diagnosed based on microscopic examination of biopsied tissues, the registry data did not include information on type of polyps and whether diagnoses were based on polyps that were completely removed, partially removed, from visually abnormal sites in the colon or rectum that were subsequently biopsied, or from random biopsies of the colorectum. Some national screening guidelines recommend earlier screening if there had been a case of CRC in the family. In theory, such practices could lead to overestimation of the incidence of familial early-onset CCIS after a patient with CRC was diagnosed in the family, but we used a dynamic approach to exclude such a bias. In fact, we considered the invasive CRC as the outcome of interest only when it occurred after the exposure to family history of CCIS, not the other way around. Moreover, there is no nationwide organized screening recommendation in Sweden for individuals with or without family history to lead to such a bias in the first place, even for invasive CRC. It should be noted that the definition and classification of advanced adenoma is not uniform in clinical practice, and challenges in subjectiveness and inaccurateness of assessment of size and histology of diagnosis of polyps are still inevitable.21,28 Some other limitations with no or trivial effect on our findings and further discussions on why dynamic family history was used can be found in supplemental eAppendix 1.

Conclusions

Our findings would supplement current screening guidelines by providing a strong recommendation, based on high-quality evidence, to consider family history of CCIS similarly to family history of invasive CRC in risk stratifications for earlier screening compared with the general population. We also recommend that future studies on familial risk of colorectal neoplasms should not only include family history of invasive CRC but also family history of CCIS. This may also lead to more precise estimates for attributable fraction and burden of familial colorectal neoplasms. Based on findings of this study, the evidence-based risk-adapted starting ages of CRC screening that we have recently provided for those with family history of invasive CRC7 should, in principle, also be applicable to those with family history of CCIS. Combining findings of these 2 robust studies would support screening guideline providers and clinicians with more detailed recommendations for those with family history of these conditions by number and degree of affected relatives as well as their age at diagnoses.

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Submitted July 24, 2020; final revision received November 29, 2020; accepted for publication January 7, 2021.

Published online September 13, 2021.

Author contributions: Study concept: Kharazmi, Fallah. Data curation: Kharazmi, Fallah. Formal analysis: Tian, Kharazmi, Fallah. Funding acquisition: Tian, Fallah. Investigation: Kharazmi. Methodology: Tian, Kharazmi, Fallah. Project administration: Kharazmi, Fallah. Resources: K. Sundquist, J. Sundquist. Software: Tian, Kharazmi, Xu. Supervision: Kharazmi, Fallah. Validation: Kharazmi, Fallah. Writing–original draft: Tian. Writing–review and editing: All authors.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Xing Xu has received support from the China Scholarship Council.

Disclaimer: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Correspondence: Mahdi Fallah, MD, PhD, Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. Email: m.fallah@dkfz.de
  • View in gallery

    Cumulative risk of invasive colorectal cancer by age in those with an affected FDR with in situ or invasive colorectal tumor. Orange and blue shaded areas represent 95% confidence intervals for family history of invasive and in situ colorectal tumor, respectively.

    Abbreviation: FDR, first-degree relative.

  • 1.

    Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209249.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Amin MB, Edge S, Greene F, et al., eds. AJCC Cancer Staging Manual, 8th ed. New York, NY: Springer International Publishing; 2017.

  • 3.

    National Cancer Institute. Stage 0 colorectal carcinoma in situ. Accessed May 29, 2020. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/stage-0-colorectal-carcinoma-in-situ

    • Search Google Scholar
    • Export Citation
  • 4.

    Fleming M, Ravula S, Tatishchev SF, et al. Colorectal carcinoma: pathologic aspects. J Gastrointest Oncol 2012;3:153173.

  • 5.

    Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer 2006;42:216227.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Tian Y, Kharazmi E, Sundquist K, et al. Familial colorectal cancer risk in half siblings and siblings: nationwide cohort study. BMJ 2019;364:l803.

  • 7.

    Tian Y, Kharazmi E, Brenner H, et al. Calculating starting age for screening in relatives of patients with colorectal cancer based on data from large nationwide datasets. Gastroenterology 2020;159:159168.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Siegel RL, Fedewa SA, Anderson WF, et al. Colorectal cancer incidence patterns in the United States, 1974–2013. J Natl Cancer Inst 2017;109:djw322.

  • 9.

    Siegel RL, Torre LA, Soerjomataram I, et al. Global patterns and trends in colorectal cancer incidence in young adults. Gut 2019;68:21792185.

  • 10.

    Kharazmi E, Fallah M, Sundquist K, et al. Familial risk of early and late onset cancer: nationwide prospective cohort study. BMJ 2012;345:e8076.

  • 11.

    Hemminki K, Ji J, Brandt A, et al. The Swedish Family-Cancer Database 2009: prospects for histology-specific and immigrant studies. Int J Cancer 2010;126:22592267.

    • Search Google Scholar
    • Export Citation
  • 12.

    Barlow L, Westergren K, Holmberg L, et al. The completeness of the Swedish Cancer Register: a sample survey for year 1998. Acta Oncol 2009;48:2733.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Mukama T, Kharazmi E, Sundquist K, et al. Familial risk of breast cancer by dynamic, accumulative, and static definitions of family history. Cancer 2020;126:28372848.

  • 14.

    Bond JH. Polyp guideline: diagnosis, treatment, and surveillance for patients with nonfamilial colorectal polyps. The Practice Parameters Committee of the American College of Gastroenterology. Ann Intern Med 1993;119:836843.

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