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Clinical criteria for genetic testing
Figure 6.1 describes the suggested process for the diagnosis and management of HDGC. The most recent published guidelines for determining which individuals to test for CDH1 mutations from the IGCLC were published in 2010 . They recommend genetic testing for patients who meet the following criteria:
- Two or more GC cases in one family, with one confirmed DGC before 50 years of age
- Three or more confirmed DGC cases in 1st or 2nd degree relatives, independent of age of onset
- DGC in individual less than 40 years of age regardless of family history
- Personal or family history of DGC and LBC, one diagnosed before 50 years of age
It is expected that these guidelines will be updated in 2015 and may provide changes in the inclusion criteria. In addition to the above guidelines, the IGCLC recommends consideration to offering genetic testing to patients where pathologists identify in situ SRCs or pagetoid spread of SRCs adjacent to DGC, as this is rarely seen in sporadic DGC .
Fig. 6.1. Flow chart for diagnosis and management of HDGC. (Modified from Blair et al. 2006 )
Using the older IGCLC guidelines, which were more restrictive, to determine which families to screen, the detection rate of CDH1 mutations was between 25 and 50% [14, 20, 24, 45, 124]. Mutations have been found in individuals from kindreds who do not meet the 2010 IGCLC criteria, and it has been suggested that recommendations for testing also include families with multiple cases of early onset LBC in the absence of DGC . Because of the inverse relationship seen between CDH1 mutations and the incidence of GC geographically, families from geographic areas with a high prevalence of sporadic GC are less likely to return a positive result on mutation testing than those from geographic areas of low incidence . The clinical decision whether to screen for a CDH1 mutation therefore needs to take into account the risk of GC for the population from which the patient and family is derived, in addition to the family and personal history of GC and other cancers.
Once a patient or family has been identified as being at risk of carrying a CDH1 mutation, a full genetic assessment needs to be carried out, and requires referral to an appropriate genetic service. A careful, at least, three-generation family pedigree should be obtained, and confirmation of DGC diagnoses should be obtained . If criteria for testing are met, formal genetic counselling and consent for genetic testing should be offered. The consultation with an expert in HDGC will provide information of the natural history of GC, the definitions of HDGC, and discussion on the concepts of autosomal dominant inheritance and incomplete penetrance. If a pathogenic mutation is identified in the proband then predictive testing for family members deemed at risk will be offered. Appropriate genetic counselling will cover issues such as the implications of a positive test result on impacts on health and life insurance and also future management of carriers of a CDH1 mutation. Psychological support can be provided throughout the testing and counselling process because of the uncertainty associated with an incompletely penetrant disorder, the implications of positive and negative results, and the distress that can be associated with this [125, 126].
Genetic testing is performed on blood from an affected family member . If blood is not available DNA of an affected individual from an archived paraffin block can also be used although this testing has technical challenges . There are no hot spots in the gene to target, hence, the entire coding sequence of the gene including intron–exon boundaries needs to be examined for mutation . As mentioned genetic testing involves sequencing and MLPA due to the finding of large intragenic deletions in families [8, 37].
It is unclear from current evidence at what age family members at risk of harbouring CDH1 mutations should be offered genetic testing given the risk of malignancy is low before the age of 20 [18, 24], however some carriers have developed overt cancer prior to the age of 18 [12, 16]. The IGCLC recommends testing be considered from the age of consent, which will vary by country. This will be partly dependent on the age of diagnosis of the earliest cancer in the family. Psychological, physical and emotional health of the individual in question and their family also need to be taken into account in the timing of genetic testing .
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