Assessing cancer family history

In order to assess cancer risk from family history there are some key general questions that need to be asked (Table 13.1) in addition to the specific questions related to the type of cancer in the family that are addressed in Chapters 14 and 15.

Categorising and calculating cancer risk from the family history

In a genetics service where full information is generally gathered about the family history, including verification of diagnoses and clinical and histological features of various cancers and/or genetic testing, a specific individualised risk assessment may be possible. However, even when a cancer-predisposing gene mutation is identified it is not possible to give definite answers about whether someone will develop cancer or not. Instead it is necessary to make an estimation of that individual’s cancer risk. It is important to be mindful of the dynamic nature of family history, ensuring that patients are aware that if the family history changes the cancer risk assessment may also change.

There are several validated risk assessment models available to estimate the probability of carrying a cancer-predisposing single gene mutation, such as those described in this section. Genome-wide association studies (GWAS) are likely to generate new and more comprehensive risk prediction models.

The models used in familial breast cancer calculate the probability of a BRCA1/2 mutation; some take into account risk factors related to family history, such as the Gail model (Gail et al., 1989) and the Manchester model (Evans et al., 2004, 2009), and some are based on the genetic risks (i.e. penetrance, mode of inheritance or mutation frequencies), such as BRCAPRO (Berry et al., 2002) or BOADICEA (Antoniou et al., 2004). There are limitations to all of these models, both in terms of the practicality of using them and the accuracy of risk assessment (Amir et al., 2010).

The empirically based Amsterdam and Bethesda criteria (see Box 9.1) provide a guide to risk assessment in families with colorectal and Lynch syndrome-related cancers. Genetic risk prediction models have been developed to identify the probability of carrying a mismatch repair gene mutation (PREMM(1,2,6), MMRPro and MMRPredict) associated with Lynch syndrome. Although it is reported that these models are superior at predicting risk than clinical criteria alone (Kastrinos et al., 2013) they have yet to be independently validated in large studies.

Table 13.1 Indicators of hereditary cancer risk, key general questions to ask of the family history in order to elicit the information and rationale for the questions

Indicators of hereditary cancer risk

Key questions to ask of the family history in order to identify the indicators of risk


A known genetic mutation in the family

Has anyone in the family been found to carry a cancer-predisposing gene mutation/fault?

If a gene mutation has been identified, genetic testing may be possible and a more specific risk assessment can be made. Sometimes it is reported within families that a relative has a gene mutation when in fact they have an unclassified variant. It is always best to ask for confirmation, such as a letter from a genetics department or a laboratory report

Multiple cancers in the family

How many relatives are affected with cancer? Have any relatives developed more than one primary cancer?

Establishing the number of cancers in the family and whether individuals have had more than one primary cancer helps with understanding the likelihood of a genetic predisposition to cancer

Similar types or clustering of cancers in the family

What type of cancer did each relative have?

It is important to be aware of the types of cancers that may be relevant to a particular genetic syndrome, such as breast, ovarian and prostate cancer or colorectal, gastric and endometrial cancer. Ideally, abdominal and pelvic cancers should be verified as these are not always accurately reported. This may need to be undertaken by the genetics service and so it is useful to gather details of the name, date of birth and treatment

Cancers on the same side of the family

Which side of the family are the affected relatives on?

If there are cancers on both sides of the family, they will need to be assessed separately as there may be a risk from both the maternal and paternal family history

Young ages at diagnosis

What are the ages at diagnosis of relatives with cancer?

Gathering this information is important for identifying early onset cancer which is more likely to be due to a cancer-predisposing gene mutation

Close relationship between the individuals with cancer and between the individuals with cancer and the person seeking risk assessment (i.e. the proband)

What is the relationship of the affected relatives to each other and to the proband? What is the current age or age at death of each relative (with and without cancer)?

Most cancer syndromes are dominantly inherited but it is important to remember that recessive inheritance can occur with some cancer syndromes. Finding out the current age or age at death of intervening unaffected relatives helps with calculating risk in a dominantly inherited cancer syndrome

Clinical or histological features that are relevant to a cancer syndrome

Are there any clinical or histological signs of hereditary cancer?

In some hereditary cancer syndromes there are particular clinical or histological features. This information may need to be obtained by the genetics service. If details of histology are available in secondary care it is helpful to provide these with a genetics referral

Ethnicity that may increase the risk of a founder mutation

What is the ethnic background of the family?

In some ethnic groups there is a greater prevalence of particular founder mutations

Various tools and charts are available for categorising family history risk or identifying patients suitable for genetics referral based on the number of affected relatives, the ages at diagnosis and the cancer type. It is important to ensure that the tools being used are up to date. Health professionals in cancer care are advised to discuss the use of particular tools with their genetics centre and to refer to national guidelines where available.

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