Familial relative risk of colorectal cancer: a population-based study

doi:10.1016/S0959-8049(03)00420-9

European Journal of Cancer

Volume 39, Issue 13, September 2003, Pages 1904-1911

https://doi.org/10.1016/S0959-8049(03)00420-9 Get rights and content

Abstract

This study aimed to assess the familial relative risk for colorectal cancer (CRC) and its variation according to age and gender. A population-based family study was carried out in France, from 1993 to 1998, including 761 families. Familial CRC risks were estimated from a cohort analysis of the relatives. No obvious decrease in CRC risk was found with increasing age, except when either the proband, or the relative, were in the youngest age class. The effect of the relatives’ and probands’ ages on the CRC risk differed according to their gender. The cumulative risk of CRC increased at an earlier age in male relatives of probands younger than 60 years of age, than in female relatives. This result suggests that mechanisms specific to females, possibly interacting with genetic factors, explain the difference in the cumulative risks between families with male and female probands.

Introduction

Colorectal cancer (CRC) is the second most common cause of death from cancer in France, with approximately 33 400 new cases diagnosed per year [1]. As with many cancers, a family history (FH) of CRC has been shown to increase an individual's risk of developing the disease. The risk associated with a FH of cancer within the population has been estimated mainly from studies of first-degree relatives, and is usually estimated as a doubling of risk 2, 3, 4. Other studies have concentrated on more selected populations (e.g. high-risk families), these have proved that some syndromes are inherited. Indeed, only a small fraction of CRC cases (less than 5%) are accounted for by the known inherited syndromes, familial adenomatous polyposis and hereditary non-polyposis colorectal cancer (HNPCC) [5]. Studies within high-risk families or the general CRC population have suggested heterogeneity in the familial risk. Indeed, some researchers have suggested that FH may have a greater impact on proximal tumours 6, 7, others have shown that familial risk may be modified by exposure to hormones [7] or by diet [8]. A population-based family study, the CCREF (Calvados ColoREctal Family) study has been carried out in Calvados, France. The main aim of this study was to define the role of inherited factors in the transmission of CRC. This population-based family study allowed the evaluation of familial risk and its variation according to potential modifier factors. In this paper, we present estimates of the CRC familial relative risk and its variation according to age and gender.

Section snippets

Patients and methods

The CCREF study consisted of the collection of the CRC incident cases in the region served by the Calvados Cancer Registry. The local Research Ethics Committee in Calvados approved the study. All patients diagnosed with CRC between September 1993 and December 1998 were eligible for the study. Information on tumour histology was collected for all CRC cases. Patients’ details were obtained from the pathology laboratories in the Calvados region, and the patients’ general practitioners (GP) were

Study acceptability

Between September 1993 and December 1998, 1351 cases of CRC were diagnosed in the Calvados region. 34 cases were already deceased when the information of a CRC diagnosis was received. Thus, the GPs of 1317 cases were contacted to obtain permission to contact their patients. 94 of their patients died in the meantime (7.1%), 138 refused to allow us to contact their patients (10.5%) and 1085 gave us permission to contact their patients (82.5%). The most common reason for the GP's refusal was the

Discussion

The CCREF study confirms that a family history of CRC increases one's risk of developing CRC (for example Refs. 3, 10, 12, 13) with estimations similar to those found in the Swedish family cancer database [14]. However, only 0.4% met the strict Amsterdam criteria I for HNPCC. This low prevalence estimate might be due to the inclusion of probands with in situ malignancies. However, when the 76 families of probands with in situ malignancy are excluded, the number of families fulfilling the

Acknowledgments

This study was made possible by the fruitful collaboration of general practitioners, anatomopathologists (Drs. J. Chasles, E. De Ranieri, P. Dupin, F. Galateau, B. Gallet, J. Jehan, A.-M. Mandard, D. Panthou, F. Petit, M. Rollet and P. Rousselot), gastro-enterologists, radiotherapists and surgeons of Calvados. This study was financed by la Fondation de France, la SNFGE, la Ligue Nationale Contre le Cancer, les ligues départementales: du Calvados, de l'Orne, de la Manche, des Yvelines, de

References (29)

H.F. Vasen et al.
New clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC, Lynch Syndrome) proposed by the International Collaborative Group on HNPCC
Gastroenterology
(1999)
F. Ménégoz et al.
Le Cancer en France: Incidence et Mortalité
(1999)
D.E. Goldgar et al.
Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands
J. Natl. Cancer Inst.
(1994)
M.L. Slattery et al.
Family history of cancer and colon cancer riskthe Utah Population Database
J. Natl. Cancer Inst.
(1994)
E. Negri et al.
Family history of cancer and risk of colorectal cancer in Italy
Br. J. Cancer
(1998)
J.D. Potter
Colorectal cancermolecules and populations
J. Natl. Cancer Inst.
(1999)
J.A. Bufill
Colorectal cancerevidence for distinct genetic categories based on proximal or distal tumour location
Ann. Intern. Med.
(1990)
P.A. Newcomb et al.
Interactions of familial and hormonal risk factors for large bowel cancer in women
Int. J. Epidemiol.
(1999)
T.A. Sellers et al.
Diet and risk of colon cancer in a large prospective study of older womenan analysis stratified on family history (Iowa, United States)
Cancer Causes Control
(1998)
Breslow NE, Day NE. The design and analysis of cohort studies. In Statistical Methods in Cancer Research. Lyon, IARC,...

H.F. Vasen et al.

The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC)

Dis. Colon Rectum

(1991)

C.S. Fuchs et al.

A prospective study of family history and the risk of colorectal cancer

N. Engl. J. Med.

(1994)

R.W. Burt

Familial risk and colon cancer

Int. J. Cancer

(1996)

D. Chuanhui et al.

Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families

Int. J. Cancer

(2001)

Cited by (49)

Familial colorectal cancer
2022, Best Practice and Research: Clinical Gastroenterology
The introduction of average-risk colorectal cancer (CRC) screening programs means that many subjects with family history of CRC and without well-described inherited syndromes can benefit from these public health policies. Therefore, the definition of which individuals should be named under the umbrella of the term “familial CRC” should be reconsidered to include only those who are outside of the protection of population-based screening and need to be moved towards a more intensive surveillance strategy. Two subgroups have been reported as having a high enough CRC risk to be included within the term “familial risk of CRC”: individuals who have ≥1 first degree relative (FDR) with CRC diagnosed at age <50 years, and those who have ≥2 FDRs with CRC. Colonoscopy-based screening starting at age 40 years is proposed as the most accepted recommendation for these individuals. Finally, the evolution of Lynch syndrome screening from clinical criteria to tumor tissue analysis and new tools for screening pathogenic gene mutations associated with cancer susceptibility in individuals with early-onset CRC might help to reduce misclassification of familial CRC.
Effects of Family History on Relative and Absolute Risks for Colorectal Cancer: A Systematic Review and Meta-Analysis
2019, Clinical Gastroenterology and Hepatology
Citation Excerpt :
In most case–control and cohort studies the FH was assessed using questionnaires or registry-based FH data. Individuals with at least 1 FDR with CRC (Figure 2) were 2.22 (95% CI, 2.00–2.48) times more likely to develop CRC according to 41 case–control studies37–70,72–78 and 1.67 (95% CI, 1.52–1.82) times more likely according to 12 cohort studies.17,19,20,26,28–32,34–36 Both case–control and cohort studies showed considerable heterogeneity (I2 = 82% and I2 = 100%, respectively).
Guidelines recommend that individuals with familial colorectal cancer undergo colonoscopy surveillance instead of average-risk screening. However, these recommendations vary widely. To substantiate appropriate surveillance strategies, precise and valid evidence-based risk estimates are needed for individuals with a family history of colorectal cancer (CRC).
We systematically searched MEDLINE, EMBASE, and Cochrane from inception to July 2018 for case–control and cohort studies investigating the effect of family history on CRC risk. We calculated summary estimates of pooled relative risks (RRs) using a random-effects model. Life tables were created to convert RR estimates into absolute risk estimates.
We screened 4417 articles and identified 42 eligible case–control and 20 cohort studies. In case–control studies, the RR for CRC in patients with 1 first-degree relative (FDR with CRC) was 1.92 (95% CI, 1.53–2.41) and 1.37 (95% CI, 0.76–2.46) for cohort studies. For individuals with 2 or more FDRs with CRC, the RR was 2.81 in case–control studies (95% CI, 1.73–4.55) and 2.40 in cohort studies (95% CI, 1.76–3.28). For individuals having a FDR diagnosed with CRC at an age younger than 50 years, the RR for CRC in their FDRs was 3.57 in case–control studies (95% CI, 1.07–11.85) and 3.26 in cohort studies (95% CI, 2.82–3.77). The cumulative absolute risks for CRC at 85 years in Western Europe were 4.8% for persons with 1 FDR with CRC (95% CI, 2.7%–8.3%), 8.2% for individuals with 2 or more FDRs (95% CI, 6.1%–10.9%), and 11% for persons with a FDR diagnosed with CRC at an age younger than 50 years (95% CI, 9.5%–12.4%).
In this systematic review and meta-analysis, we found that the RR of CRC among FDRs is lower than previously expected, especially based on cohort studies. Risk estimates are affected by the number of relatives with CRC and their age at diagnosis. Intensified colonoscopy surveillance strategies could be considered for high-risk groups. PROSPERO trial identification no: CRD42018103058.
Postoperative adjuvant chemotherapy is associated with a lower incidence of colorectal adenomas in patients with previous colorectal cancer
2018, Gastrointestinal Endoscopy
The effects of chemotherapeutic agents on the development of colorectal adenomas in patients with previous colorectal cancer (CRC) are not defined. Therefore, we evaluated the potential effect of adjuvant chemotherapy on the incidence of colorectal adenomas in patients with previous CRC.
We selected patients with low-risk stage II CRC with or without postoperative 5-fluorouracil–based adjuvant chemotherapy to reduce selection bias. Among 1808 patients with stage II CRC who underwent colonoscopic surveillance after curative resection of CRC between 2006 and 2013, 192 patients were retrospectively enrolled in this study after matching for age and sex. The patients were divided into 96 patients receiving and 96 patients not receiving 5-fluorouracil–based chemotherapy.
Forty patients (41.7%) exhibited colorectal adenomas among 96 patients who received adjuvant chemotherapy, compared with 50 patients (52.1%) with colorectal adenomas among 96 patients who received surgery only. The incidence rate of advanced adenoma was significantly lower in the chemotherapy group than in the nonchemotherapy group (3.1% vs 10.4%, P = .044). After adjustment for clinically relevant factors such as body mass index, aspirin use, metformin use, number of follow-up colonoscopies, and operation type, adjuvant chemotherapy was found to be associated with a decreased incidence of advanced adenoma (odds ratio, .151; 95% confidence interval, .035-.653; P = .011) in patients with stage II CRC.
The results showed that chemotherapy in patients with CRC may be associated with a lower risk of colorectal advanced adenoma development.
Increased Risk of Colorectal Cancer Among Family Members of All Ages, Regardless of Age of Index Case at Diagnosis
2015, Clinical Gastroenterology and Hepatology
It is not clear whether familial risk of colorectal cancer (CRC) varies with age of index CRC patients or their relatives. We quantified the risk of CRC in first-degree relatives (FDRs), second-degree relatives, and first-cousin relatives of individuals with CRC, stratified by ages and sexes of index patients and ages of relatives.
CRCs diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and sex-matched CRC-free individuals were selected to form the comparison group. CRC risk in relatives was determined by Cox regression analysis.
Of 18,208 index patients diagnosed with CRC, the highest familial risk was observed in FDRs of index CRC patients who were diagnosed at an age younger than 40 years (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.7–3.79). However, familial risk was increased in FDRs even when the index case was diagnosed with cancer at an advanced age (>80 years; HR, 1.76; 95% CI, 1.59−1.94). Ages of relatives and ages of index cases of CRC each affected familial cancer risk; the highest risk was found in young relatives (<50 years) of individuals with early-onset CRC (<40 years; HR, 7.0; 95% CI, 2.86–17.09).
All relatives of individuals with CRC are at increased risk for this cancer, regardless of the age of diagnosis of the index patient. Although risk is greatest among young relatives of early-onset CRC cases, relatives of patients diagnosed at advanced ages also have an increased risk.
Incidence and Mortality of Colorectal Cancer in Individuals with a Family History of Colorectal Cancer
2015, Gastroenterology
Little is known about the change in risk conferred by family history of colorectal cancer (CRC) as a person ages. We evaluated the effect of family history on CRC incidence and mortality after 55 years of age, when the risk of early onset cancer had passed.
We collected data from participants in the randomized, controlled Prostate, Lung, Colorectal and Ovarian cancer screening trial of flexible sigmoidoscopy versus usual care (55–74 years old, no history of CRC), performed at 10 US centers from 1993 to 2001. A detailed family history of colorectal cancer was obtained at enrollment, and subjects were followed for CRC incidence and mortality for up to 13 years.
Among 144,768 participants, 14,961 subjects (10.3%) reported a family of CRC. Of 2090 incident cases, 273 cases (13.1%) had a family history of CRC; among 538 deaths from CRC, 71 (13.2%) had a family history of CRC. Overall, family history of CRC was associated with an increased risk of CRC incidence (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.10–1.50; P<.0001) and increased mortality (HR, 1.31; 95% CI, 1.02–1.69; P = .03). Subjects with 1 first degree relative (FDR) with CRC (n = 238; HR, 1.23; 95% CI, 1.07–1.42) or ≥2 FDRs with CRC (n = 35; HR, 2.04; 95% CI, 1.44–2.86) were at increased risk for incident CRC. However, among individuals with 1 FDR with CRC, there were no differences in risk based on age at diagnosis in the FDR (for FDR <60 years of age: HR, 1.27; 95% CI, 0.97–1.63; for FDR 60–70 years of age: HR, 1.33; 95% CI, 1.06–1.62; for FDR >70 years of age: HR, 1.14; 95% CI, 0.93–1.45; P trend = .59).
After 55 years of age, subjects with 1 FDR with CRC had only a modest increase in risk for CRC incidence and death; age of onset in the FDR was not significantly associated with risk. Individuals with ≥2 FDRs with CRC had continued increased risk in older age. Guidelines and clinical practice for subjects with a family history of CRC should be modified to align CRC testing to risk. ClinicalTrials.gov number, NCT00002540.
Increased risk of colorectal neoplasia among family members of patients with colorectal cancer: A population-based study in Utah
2014, Gastroenterology
Citation Excerpt :
The breakdown by age group of first- and second-degree relatives of cases diagnosed with CRC stratified by age shows that 3% of CRCs would have been missed using present guidelines that do not advise screening at a younger age for FDRs of persons with CRC older than age 60 years (Table 6). The risks for CRC in FDRs (ie, immediate relatives) of large-bowel cancer patients in the present study are similar to findings of studies from France,19 Sweden,20 and Australia.21 In addition, systematic reviews and meta-analyses incorporating 47 CRC familial risk studies provide similar risks in FDRs, despite differences in study design and populations examined.22–24
Colorectal cancer (CRC) frequently develops in multiple members of the same families, but more data are needed to prepare effective screening guidelines. We quantified the risk of CRC and adenomas in first-degree relatives (FDRs) and second-degree relatives and first cousins of individuals with CRC, and stratified risk based on age at cancer diagnosis.
We performed a case-control study of Utah residents, 50–80 years old, who underwent colonoscopy from 1995 through 2009. Index cases (exposed to colonoscopy) were colonoscopy patients with a CRC diagnosis. Age- and sex-matched individuals, unexposed to colonoscopy (controls) were selected to form the comparison groups for determining risk in relatives. Colonoscopy results were linked to cancer and pedigree information from the Utah Population Database to investigate familial aggregation of colorectal neoplasia using Cox regression analysis.
Of 126,936 patients who underwent a colonoscopy, 3804 were diagnosed with CRC and defined the index cases. FDRs had an increased risk of CRC (hazard rate ratio [HRR], 1.79; 95% confidence interval [CI],1.59–2.03), as did second-degree relatives (HRR, 1.32; 95% CI, 1.19–1.47) and first cousins (HRR, 1.15; 95% CI, 1.07–1.25), compared with relatives of controls. This risk was greater for FDRs when index patients developed CRC at younger than age 60 years (HRR, 2.11; 95% CI, 1.70–2.63), compared with older than age 60 years (HRR, 1.77; 95% CI, 1.58–1.99). The risk of adenomas (HRR, 1.82; 95% CI, 1.66–2.00) and adenomas with villous histology (HRR, 2.43; 95% CI, 1.96–3.01) also were increased in FDRs. Three percent of CRCs in FDRs would have been missed if the current guidelines, which stratify screening recommendations by the age of the proband, were strictly followed.
FDRs, second-degree relatives, and first cousins of patients who undergo colonoscopy and are found to have CRC have a significant increase in the risk of colorectal neoplasia. These data should be considered when establishing CRC screening guidelines for individuals and families.

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Familial relative risk of colorectal cancer: a population-based study

Abstract

Introduction

Section snippets

Patients and methods

Study acceptability

Discussion

Acknowledgments

Gastroenterology

Le Cancer en France: Incidence et Mortalité

Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands

J. Natl. Cancer Inst.

Family history of cancer and colon cancer riskthe Utah Population Database

J. Natl. Cancer Inst.

Family history of cancer and risk of colorectal cancer in Italy

Br. J. Cancer

Colorectal cancermolecules and populations

J. Natl. Cancer Inst.

Colorectal cancerevidence for distinct genetic categories based on proximal or distal tumour location

Ann. Intern. Med.

Interactions of familial and hormonal risk factors for large bowel cancer in women

Int. J. Epidemiol.

Diet and risk of colon cancer in a large prospective study of older womenan analysis stratified on family history (Iowa, United States)

Cancer Causes Control

The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC)

Dis. Colon Rectum

A prospective study of family history and the risk of colorectal cancer

N. Engl. J. Med.

Familial risk and colon cancer

Int. J. Cancer

Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families

Int. J. Cancer