Oncogenetics

Principles

‘All cancer is genetic but some cancers are more genetic than others.’ This paraphrase from George Orwell’s Animal Farm conveys the es­sence of the genetic basis of malignancy.

Genes in which mutations predispose to cancer are broadly classi­fied under two categories: proto-oncogenes and tumour suppressor genes (TSGs). Genes of both categories fulfil important functions in the human body. Proto-oncogenes play important roles in regu­lated growth and proliferation and include growth factors and com­ponents of signal transduction pathways. Mutations can result in a proto-oncogene becoming an oncogene, driving uncontrolled growth and tumour formation. On the other hand, TSGs function as guards against unregulated growth either by controlling prolif­eration, promoting programmed cell death (apoptosis) of abnor­mally proliferating cell clones, or, at a more fundamental level, by repairing damage to DNA. This class of TSGs are known as DNA repair genes and mutations in them do not directly lead to tumori- genesis but increase the likelihood of mutations in other TSGs or proto-oncogenes.

Figure 4.7 Quantitative fluorescent PCR electropherogram in (a) showing three copies of amplified markers specific for chromosome 21 as indicated by the three peaks (arrow). Trisomy 21 is confirmed by the G-banded karyotype in (b).

Courtesy Dr Carolina Sismani, Cyprus Institute of Neurology & Genetics.

Mutations in both proto-oncogenes and TSGs are linked to spe­cific cancer predisposition syndromes which are most commonly inherited in an autosomal dominant manner. In the case of proto­oncogenes, gain-of-f unction mutations in the heterozygous state confer increased cancer susceptibility as the abnormal gene products of the mutated allele drive growth. On the other hand, both alleles of TSGs need to be altered at the tissue level for that specific tumour suppressor function to be deficient. So, the TSG mutations (and the resulting syndromes) are inherited in the heterozygous state but the inactivation of the second allele at the organ level is required for the sequence of events leading to tumour formation to be initiated. This is the principle underlying the so-called Knudson's two-hit hypoth­esis (one germline and one tissue-specific) (127). In essence, TSG mutations are inherited dominantly but act recessively at the level of the organs.

Genetics and gynaecological malignancies

Though the majority of gynaecological malignancies occur spor­adically, both ovarian and endometrial cancers are prominent fea­tures of key cancer predisposition syndromes, illustrating the role of germline mutations in the aetiology of cancer. The lifetime risk of women developing ovarian cancer is very significantly increased in two of the most common cancer predisposition syndromes: BRCA hereditary breast and ovarian cancer syndrome and Lynch syn­drome. Both syndromes are caused by mutations in TSGs and in both cases these are TSGs involved in DNA repair.

The BRCA hereditary breast and ovarian cancer syndrome is caused by mutations in the genes BRCA1 and BRCA2 which are in­volved in post-replication DNA repair (128-130).

Lynch syndrome is caused by mutations in a family of genes in­volved in DNA repair known as mismatch repair genes (135-138). The function of the gene products is to correct errors in base­matching following DNA replication. As with BRCA, the presence of germline mutations in these genes confers susceptibility to cancer and it is the loss of the second, functioning allele that results in loss of the mismatch repair function and the subsequent sequence of events that leads to cancer development. The syndrome is associated with an increased risk of many cancers including colorectal, endo­metrial, gastric, and ovarian (139-141).

Oncogenetics in clinical practice

In assessing a woman diagnosed with a malignancy such as ovarian or endometrial cancer, a gynaecologist may consider the possibility that the disease developed in the context of a cancer predisposition syndrome. The woman's age, previous personal history of cancer, and relevant family history of malignant disease can be pointers to a possible genetic predisposition and the genogram is particu­larly useful in that context. A woman being diagnosed with ovarian cancer in her early 40s with a strong family history of breast cancer will need to be counselled for the possibility of an underlying BRCA mutation. In a woman diagnosed with endometrial cancer in her 50s who has a past history of colorectal cancer, the possibility of Lynch syndrome will need to be considered.

The identification of an underlying genetic predisposition is im­portant and may influence the therapeutic options available and subsequent surveillance. For example, women with breast cancer and an underlying BRCA mutation have a significant lifetime risk of developing a second primary breast cancer (142-145). This has an impact on the choice of surgical procedure and follow-up and may also raise the possibility of prophylactic surgery (contralat­eral mastectomy) to manage the risk (146-149). Women may also consider prophylactic bilateral salpingo-oophorectomy after com­pleting their families to reduce the significant associated ovarian cancer risk as well as the breast cancer risk in the premenopausal pe­riod, though the latter is currently the subject of debate (150-153). In Lynch syndrome, the option of prophylactic hysterectomy and bilateral salpingo-oophorectomy should be discussed (154, 155).

A test for a cancer predisposition syndrome offered to a woman already affected from cancer is described as a diagnostic test. Tests offered to unaffected family members to establish whether they carry a known familial mutation are described as predictive. Women offered genetic testing should be counselled comprehensively about the nature of the tests and the implications of their results. Such counselling should address the complex medical, ethical, and psy­chosocial aspects that are inherent to this process (156-159). In diagnostic tests, the possibility of identifying variants of unknown significance should be discussed (160, 161). Beyond the relevance to management decisions, the psychological impact, at a time when a woman is dealing with her own diagnosis of cancer, should be ex­plored, also taking into account the implications for other family members who are potentially at risk.

There are a number of considerations in relation to predictive tests. The ability to achieve prevention through close surveillance is one of the main indications and this relies on the availability of validated screening programmes for the relevant cancers.

The inheritance implications for existing or future children should be discussed. Some women may consider the option of pre­natal (or preimplantation) genetic diagnosis though this is unusual because of the incomplete penetrance of many of the syndromes and the opportunities for prevention (166, 167). The potential impact on the ability of women to secure appropriate personal insurance once tested positive for a cancer predisposition syndrome needs to be part of pretest counselling though legislation has been passed in many countries to protect individuals from resulting discrimination (168, 169).

Novel therapeutic implications of oncogenetics

Establishing the molecular basis of cancer susceptibility has revealed new potential targets for treatment. Paradoxically, the chink in the armour of the cell's repair mechanisms may offer hope for novel therapeutic targeting of tumour cells (170). As described previously, loss of BRCA DNA-repair activity leaves cells vulnerable to other mutations and predisposes to oncogenesis. If manipulated, however, that disturbance in DNA repair ability can compromise the viability of tumour cells leading to cell death. One such manipulation is the use of poly ADP ribose polymerase (PARP) inhibitors which makes cells even more dependent on BRCA and has shown promising re­sults in treating tumours which form part of the BRCA hereditary breast and ovarian cancer syndrome. PARP supports single- stranded DNA repair and if its function is impaired, cells rely on more com­plex double-stranded repair mechanisms, such as homologous re­combination and non-homologous end joining which are mediated by BRCA. If BRCA-mediated repair is itself deficient as a result of a germline mutation then PARP inhibition tips the balance towards genomic instability and cell death in these tumour cells (171-174).