The utility of genetics in inherited cancer

Actress Angelina Jolie’s recent public disclosure of her BRCA1 gene mutation1 has highlighted the role of genetic testing in cancer prevention and management. Her endorsement of the genetic counselling and BRCA1 predictive testing process as helping her to be “empowered” and enabling “informed choices” to pursue preventive surgery has energised many people to actively participate in clinical decision making.

Over the past two decades, genetic services have increasingly used cancer predisposition genetic data to deliver benefits to patients. But any benefit depends on two factors. First, any gene implicated in pathogenesis needs to be validated as a significant and reproducible component of heritability. Second, penetrance — the likelihood that the carrier of the gene mutation will develop cancer — is pivotal for disease risk analysis. This affects counselling, surveillance for disease and the surgical options available.

Cancer genetic services can deliver significant benefits to both patients and families. For patients, it provides optimised management of both the sentinel cancer and future cancer risks. For instance, a colon cancer can be analysed for the expression of protein products of the mismatch repair genes that cause Lynch syndrome. Absent staining leads to expedited genetic testing, and the option of subtotal colectomy for mutation carriers to remove the high risk of a second cancer,2 and, for women, the option of risk-reducing surgery for gynaecological cancers. Similarly, detection of BRCA1 and BRCA2, TP53 or PTEN mutations in a breast cancer triggers risk management for a second cancer. Cancer predisposition gene testing in patients and their relatives has been the standard of care for many years in a number of other cancers: familial adenomatous polyposis (APC gene),3 hereditary retinoblastoma (RB1 gene), multiple endocrine neoplasia type 1 (MEN1 gene) and type 2 (RET gene), and von Hippel–Lindau syndrome (VHL gene). Testing is also standard for bowel cancer predisposition genes (APC, MLH1, MSH2, MSH6, PMS2), renal cancer predisposition genes (VHL, BHD, SDHB, FH, MET) and genes associated with paraganglioma-phaeochromocytoma syndrome (genes for SDH subunit A, B, C and D).

Detecting mutation carriers among the patient’s relatives enables disease risk management. For instance, risk-reducing salpingo-oophorectomy alone increases absolute survival in BRCA1 carriers by 15%, and by a further 6% with the addition of breast imaging.4 Finding an APC mutation in a patient with multiple colonic polyps allows preventive strategies for mutation-carrying relatives, saving lives and sparing non-carriers unnecessary burden and cost.3 Reproductive options including pre-implantation genetic diagnosis are discussed where appropriate; combined with in-vitro fertilisation, at-risk couples have the option of ensuring their offspring do not carry the family-specific mutation.

Understanding the biology of the genetic component of neoplastic processes can lead to appropriate disease surveillance in both sentinel cases and relatives carrying the mutation. For instance, the interval between colonoscopies in people with Lynch syndrome needs to be shorter than in the general population because of the associated accelerated malignant transformation of polyps.

In the absence of a significant known family history — an issue in Australia with its high proportion of immigrant families — certain histopathological characteristics of tumours can indicate mutation carriage.5 Immuno-histochemical analysis of colorectal cancers in patients under 50 years and of endometrial cancers in younger women frequently shows loss of expression of the proteins encoded by mismatch repair genes. It is now standard practice to perform BRCA1 and BRCA2 gene mutation analysis in women under 40 years with oestrogen receptor-, progestogen receptor- and human epidermal growth factor receptor 2-negative breast cancers, especially in the presence of high-grade tumours.

Clinical presentation alone is enough to necessitate genetic analysis in some cases, such as in patients under 40 years with central nervous system haemangiomas, those with bilateral or multiple schwannomas, and in patients under 50 years with phaeochromocytoma or paraganglioma.