Colorectal cancer risk according to family history

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Background

The best evidence for the association between colorectal cancer risk and family history of the disease comes from cohort studies that compare the risk of colorectal cancer for people with and without a family history of colorectal cancer. Ideally, these studies should take into account any differences between people with and without a family history for colorectal cancer risk factors.

Such studies consistently report an elevated risk of colorectal cancer associated with family history. The strength of this association increases with the number of relatives with colorectal cancer, the closeness of genetic relationship of the relative(s) with colorectal cancer, and the diagnosis age of relative(s) diagnosed with colorectal cancer.

Case control studies and cohort studies which have been well designed including stringent methods for collection of family cancer data in relatives, reported an approximate doubling of lifetime risk.[1][2][3][4] For example:

  • A Danish study of parents of colorectal cancer patients diagnosed before age 60 years[1] reported that, compared with the average population, the risk of colorectal cancer was 1.6 times higher among patients’ mothers and 1.9 times higher among patients’ fathers.
  • An Australian study reported that, compared to people with no relative with colorectal cancer, those with one relative with colorectal cancer had 1.8 times the colorectal cancer risk.[2]
  • A US study of people reported that the risk of colorectal cancer for men and women of first-degree relatives with colorectal cancer was 1.72 greater than for those without a family history of the disease[3]
  • A US study reported that the risk of colon cancer was 2.2 times higher among patients with a first-, second- or third-degree relative with colon cancer than for those with no family history.[4]

In contrast to these modest levels of increased risk, colorectal cancer risk has been found to be substantially (three- to six-fold) greater for those who have a first-degree relative with colorectal cancer diagnosed at an early age (below age 55) or when two close relatives have had colorectal cancer, irrespective of the age at diagnosis.[3][4][3]

For information on risk associated with specific high-risk familial syndromes, see High-risk familial syndromes.

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Update of systematic review evidence

For individuals, has a family history of colorectal cancer been shown to be reliably associated with an increase in risk of occurrence of or death from colorectal cancer when compared to individuals who do not have a family history of colorectal cancer? (FHS2)

A systematic review of cohort studies since 2005 (the publication of the previous guidelines[5]) was undertaken to update the evidence for the estimated risk of colorectal cancer for relatives of patients with colorectal cancer. Cohort studies are less subject to recall misclassification than case-control studies in which people with colorectal cancer more likely to report any existing family history than controls.

The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.

Six studies were identified: one analysis of pooled data from two prospective cohort studies,[6] and five cohort studies[7][8][9][10][11]. All measured colorectal cancer outcomes (diagnosis or mortality) for people without a colorectal cancer diagnosis (or symptoms that might indicate colorectal cancer) at time of recruitment, and assessed risk according to the individual’s independently confirmed family history of colorectal cancer. An additional modelling study[12] was also identified.

Of the cohort studies, one[9] was deemed to have a low risk of producing biased estimates, two[7][11] were deemed to have a moderate risk of bias, and three[6][8][10] were deemed to have a high risk of bias.

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Increased risk of colorectal cancer by family history

Overall, cohort studies report that people with a family member diagnosed with colorectal cancer have an increased risk of colorectal cancer, compared with the average population. Estimated increases in risk depend on the age at which the family member was diagnosed, and the number of first-degree and second-degree relatives with colorectal cancer (Table 5.1).

Individual colorectal cancer risk (personal risk) could, in theory, be estimated based on a person’s specific family history and personal screening recommendations could be devised based on this increased risk. However, for practical reasons, only three categories of risk have been developed (Table 5.1), each with screening recommendations based on the average risk for that category.  

Table 5.1. Increased risk of colorectal cancer based on family history: results from cohort studies published since 2005

Family history of colorectal cancer ColorectalReferring to the large bowel, comprising the colon and rectum. cancer risk
relative to the average population risk
No family history 0.86[11]

(14% decrease)

One or more first-degree relative diagnosed at any age 1.4[10] – 2.1[8], 2.05[11]

(40–110% increase)

One first-degree relative diagnosed before age 50 3.3[11]

(230% increase)

One first-degree relative diagnosed between ages 50 and 60 2.2[10] to 2.5[11]

(120–150% increase)

Two or more first-degree relatives 3.0[11]

(200% increase)

No first-degree relative, at least one second-degree relative 1.1-1.5[11]

(10–50% increase)

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Category 1 — those near average risk

Lifetime risk is to age 75 years: approximately 5% to 10% (assuming no colorectal cancer screening).

Some examples of asymptomatic people who fit into this category are the following (for a full description see Table 5.3 below):[2][4][3][6][8][10][12][13]:

  • no first- or second-degree relative with colorectal cancer
  • one first-degree or one first and one second-degree relative with colorectal cancer diagnosed at age 55 years or older.
For those with an affected first-degree relative, risk is double the average risk, although most of that extra risk is expressed after the age of 60 years. When the affected relative is second-degree (e.g. a grandparent, uncle or aunt), lifetime risk is only up to 1.5 times higher than average.[4][11]

Category 2 — those at moderately increased risk

Lifetime risk to age 75 years: approximately 15–30% (assuming no colorectal cancer screening).

Some examples of asymptomatic people who fit into this category if they have none of the high-risk features listed in category 3 and have either of the following (for a full description see Table 5.3 below):

  • one first-degree relative with colorectal cancer diagnosed before the age of 55 years[2][4][11][14][15][16]
  • two first-degree relatives or one first-degree relative and at least two second-degree relative diagnosed with colorectal cancer at any age.[11][15][16][17]^

Relative risk in these two situations is increased to 3–6 times average risk. For the majority of people in this category, the risk of colorectal cancer is 3–4 times higher than average.

^Note: Previous guidelines specified that relatives with cancer needed to be on the same side of the family in order to meet eligibility of this risk category. Recent data suggests that a similar level of risk occurs if the relatives with cancer are on opposite sides of the family,[11] therefore this restriction has now been omitted.

Category 3 — those at high risk

Lifetime risk to age 75: approximately 30–40% (assuming no colorectal cancer screening).

Asymptomatic people fit into this category if they have any of the following:

  • at least three first-degree relatives diagnosed with colorectal cancer at any age[11]
  • at least three first-degree or second-degree relative with colorectal cancer with at least one diagnosed before age 55 years.

Relative risk for category 3 is 7–10 times average risk. For the majority of people in this category, the risk of colorectal cancer is 7 times higher than average.


Category 2 and 3 excludes people known to be, or have a high probability of having a high-risk familial syndrome due a genetic predisposition to colorectal cancer. These people have potentially a much higher risk of colorectal cancer and therefore more intensive screening is recommended. See High-risk familial syndromes.

Therefore these categories excludes people who have:

  • a relative confirmed as carrying a pathogenic mutation in a gene associated with a high-risk familial syndrome, who have not themselves been tested
  • a relative with multiple colorectal cancers
  • a relative with familial adenomatous polyposis
  • at least three first-degree or second-degree relatives with a Lynch syndrome-related cancer (endometrial, ovarian, stomach, small bowel, renal pelvis or ureter, biliary tract, brain) with at least one diagnosed before age 55 years).
All the above should be referred to a familial cancer clinic for testing for a high-risk familial syndrome.


For guidance on managing risk in people in category 3 with a known or suspected genetic syndrome, see High-risk familial syndromes.

Table 5.2. Relative risk of colorectal cancer based on family history

Category Examples of Family history (full description in Table 5.3) Risk compared with the average population.
1 No first- or second-degree relative with colorectal cancer 10% decreased risk
One first-degree relative with colorectal cancer diagnosed at 55 years or older

One first-degree and one second-degree with colorectal cancer diagnosed at 55 years or older

Up to 2-fold increased risk
2 One first-degree relative with colorectal cancer diagnosed under 55 years

Two first-degree relatives with colorectal cancer diagnosed at 55 years or older

One first-degree relative and at least two second-degree relative with colorectal cancer diagnosed at 55 years or older

3- to 6-fold increased risk
3 At least three first-degree or second-degree relatives with colorectal cancer, with at least one diagnosed under 55 years

At least three first-degree relatives with colorectal cancer diagnosed at 55 years or older

7- to 10-fold increased risk
Sources: St John et al (1993)[2], Fuchs et al (1994)[3], Slattery et al (1994)[4], Bass et al (2008)[7], Schoen et al (2015)[9], Taylor et al (2011)[11], Lynch et al (2003)[13], Hall et al (1996)[14], Leu et al (2008)[12], Benhamiche-Bouvier et al (2000)[15], Sandhu et al (2001)[16], Aitken et al (1996)[17], Anderson et al (2003)[18]

Note: Relative risk is the ratio of the risk of developing colorectal cancer in a particular exposed group to the average risk in the whole population.

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Table 5.3. ColorectalReferring to the large bowel, comprising the colon and rectum. cancer risk categories by family history

Risk category by family history

Number of 1st degree relatives with CRC before age 55
0 1 2
Number of 1st degree relatives with CRC at 55 or older
0 1 2 3 0 1 2 0 1
Number of 2nd degree relatives with CRC before age 55
0
Number of 2nd degree relatives with CRC at 55 or older
0 1 1 2 3 2 2 3 2 3
1 1 1 2 3 2 3 3 3 3
2 1 2 3 3 3 3 3 3 3
3 2 2 3 3 3 3 3 3 3
4 2 3 3 3 3 3 3 3 3
1 0 1 2 3 3 2 3 3 3 3
1 2 3 3 3 3 3 3 3 3
2 3 3 3 3 3 3 3 3 3
2 0 2 3 3 3 3 3 3 3 3
1 3 3 3 3 3 3 3 3 3

Evidence summary and recommendations

Evidence summary Level References
Category 1 – Those near average risk

Approximately 95–98% of the population are in this category. Those with a weak family history, which is approximately 65% of those with any family history, will also be in this category.

For the majority of people, the risk of colorectal cancer ranges from slightly below average to slightly above average. For some people, risk will be increased up to two-fold the average risk.

Approximately 10% of people in this group will develop colorectal cancer in their lifetime.

II, III-2 [17], [18], [19], [20], [21], [22], [23], [24]
Category 2 – Those at moderately increase risk

Approximately 2–5% of the population are in this category.

The risk of colorectal cancer is approximately three- to six-fold higher than average.

Approximately 15–30% of people in this group will develop colorectal cancer in their lifetime.

II, III-2 [2], [4], [14], [15], [16], [17]
Category 3 – Those at potentially high risk

Less than 1% of the population are in this category. The risk of colorectal cancer is approximately seven to ten-fold higher than average.

Approximately 30–40% of people in this group will develop colorectal cancer in their lifetime.

II, III-2 [25], [26], [27], [28]
Important note:

These recommendations are in relation to the risk of colorectal cancer for relatives of patients with colorectal cancer. For recommendations about tailored screening categories 1-3, please see Screening strategies for people with a family history of colorectal cancer.

Evidence-based recommendationA recommendation formulated after a systematic review of the evidence, indicating supporting references.Question mark transparent.png Grade
Category 1

People who have one relative with colorectal cancer diagnosed at age 55 or older should be advised that their own risk of developing colorectal cancer could be up to twice the average risk, but is still not high enough to justify CRC screening by colonoscopy.

C
Evidence-based recommendationA recommendation formulated after a systematic review of the evidence, indicating supporting references.Question mark transparent.png Grade
Category 2

People should be advised that their risk of developing colorectal cancer is at least three times higher than average, but could be up to six times higher than average, if they have any of the following:

  • one first-degree relative with colorectal cancer diagnosed before age 55 years
  • two first-degree relatives with colorectal cancer diagnosed at any age
  • one first-degree relative and at least two second-degree relative diagnosed with colorectal cancer at any age.
C
Evidence-based recommendationA recommendation formulated after a systematic review of the evidence, indicating supporting references.Question mark transparent.png Grade
Category 3

People should be advised that their risk of colorectal cancer is at least seven times higher than average, but could be up to 10 times higher than average, if they have either of the following:

  • at least three first-degree or second-degree relatives with colorectal cancer, with at least one diagnosed before age 55 years
  • at least three first-degree relatives with colorectal cancer diagnosed at any age.
C
Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Approximately 95-98% of the population are in Category 1 (near average risk of developing colorectal cancer).

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Approximately 65% of those with a family history of colorectal cancer only have a weak family history which means they are category 1 risk.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Medical information that patients provide about their relatives is often inaccurate. (St John et al 1993, Love et al} 1985, Douglas et al 1999, Ruo et al 2001, Mitchell et al 2004) The percentage of colorectal cancer reports that are correct (positive predictive value) is 86% meaning that reports by relatives are usually true. However, a high proportion of people appear to be unaware that their relatives have had colorectal cancer, with the percentage of all colorectal cancers in first-degree relatives that are reported (sensitivity) being 27%. (Mai 2011).

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

Given the potential importance of an accurate risk prediction for an individual, every effort should be made to collect reliable information.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

When there is uncertainty on family history, people should be encouraged to seek clarification within their family including details on which relatives have had colorectal cancer and their ages of diagnoses.

Practice pointA recommendation on a subject that is outside the scope of the search strategy for the systematic review, based on expert opinion and formulated by a consensus process.Question mark transparent.png

If a family medical history appears to be significant but diagnoses prove difficult to confirm, it may be appropriate to seek expert help from a familial cancer clinic who have resources available to confirm cancer diagnoses.

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Considerations in making these recommendations

There was robust discussion by the Working Party about the categories of risk outlined in this chapter. For category 3, there was discussion regarding the decision to exclude people known to have, or with a high probability of having, a high-risk familial syndrome due to a genetic predisposition to colorectal cancer. Ultimately the Working Party was in agreement about the three-level risk categorisation and feel this is adequately outlined in the chapter.

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Health system implications

Clinical practice

The RACGP recommended use of validated family history screening questionnaire to identify people in general practice with significant family history of cancer.[29]

Under-ascertainment of people with a significant family history to general practice requires the need for more proactive approaches in primary care to identify families at increased risk of CRC.

Resourcing

There are no known resourcing implications.

Barriers to implementation

Current GPA medical professional who treats acute and chronic illnesses and provides preventive care and health education to a wide range of patients. software systems do not support systematic family history collection or risk assessment here.

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Discussion

Unresolved issues

The effect of a family history of adenoma on colorectal cancer risk is unknown, although increased risk is likely. There is insufficient evidence from which to determine the effect of family history of adenomas or advanced adenomas on colorectal cancer risk.

Because of the increasing uptake of colonoscopy in the population and the removal of pre-malignancies, recent studies of family history as a risk factor may be underestimating the true association of colorectal cancer risk with family history of the disease. Therefore older studies may be more relevant to estimates of familial risk.

Studies currently underway

We are not aware of any current trials that would provide more data on this question.

Future research priorities

Inherent difficulties in deciding the demarcation between categories or the number of categories argues for an algorithm that summarises the family history of colorectal cancer into a risk score that can then be used to decide age and modality of screening. These algorithms should also assess the effect on the accuracy of risk stratification of including personal risk factors for colorectal cancer other than family history.

Identifying the causes for familial risk of colorectal cancer will assist the evaluation of risk within these risk categories, so that more personalised screening can be recommended based on more precise estimates of risk.

Next section: screening strategies for people with a family history of colorectal cancer

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References

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Appendices


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