Familial Risk Of Colorectal Cancer Research Articles

Long-term benefits and harms of early colorectal cancer screening in German individuals with familial cancer risk.

Individuals with a family history of colorectal cancer (CRC) may benefit from early screening with colonoscopy or immunologic fecal occult blood testing (iFOBT). We systematically evaluated the benefit-harm trade-offs of various screening strategies differing by screening test (colonoscopy or iFOBT), interval (iFOBT: annual/biennial; colonoscopy: 10-yearly) and age at start (30, 35, 40, 45, 50 and 55 years) and end of screening (65, 70 and 75 years) offered to individuals identified with familial CRC risk in Germany. A Markov-state-transition model was developed and used to estimate health benefits (CRC-related deaths avoided, life-years gained [LYG]), potential harms (eg, associated with additional colonoscopies) and incremental harm-benefit ratios (IHBR) for each strategy. Both benefits and harms increased with earlier start and shorter intervals of screening. When screening started before age 50, 32-36 CRC-related deaths per 1000 persons were avoided with colonoscopy and 29-34 with iFOBT screening, compared to 29-31 (colonoscopy) and 28-30 (iFOBT) CRC-related deaths per 1000 persons when starting age 50 or older, respectively. For iFOBT screening, the IHBRs expressed as additional colonoscopies per LYG were one (biennial, age 45-65 vs no screening), four (biennial, age 35-65), six (biennial, age 30-70) and 34 (annual, age 30-54; biennial, age 55-75). Corresponding IHBRs for 10-yearly colonoscopy were four (age 55-65), 10 (age 45-65), 15 (age 35-65) and 29 (age 30-70). Offering screening with colonoscopy or iFOBT to individuals with familial CRC risk before age 50 is expected to be beneficial. Depending on the accepted IHBR threshold, 10-yearly colonoscopy or alternatively biennial iFOBT from age 30 to 70 should be recommended for this target group.

Detection of germline variants with pathogenic potential in 48 patients with familial colorectal cancer by using whole exome sequencing

BackgroundHereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones.MethodsWe performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants.ResultsWe identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer.ConclusionsIdentification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.

CO4 How Can the Long-Term Benefits and Harms of Screening Be Transparently Quantified and Contrasted for Informed Decision-Making? Colorectal Cancer Screening for Persons at Familial Risk (FARKOR)

Our aim was to systematically evaluate and compare the long-term benefit-harm balance of different screening strategies (colonoscopy or immunologic fecal blood testing (iFOBT) for individuals younger than age 50 with identified familial colorectal cancer (CRC) risk in Germany.

EE131 Health-Economic Evaluation of Early Screening for Individuals Younger Than Age 50 with Familial Colorectal Cancer Risk Based on a Decision Analysis within the Farkor Study

To systematically evaluate the benefit-harm and cost-effectiveness ratios of different screening strategies using colonoscopy or immunologic fecal blood testing (iFOBT) in German individuals younger than age 50 with familial colorectal cancer (CRC) risk.

Shared environment and colorectal cancer: A Nordic pedigree registry-based cohort study.

Risk of colorectal cancer (CRC) increases in relatives of patients with CRC. The extent to which this is attributable to genetic predisposition or shared environment is unclear. We explored this question using nationwide cohorts from Denmark, Finland and Sweden. From 1977 to 2013, we identified 359 879 individuals with a CRC diagnosis and 2 258 870 of their relatives who we followed for CRC incidence. We calculated standardized incidence ratios (SIR) and 95% confidence intervals (CI) for CRC in individuals with an affected relative. We used nationwide household and pedigree data along with national SIR estimates to calculate risk ratios (RR) for the contribution of shared household environment, childhood environment and genetic relationship to CRC risk in those with an affected relative. SIR of CRC was increased for individuals with an affected relative, across all countries and ages. For those with an affected parent, the SIR was 1.65 (95% CI: 1.61‐1.69), 1.98 (95% CI: 1.87‐2.09), for those with an affected sibling and 2.14 (95% CI: 1.84‐2.49) for those with an affected halfsibling. In those <65 years old, shared childhood (RR: 1.41, 95% CI: 1.26‐1.57) and household (RR: 2.08, 95% CI: 1.25‐3.46) environments were significantly greater contributors to familial risk of CRC than genetics (RR: 0.88, 95% CI: 0.53‐1.46). This large‐scale Nordic population‐based study of excess risk of CRC among relatives of those with CRC addresses the difficult disentangling of shared environment from genetic predisposition in the heritability of CRC. We found shared environment to be the most important contributor to CRC risk.

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

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. 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. 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. 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.

Single nucleotide variants c.-13G→C (rs17429833) and c.108C→T (rs72466472) in the CLDN1 gene and increased risk for familial colorectal cancer.

The Claudin-1 (CLDN1) protein plays an important role in the function of the tight junction and studies have shown it is aberrantly downregulated in many tumors including colorectal cancer (CRC). The aim of this study was to determine the relationship between four SNVs in the CLDN1 gene [c.-13G→C (rs17429833), c.108C→T (rs72466472), c.369T→C (rs9869263), and c.370G→A (rs140846629)] and the risk of familial colorectal cancer (FCC). A case-control study was conducted with peripheral blood DNAs from 50 patients with CRC that belong to FCC families and 96 healthy control individuals. The analysis of genetic variants was performed by PCR and restriction enzymatic digestion. The patients and control groups presented in Hardy-Weinberg equilibrium for all evaluated SNVs. No significant differences occurred in wild-type homozygous, heterozygous and variant homozygous genotypes, separately or together, in patient and control groups for the SNVs rs72466472, rs9869263, and rs140846629. However, for the SNV rs17429833, increased frequency of GC genotype occurred in patients compared to healthy individuals (58.30% vs. 41.70%), with an OR=3.28 (95%CI=1.22 to 9.09) for CRC. In the patients' group, individuals harboring combined genotypes rs17429833 (GC) and rs72466472 (CC) (26% vs. 8.42%) showed an OR=3.78 (95%CI=1.33 to 11.48). Moreover, patients harboring GC genotype for SNV rs17429833 presented significantly association with well differentiated adenocarcinoma when compared to moderately differentiated adenocarcinoma [60% vs. 22.58%, OR=6.3 (95%CI=1.15 to 39.76)]. The GC genotype for the SNV rs17429833 or combined genotypes for SNVs rs17429833 (GC) and rs72466472 (CC) seems to be risk factors for patients with FCC in Brazilian patients; however, a larger number of patients needs to be evaluated to confirm our results.

FANCM c5791C>T stopgain mutation (rs144567652) is a familial colorectal cancer risk factor.

ABSTRACTPurposeWhile familial aggregation of colorectal cancer (CRC) is recognized, the majority of the germline predisposition factors remain unidentified, and many high‐risk CRC pedigrees remain unexplained by known risk variants. Fanconi Anemia genes have been recognized to be associated with cancer risk. Notably, FANCM (OMIM 609644) variants have been reported to confer risk for CRC and breast cancer.MethodsExome sequencing of CRC‐affected cousins in a set of 47 independent extended high‐risk CRC pedigrees identified a candidate set of rare, shared variants. Variants were tested for association with risk in 744 Utah CRC cases and 1525 controls, and for segregation with CRC in affected relatives.ResultsA FANCM stopgain variant was observed in two CRC‐affected cousin pairs, each from an independent Utah high‐risk pedigree, and yielded a nonsignificant, but elevated OR = 2.05 in a set of Utah cases and controls. Segregation of the variant to other related CRC‐affected cases was observed in the two extended pedigrees.ConclusionA rare stopgain variant in FANCM (rs144567652) that is recognized as a breast cancer predisposition variant, and that has previously been proposed, but not confirmed, as a CRC predisposition variant, is validated here as a risk factor for familial CRC.

Increased Risk of Colorectal Cancer Tied to Advanced Colorectal Polyps: An Untapped Opportunity to Screen First-Degree Relatives and Decrease Cancer Burden.

Advanced adenomas represent a subset of colorectal polyps that are known to confer an increased risk of colorectal neoplasia to the affected individual and their first-degree relatives (FDRs). Accordingly, professional guidelines suggest earlier and more intensive screening for FDRs of those with advanced adenomas similar to FDRs of those with colorectal cancer (CRC). Although the risk to family members is less clear among patients with advanced serrated polyps, they are often considered in the same category. Unfortunately, there is a growing concern that patients, endoscopists, and primary care providers are unaware of the familial risk associated with these polyps, leaving a wide gap in screening these high-risk individuals. Herein, we propose a standardized language around advanced colorectal polyps and present a detailed review of the literature on associated familial risk. We outline the challenges to implementing the current screening recommendations and suggest approaches to overcome these limitations, including a proposed new colonoscopy quality metric to capture communication of familial CRC risk. Improving screening in these high-risk groups has the potential to substantially reduce the burden of CRC.

Poor Knowledge of Personal and Familial Colorectal Cancer Risk and Screening Recommendations Associated with Advanced Colorectal Polyps.

Advanced colorectal polyps (adenoma or sessile serrated polyp ≥ 1cm, adenoma with villous features, adenoma with high-grade dysplasia, or any sessile serrated polyps with dysplasia) are associated with an increased risk of future advanced colorectal neoplasia and confer an increased risk of advanced neoplasia to first-degree family members. Professional societies therefore recommend more intensive surveillance of these polyps and earlier screening for first-degree relatives. The aim of this study was to assess knowledge of personal and familial risk and recommendations among patients with advanced colorectal polyps and identify predictors of knowledge. An online survey was designed to assess the domains of knowledge and risk perception regarding personal and familial colorectal cancer risk and screening recommendations. After expert review and pilot testing, the 37-item survey was electronically sent to all patients diagnosed with an advanced colon or rectal polyp under the age of 60. Patient report of polyp findings was compared to documented findings in the medical record. Univariable and multivariable regressions were performed to evaluate predictors of knowledge. One hundred thirty-seven out of 344 (39.8%) eligible patients responded to the survey. 28.5% of participants reported that the polyp they had removed was precancerous. 54.8% of participants reported that they have a higher risk of CRC, and 65.2% reported that they should be undergoing colonoscopy surveillance in 3years or less. 40.1% reported that their first-degree family members are at increased CRC risk, and 38.0% reported that first-degree family members should get earlier screening. Participants reported their endoscopists as their top source of information about risk and recommendations, though only 7.3% of endoscopists made recommendations for family members. Female gender and higher income were predictors of accurate knowledge, as endoscopist was the main source of knowledge. Patients with advanced colorectal polyps have poor knowledge of personal and familial CRC risk and recommendations. Endoscopists who remove advanced polyps are in an ideal position to educate their patients about their personal risk and the risk and recommendations for first-degree family members.

Challenges With Colorectal Cancer Family History Assessment—Motivation to Translate Polygenic Risk Scores Into Practice

Challenges With Colorectal Cancer Family History Assessment—Motivation to Translate Polygenic Risk Scores Into Practice

Endoscopic Management of Patients with Lynch Syndrome or Familial Colorectal Cancer Risk

Sponsoring Organization: European Society of Gastrointestinal Endoscopy (ESGE)Background and ObjectiveBecause of the increased risk for cancer in

Endoscopic management of Lynch syndrome and of familial risk of colorectal cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

ESGE recommends that individuals with Lynch syndrome should be followed in dedicated units that practice monitoring of compliance and endoscopic performance measures.Strong recommendation, low quality evidence, level of agreement 100 %.ESGE recommends starting colonoscopy surveillance at the age of 25 years for MLH1 and MSH2 mutation carriers and at the age of 35 years for MSH6 and PMS2 mutation carriers.Strong recommendation, moderate quality evidence, level of agreement 100 %. ESGE recommends the routine use of high-definition endoscopy systems in individuals with Lynch syndrome. Strong recommendation, high quality evidence, level of agreement 100 %. ESGE suggests the use of chromoendoscopy may be of benefit in individuals with Lynch syndrome undergoing colonoscopy; however routine use must be balanced against costs, training, and practical considerations.Weak recommendation, moderate quality evidence, level of agreement 89 %.ESGE recommends definition of familial risk of colorectal cancer as the presence of at least two first-degree relatives with colorectal cancer or at least one first-degree relative with colorectal cancer before the age of 50 years.Strong recommendation, moderate quality evidence, level of agreement 92 %.ESGE recommends colonoscopy surveillance in first-degree relatives of colorectal cancer patients in families that fulfill the definition of familial risk of colorectal cancer.Strong recommendation, moderate quality evidence, level of agreement 100 %.

Genetic epidemiology of colorectal cancer and associated cancers.

We review here data on familial risk in colorectal cancer (CRC) generated from the Swedish Family-Cancer Database, the largest resource of its kind in the world. Although the concordant familial risk for CRC (i.e. CRC risk in families of CRC patients) has been reasonably well established, the studies on discordant familial risks (i.e. CRC risk in families with any other cancers) are rare. Because different cancers could be caused by shared genetic susceptibility or shared environment, data of associations of discordant cancers may provide useful information for identifying common risk factors. In analyses between any of 33 discordant cancers relative risks (RRs) for discordant cancers were estimated in families with increasing numbers of probands with CRC; in the reverse analyses, RRs for CRC were estimated in families with increasing numbers of probands with discordant cancers. In separate analyses, hereditary non-polyposis colorectal cancer (HNPCC) families were excluded from the study, based on HNPCC related double primary cancers, to assess the residual familial RRs. We further reviewed familial risks of colon and rectal cancers separately in search for distinct discordant associations. The reviewed data suggested that colon cancer was associated with a higher familial risk for CRC compared to rectal cancer. The previous data had reported associations of CRC with melanoma, thyroid and eye cancers. Nervous system cancer was only associated with colon cancer, and lung cancer only associated with rectal cancer. The reviewed data on discordant association may provide guidance to gene identification and may help genetic counseling.

Effectiveness of interventions to identify and manage patients with familial cancer risk in primary care: a systematic review.

This systematic review evaluated the effectiveness of strategies to identify and manage patients with familial risk of breast, ovarian, colorectal and prostate cancer in primary care to improve clinical outcomes. MEDLINE, EMBASE, CINAHL and Cochrane library were searched from January 1980 to October 2017. We included randomised controlled trials (RCT) and non-randomised studies of interventions (NRSI). Primary outcomes were cancer incidence, cancer-related clinical outcomes or the identification of cancer predisposition; secondary outcomes were the appropriateness of referral, uptake of preventive strategies and cognitive and psychological effect. From 11,842 abstracts, 111 full texts were reviewed and three eligible studies (nine articles) identified. Two were cluster RCTs and one NRSI; all used risk assessment software. No studies identified our primary outcomes, with no consistent outcome across the three studies. In one RCT, intervention improved the proportion of genetic referrals meeting referral guidelines for breast cancer (OR 4.5, 95% CI 1.6 to 13.1). In the other RCT, there was no difference in screening adherence between the intervention and control group. However, there was borderline increased risk perception (OR 1.89, 95% CI 0.99 to 3.59) in the subgroup that under-estimated their colon cancer risk. In the NRSI, there was no change in psychological distress in patients at increased familial breast cancer risk, but population risk patients had reduced anxiety after intervention (state anxiety mean change - 3, 95% CI - 5 to - 2). Future studies should have better-defined comparator groups and longer follow-up and assess outcomes using validated tools.

Familial colorectal cancer risk in half siblings and siblings: nationwide cohort study

ObjectiveTo explore the risk of colorectal cancer in family members of patients with colorectal cancer, with an emphasis on subtypes of second degree relatives, especially half siblings, which were lacking...

Utilization of colonoscopy and colonoscopic findings among individuals aged 40-54 years with a positive family history of colorectal cancer: a cross-sectional study in general practice.

Guidelines recommend early colonoscopy for individuals with a positive family history of colorectal cancer (CRC), but little is known about the utilization of colonoscopy and the frequency of colorectal neoplasms among younger affected individuals in Germany. The aim of this study was to determine the utilization of colonoscopy and the frequency of colorectal neoplasms in this risk group. We conducted a cross-sectional study in a general practice setting. Patients aged 40-54 years with at least one first-degree relative with CRC were identified, counseled on their increased risk, and referred to colonoscopy if they decided to undergo this procedure. We assessed the reported utilization of colonoscopy before study participation with a questionnaire and obtained results of colonoscopies performed during the study period from colonoscopy reports. Out of 484 patients with a positive family history of CRC, 191 (39.5%) fulfilled the inclusion criteria and participated in the study: 54% reported that at least one colonoscopy had been performed before study participation. Out of 191 participants, 86 (45%) underwent a colonoscopy during study period. No CRC was found, but 16.3% had any adenoma, and 7.0% had advanced adenomas. Overall, 155 (82%) study participants underwent a colonoscopy either before or during the study period. The utilization of colonoscopies among participants was remarkably high even before study participation. This rate increased up to 82% after counseling by general practitioners. A relevant number of participants had (advanced) adenomas. It appears worthwhile to involve general practitioners in identifying and counseling younger individuals with familial risk for CRC.

Invitation to Screening Colonoscopy in the Population at Familial Risk for Colorectal Cancer.

Screening colonoscopy can lower the incidence of colorectal cancer (CRC), yet participation rates are low even in groups at high risk. The goal of this study was to double the rate of participation in screening colonoscopy among persons at familial risk and then to determine the frequency of neoplasia in this risk group. In a nationwide, cluster-randomized, multicenter study, first-degree relatives (FDR) of patients with CRC across Germany received written informational materials concerning the familial risk of CRC, along with an invitation to undergo colonoscopy. Participants in the intervention group were additionally counseled by nurses over the telephone. The primary endpoint of the study was colonoscopy uptake within 30 days. The participants' mean age was 50.8 years. The colonoscopy uptake rates were 99/125 (79%) in the intervention group and 97/136 (71%) in the control group (RR = 1.11; 95% confidence interval [0.97; 1.28]). A polypectomy was performed in 72 of 196 asymptomatic persons (37%). In 13 cases (7%), an advanced neoplasia was detected; two of these persons had colon cancer (stages T0 and T1). 42% of the participants expressed barriers against colonoscopy. 22 reported mild side effects; there were no serious side effects. Additional counseling by nurses over the telephone does not increase the participation rate. Approaching patients who have CRC is an opportunity to increase the participation of their first-degree relatives in screening colonoscopy. The frequency of neoplasia that was found in this study underscores the need to screen relatives even before they reach the usual age threshold for screening.

An online self‐test added to colorectal cancer screening can increase the effectiveness of familial cancer risk assessment without increasing distress

Most people who are at increased familial colorectal cancer (FCRC) risk are not identified, despite the need for enhanced surveillance colonoscopy for effective CRC prevention. An online self-test may enhance this identification. We assessed whether taking an online self-test to identify increased FCRC risk increases anxiety, distress or CRC risk perception in population-based CRC screening. After the precolonoscopy consultation, patients who had a positive immunohistochemical occult faecal blood test (iFOBT+) in population-based CRC screening were invited by email to take an online self-test at home which returned details of family history. Anxiety (STAI-DY), distress (HADS) and CRC risk perception were assessed immediately before and after taking the online self-test and 2 weeks later. Of 250 participants invited, 177 (71%) completed the online self-test and psychological questionnaires and 153 (61%) completed questionnaires 2 weeks later. The median age was 65 years (range 61-75). The FCRC risk was increased in 17 participants (9.6%). Of these, 12 (6.8%) had a highly increased FCRC risk and may benefit from germline genetic testing for Lynch syndrome. In 7 of 17 participants (40%) the self-test obtained novel information on family history. Anxiety and distress levels were, and remained, below a clinically relevant level. Perception of CRC risk remained unchanged. Most participants (83%) would recommend the online self-test to others. Of those with a iFOBT+, 9.6% had a previously unidentified increasedFCRC risk and require an enhanced surveillance colonoscopy instead of iFOBT. As screening for this risk did not increase anxiety or distress, and was highly acceptable, we recommend adding the online self-test to population-based CRC screening.

PO-084 Familial risk of colorectal cancer in half-siblings similar to that in siblings

IntroductionFor improving evidence-based strategies for colorectal cancer (CRC) screening and making more informed decision about early counselling of CRC, we aimed to explore the risk of CRC in family members of CRC patients.Material and methodsUsing the world’s largest population-based Family-Cancer data from Sweden (follow up: 1958–2015), we calculated the lifetime cumulative risk (0–79 years) and relative risk of CRC for first- and second-degree relatives (FDRs and SDRs) of patients with CRC. All family histories reported below are exclusive, meaning that risk reported for one affected half-sibling does not include those with both an affected half-sibling and any other first/second-degree relatives.Results and discussionsA total of 15,880,734 persons were followed for up to 58 years, out of them 1 58 428 with clear and complete family information developed CRC. The overall lifetime risk of CRC in siblings of CRC patients was 7% (8% in men; 6% in women), which represents 1.7-fold (95% CI: 1.6–1.7; n=2055) increase over the 4% risk in those without any family history of CRC (5% in men; 3% in women). Significantly increased lifetime risk (6%) was found among half-siblings of CRC patients (SIR=1.6, 95% CI: 1.3–1.8; n=140), 8% in male half-siblings and 5% in female half-siblings. The risk in those with CRC in both a parent and a half-sibling (SIR=3.6, 95% CI: 2.5–5.1; n=32) was close to risk of those with an affected parent and an affected sibling (SIR=2.7, 95% CI: 2.4–3.0; n=391). Highly increased risk of CRC was also found in those with two affected half-siblings (SIR=3.5, 95% CI: 1.3–7.6; n=6). Family history of CRC in other SDRs such as a grandparent (SIR=1.2, 95% CI: 1.1–1.3; n=460), an uncle/aunt (SIR=1.2, 95% CI: 1.0–1.4; n=189) without any affected FDRs showed minor contribution to the familial risk of CRC, but we found higher risks for those with both an affected FDR and a grandparent (SIR=3.0, 95% CI: 2.4–3.8; n=82) or both an affected FDR and an uncle/aunt (SIR=2.2, 95% CI: 1.5–3.2; n=28), which approximate to that with two affected FDRs (SIR=2.5, 95% CI: 2.3–2.7; n=946).ConclusionFamily history of CRC in half-siblings contributes similar CRC risk to that in siblings. The CRC risk among those with one affected SDR was negligible except among half-siblings, but combination of family history in one affected SDR and an affected FDR (or even another SDR) increased the risk substantially. These evidence-based findings provide novel information to improve counselling for screening for individuals with family history of CRC.