Information for Health Professionals

Hereditary Breast and Colorectal Cancer – what is the genetic link?


The association between breast and colorectal cancer in not clear.  There is an increased incidence of breast cancer and colorectal hamartomas which may lead to colorectal cancer in PTEN-mutation spectrum disorders such as Cowden’s Syndrome, and in Peutz-Jeghers Syndrome.  Data from genome-wide association studies demonstrates association of a common but low penetrance (weak) risk locus at chromosome 8q24.

Lynch Syndrome
The link between Lynch Syndrome has been controversial, but two recent studies have added weight to Lynch Syndrome as a risk factor for breast cancer.  A recent study in JNCI (Win et al 2012) suggests that amongst Lynch Syndrome patients the risk of breast cancer as a second cancer after a diagnosis of colorectal cancer may be increased by about 76%.  An earlier study this year suggests that their is molecular evidence for this association (Buerki et al Genes Chromosomes Cancer 2012).

CHEK2

Some studies in Li-Fraumeni Syndrome families identified mutations in CHEK2 as possible cause for this condition (Bell et al Science 1999).  This link has not been reproducible but the variant 1100 may be a population variant which increases risk in Ashkenazi Jewish populations.

Families with Li-Fraumeni Syndrome and CHEK2 mutations

Evidence demonstrates that a subset of families with hereditary breast and colon cancer may have a cancer family syndrome caused by a mutation in the CHEK2 gene. Although the penetrance of CHEK2 mutations is clearly less than 100%, additional studies are needed to determine the risk of breast, colon, and other cancers associated with CHEK2 germline mutations. One large study showed that truncating mutations in CHEK2 were not significantly associated with CRC; however, a specific missense mutation (I157T) was associated with modest increased risk (odds ratio [OR], 1.5; 95% CI, 1.2–3.0) of CRC.

Similar results were obtained in another study conducted in Poland. In this study, 463 probands from LS and LS–related families and 5,496 controls were genotyped for four CHEK2 mutations, including I157T. The missense I157T allele was associated with LS–related cancer only for MMR mutation-negative cases (OR, 2.1; 95% CI, 1.4–3.1). There was no association found with the truncating mutations. Further studies are needed to confirm this finding and to determine whether they are related to familial CRC type X.

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About kjmonahan

Service lead for Family History of Bowel Cancer Clinic

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