Genetic predisposition to cancer

Genetic predisposition to cancer

CANCER TRIALS AND SERVICES Genetic predisposition to cancer Key points C Better risk prediction in common cancers such as breast, colorectal and pr...

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Genetic predisposition to cancer

Key points C

Better risk prediction in common cancers such as breast, colorectal and prostate, using multiple validated common single-nucleotide polymorphisms and gene panel testing, is allowing population risk stratification


The 100,000 Genomes Project is hoping to identify the remaining inherited components by genome sequencing


Licensing of gene-based treatments, such as PARP and MEK inhibitors, are leading to new personalized treatments

D Gareth Evans Emma R Woodward

Abstract Over the last 30 years there has been a burgeoning development of genetic risk assessment and ‘family history’ clinics to deal with the ever-increasing demand from individuals at increased risk of cancer because of their family history. More recently, even those with no family history who develop certain cancers are at substantial risk of having underlying germline pathogenic genetic variants, whose identification alters their treatment. Risk of inherited cancer can be divided into (1) known syndromes characterized by specific clinical features (e.g. familial polyposis), and (2) conditions with increased risks of common cancers, characterized by familial clustering, early onset and specific cancer features. Cancer risk can be assessed in three categories: average (near population-risk), moderate and high. Individuals at high risk are generally referred to regional genetics centres. Moderate-risk individuals can benefit from early surveillance in secondary care, particularly for breast and colorectal cancer. Averagerisk individuals can be reassured in primary care. Newer surveillance techniques such as magnetic resonance imaging are now being approved for high-risk categories. Genetic testing of a minority of high-risk individuals in specific clinical situations is now routine practice, and surgical management options have gained validity. Much research is still necessary to improve early detection and develop non-surgical prevention in high-risk individuals.

abnormalities were demonstrated in cancer-predisposing genes. Only in the last 30 years has the hereditary nature of a small proportion of certain common cancers been proven. (See The Biology of Cancer on pages xxxexxx of this issue for Further reading.)

Molecular basis of cancer That cancer is ‘genetic’ at the cellular level is now beyond dispute. All tumours result from mutations of either tumour suppressor genes (TSGs), which must be inactivated to enable growth, or proto-oncogenes, which require activation to promote growth. Most of these genetic events are acquired, as a result of replication error (in simple copying of DNA during cell division), exposure to external agents (radiation, chemicals, viruses) or epigenetic factors such as ageing, which increase gene silencing through methylation.

Keywords APC; BRCA1; BRCA2; breast cancer; familial polyposis; Inherited cancer

MRCP; oncogene; tumour suppressor gene

Occasionally, mutations in TSGs and proto-oncogenes can be inherited rather than acquired. Identifying the genes that cause hereditary disease has given insight into many cancers. The role of cancer-predisposing genes in causing sporadic cancer is still being widely researched, but much can be learnt from cancerprone syndromes. Broadly, predisposition can be subdivided into rare genetic syndromes, which have a well-defined predisposition to rarer tumour types, and a larger group that cannot be easily identified clinically, which have a strong family history of one or more common malignancies. However, identifying patients with genetic predisposition to cancer is important not only for riskreduction strategies in at-risk family members, but also in guiding treatment selection. This is because the genetic abnormality underlying their cancer can render the tumour particularly susceptible to certain therapeutic genes or, conversely, to enhanced treatment-related toxicity, especially where DNA damage and repair pathways are involved.

Introduction There has been increasing evidence of a familial predisposition to cancer since the classic model of hereditary retinoblastoma was outlined.1 The earliest reports of cancer families date back 200 years to a large cluster of breast cancer in the family of French physician Broca, and a cluster of gastric cancer in Napoleon’s family. Despite the pioneering work of clinicians and researchers such as Henry Lynch and Mary-Claire King in the 1960s to 1980s demonstrating the hereditary nature of at least a proportion of cancers (e.g. breast, colon), the hereditary element was not proven until the advent of molecular biology, when

D Gareth Evans MD FRCP is a Professor of Medical Genetics and Cancer Epidemiology at the University of Manchester, UK. Competing interests: none declared.

Retinoblastoma Retinoblastoma is the model from which much of our current knowledge of TSGs has been gained. A familial tendency to this early childhood eye malignancy was recognized in the 19th century. About 50% of cases result from inheritance of a gene

Emma R Woodward PhD FRCP is an Honorary Senior Clinical Lecturer, Division of Evolution and Genomic Sciences, University of Manchester, UK. Competing interests: none declared.

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defect in one copy of the retinoblastoma gene (RB1 on chromosome 13), and >90% of individuals who carry a pathogenic gene variant develop retinoblastoma, usually bilaterally. In 1971, Knudson proposed that tumour development requires mutational events in both copies of the gene.1 Individuals who inherit a mutated copy need only one further mutation and are far more likely to develop the malignancy, which occurs at a younger age and is usually bilateral. Sporadic cases require two mutations (‘hits’) in a retinal cell rather than one (Figure 1), so bilateral tumours are unlikely to occur and the unilateral tumours present later. This hypothesis, which has since been validated in other conditions, now bears the originator’s name.

issue). Much of the remaining inherited component has been unpicked in the last 10 years by genome-wide association studies to find lower risk genetic components that additively modify an individual’s cancer risk.2

Genetic syndromes These are usually readily identifiable by a clinical phenotype (group of associated clinical features) or laboratory tests. The syndromes can be autosomal dominant, recessive or X-linked (Tables 1 and 2). Although the conditions are generally uncommon, the TSGs involved also play a fundamental role in the genesis of sporadic tumours, which affect 35e40% of people in developed countries. The identification of genetic syndromes has led to the use of targeted therapies in both rare familial settings and more common sporadic forms of the cancer, as well as

The route to discovering cancer genes The discovery of retinoblastoma cases with constitutional deletions of chromosome 13 visible under the microscope concentrated research on that region. ESD, which was deleted, acted as a genetic marker for further studies. The gene for retinoblastoma was eventually localized and identified by gene linkage analysis in 1986. This same approach using chromosome studies of individuals, their tumours and genetic linkage have led to the discovery of nearly all high-risk genes that predispose to cancer (Table 1). Most of these genes and their products (proteins) were found in a heady 6-year period between 1989 and 1995. The last 25 years has seen progress towards understanding how these genes function through their protein products, and development of the first line of gene-based treatments, such as trastuzumab, imatinib and a new breed of synthetic lethal drugs, the poly(ADPribose) polymerase (PARP) inhibitors, to treat BRCA1/2-related cancers (see Targeted Agents in Cancer on pages xxxexxx of this

Examples of autosomal dominant and recessive syndromes predisposing to cancer, chromosomal location and protein product Name of disease/ syndrome Autosomal dominant Familial adenomatous polyposis Neurofibromatosis 1 Neurofibromatosis 2 von HippeleLindau Multiple endocrine neoplasia 1 Multiple endocrine neoplasia 2 Tuberous sclerosis

Ideogram of the ‘two hit’ hypothesis which causes disruption of the protein product. The second hit is often loss of the whole gene by deletion of part or all of the chromosome on which the gene resides. INHERITED


Juvenile polyposis PeutzeJeghers Cowden Tylosis Phaeochromocytoma/ paraganglioma predisposition



Autosomal recessive Fanconi’s anaemia Bloom Ataxia telangiectasia Xeroderma pigmentosa ChediakeHigashi Albinism X-linked Bruton WiskotteAldrich






17q 22q 3p 11q

Neurofibromin Merlin/schwannomin pVHL Menin



(TSC1) 11q (TSC2) 16q 18q and other(s) 19p and other(s) 10q 17q Various different genes and loci involved


14 loci 15q NBN 11q ATM Seven types 1q 11q

Many, including BRCA2 pBLM pATM Two types pLYST OCA1, OCA2

Xq Xp



SDHB/C/D subunits are the most common in phaeochromocytoma/paraganglioma predisposition, and SDHD subunit mutations show a parent of origin effect.

Table 1

Figure 1

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Location (chromosomal)


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earlier stage detection of familial disease through surveillance and disease-reduction strategies.

codon 1450 showed typical features of Gardner’s syndrome (osteomas, cysts, desmoid disease) without retinal signs, and also mild polyp disease. The APC gene is of fundamental importance in most ‘sporadic’ colorectal cancers, although an acquired loss of both functioning copies of the gene is required. Use of genetic registers and genetic testing to target screening, along with appropriately timed removal of the colon, has led to an improved life expectancy in FAP of 15e30 years. An autosomal recessive form of polyp predisposition caused by individuals inheriting pathogenic variants in both copies of the MUTYH gene causes a small minority of apparently isolated de novo cases or disease in two siblings with no family history of FAP.

Familial adenomatous polyposis (FAP) FAP has been the model for transposing knowledge of a rare genetic disease to a commonly occurring cancer. FAP is an autosomal dominant condition characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, usually by 30 years of age. Untreated, this leads to the almost inevitable development of colorectal cancer by the age of 60. The condition is associated with osteomas, epidermal cysts and increased risks of other malignancies such as duodenal cancer, hepatoblastoma, glioma and thyroid cancer. The gene for FAP (APC ) was localized to 5q21eq22 and identified in 1991. FAP was one of the first conditions to show a clearecut correlation between genotype (genetic changes in APC ) and phenotype (clinical picture). Patients with mutations in the early part of the gene (50 , exons 2e5) had a mild clinical picture with late-onset polyps, whereas individuals with mutations from exon 9 through to codon 1450 of exon 15 had classical disease, with nearly all patients manifesting typical congenital retinal pigmentation. However, those with mutations beyond

Other dominant tumour syndromes A number of other important dominantly inherited conditions are now well outlined clinically and genetically. von HippeleLindau syndrome predisposes to retinal angioma, cerebellar haemangioblastoma, renal cell carcinoma and phaeochromocytoma. The neurofibromatoses, which consist of three subtypes e NF1, NF2 and schwannomatosis e carry an increased risk of mainly benign nervous system tumours. In NF1, the predominant


Tumour typesa

Lifetime risk of developing one of the tumour types (%)

Age to start screening and specific feature

Familial adenomatous polyposis

Adenoma, bowel cancer, duodenal cancer (10%), desmoid (10%) Neurofibroma, glioma (20%), sarcoma Schwannoma, meningioma, ependymoma (5%) Haemangioblastoma, renal cell carcinoma (RCC), phaeochromocytoma (30%) Parathyroid hyperplasia, insulinoma, gastrinoma Medullary thyroid cancer, parathyroid hyperplasia (30%), phaeochromocytoma (50%) As in multiple endocrine neoplasia 2a, with addition of characteristic facies and mucosal neuromas Basal cell carcinoma, medulloblastoma (5 e30%) Breast, thyroid, endometrium


10e16 years (adenomas)

100 100

Birth Birth

90 95

5 years (retinal angiomata) 16 years (RCC and CHB) 5 years


5 years


5 years


Birth (medulloblastoma)

30 80

13e16 years (thyroid) 35 years (breast) First year (adrenal)

80e90 (females) 80e90 (females)

30 years (breast) 30 years (breast)


25 years (colorectal)

Neurofibromatosis type 1 Neurofibromatosis type 2 von HippeleLindau Multiple endocrine neoplasia 1 Multiple endocrine neoplasia 2a

Multiple endocrine neoplasia 2b

Gorlin Cowden LieFraumeni BRCA1 BRCA2 Lynch

Sarcoma (bone/soft tissue), adrenal cortex, breast cancer, glioma Breast, ovary, prostate (5%) Breast, ovary, prostate (15%), male breast (5%) Colorectal (60e80%), ovary (10%), endometrium (40e60%), ureter (10%), gastric (10%), pancreas (5%)

Examples of hereditary cancer predisposition syndromes, their main clinical features and screening advice a Additional risks in brackets where helpful for some of specific tumour types in that condition.

Table 2

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Hereditary conditions predisposing to breast cancer Gene

Other tumour susceptibility

Population frequency (%)

Proportion of breast cancer (%)

Proportion of HPHBC (%)

Proportion of familial breast cancer risk (%)

Lifetime risk in women (%) (RR)

BRCA1 BRCA2 TP53 LFS PTEN Cowden’s CHEK2 ATM STK11 BRIP1 PALB2 RAD51D 313 SNPs Ref. 2 Totals

Ovary/prostate, colorectal Ovary/prostate, pancreas Sarcoma, glioma, adrenal Thyroid, colorectal Colorectal, prostate HoZ (AR) lymphoma, leukaemia Colorectal Ovary, HoZ-Fanconi (AR) HoZ-Fanconi (AR) Ovary, HoZ-Fanconi (AR)

0.1 0.1 0.0025 0.0005 0.5 0.5 0.001 0.1 0.1 0.001 25e46 100 for any

1.5 1.5 0.02 0.004 0.5 0.5 0.001 0.1 0.1 0.1 0.5 30

40 40 2 0.3 0 0 0.6 0 2 0 0 84

5e10 5e10 0.1 0.02 2 2 0.04 0.4 0.8 0.2 20 40

50e85 40e85 80e90 25e50 18e20 (2e3) 20 (2e3) 50 18e20 (2.0) 40 (4.0) 15e20 11e13 (1.1e1.4)

AR, autosomal recessive; HoZ, homozygous; HPHBC, highly penetrant hereditary breast cancer (e.g. >3 affected relatives); RR, relative risk; SNP, single-nucleotide polymorphism.

Table 3

combination of loss of function of TSGs and oncogene activation is usually involved. The combination and order can alter the histological as well as invasive nature of the cancer. The molecular evolution of some tumours has recently been elucidated, with tumours requiring a single rate-limiting, or driver, mutation and additional clonal mutations acquired to enable evolution and metastasis. There is clear evidence that a minority of people who develop common cancers have inherited a pathogenic variant in a gene that puts them at high risk of malignancy, but this cannot usually be recognized as a syndrome without a family history. Adenocarcinomas are more likely than carcinomas of squamous epithelium to have a strong hereditary component, with 4e15% of all breast, ovarian and colon cancer resulting from inherited high-risk gene defects; however, twin studies show that around 30% have some inherited component.3 Cancers are also more likely to be hereditary if they are early onset, bilateral or associated with other related primaries. The discovery of inherited mutations in TP534 in rare families with a horrific pattern of malignancy was the first major discovery in this area. Li eFraumeni syndrome, arising from germline TP53 mutations, predisposes to sarcoma, breast cancer, glioma and other tumours in children and adults. In view of the associated breast cancer risk, the risk of cancer approaches 100% for female mutation carriers by age 50 years. These single-gene disorders conferring a predisposition to more common cancers are well defined but still uncommon. Recent evidence has shown that predisposition to common cancers more commonly involves a polygenic pattern with multiple common gene variations, each associated with small elevations in risk.

tumour, the neurofibroma, is associated with at least a 10e15% lifetime risk of developing malignant peripheral nerve sheath tumours that are usually fatal. The second type, NF2, is largely associated with schwannomas and meningiomas, most individuals becoming deaf from bilateral VIIIth cranial nerve involvement. Gorlin’s syndrome is characterized by multiple jaw keratocysts and basal cell carcinomas and a 2e5% risk of childhood medulloblastoma. In the multiple endocrine neoplasias, MEN1 affects the parathyroid glands, pituitary and pancreas, and in MEN2, arising from specific activating mutations of the RET proto-oncogene, patients may develop medullary thyroid carcinoma, primary hyerperparathyroidisn and phaeochromocytoma. Some conditions, for example a predisposition to paraganglioma/phaeochromocytoma associated with pathogenic SDHD variants, only manifest if individuals have inherited the variant from their father. This is known as a parent of origin effect. These conditions have benefited from gene identification and are important to recognize as they provide opportunities for disease prevention through pre-symptomatic surveillance and interventions that, in most cases, improve life expectancy. This can mean intervention in childhood; for example in MEN2, the thyroid is removed preventively. Understanding of the underlying cellular pathway has led to the introduction of targeted therapies, for example mitogen-activated protein kinase (MEK) inhibitors in NF1 and the vascular endothelial growth factor antibody bevacizumab in NF2, which have benefit in treating these conditions.

Common cancer predisposition Most cancers require a number of genetic changes in a cell before an invasive tumour results. This number probably varies between four and 10, and few cancers are likely to be caused purely by the loss of two copies of a single TSG, as in retinoblastoma. A

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Breast/ovarian cancer Breast cancer can occur as part of a high-penetrance predisposition such as LFS, BRCA1 and BRCA2, but can also be


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>100 genes, are now available. However, such tests should be considered in the context of accurate variant interpretation as we all harbour genetic variation, and the distinction between benign and pathogenic variants requires specialist knowledge. Indications on how to assess risks and who to refer for screening and genetic testing are available in more detailed texts. A

contributed to by mutations in genes such as ATM, CHEK2, PTEN and PALB2. ATM and CHEK2 variants confer lifetime risks of 20 e30% and are ‘moderate’ risk, whereas PALB2 and PTEN confer risks of 40e50% and are ‘high-risk’ genes (Table 3). The greatest interest has focused on BRCA1/2 mutations, each of which is carried by approximately 0.1e0.15% of the population (rising to 2.5% combined in Ashkenazi Jewish individuals). This is because of the high lifetime risk of 40e85% of breast cancer, with an associated 20e60% risk of ovarian cancer. Many women who test positive for mutations now opt for risk-reducing surgery, which can reduce risk of both cancers by >90%, with oophorectomy conferring some protection against breast cancer. The advent of magnetic resonance imaging surveillance and better treatments can reduce the use of mastectomy. In the last few years much better risk prediction has been possible using information from mammographic density and multiple validated common single-nucleotide polymorphisms.2 There is also huge promise of improved outcomes from the use of PARP inhibitors in BRCA1/2-related tumours.5

KEY REFERENCES 1 Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68: 820e3. 2 Mavaddat N, Michailidou K, Dennis J, et al. Polygenic risk scores for prediction of breast cancer and breast cancer subtypes. Am J Hum Genet 2019; 104: 21e34. 3 Peto J, Mack TM. High constant incidence in twins and other relatives of women with breast cancer. Nat Genet 2000; 26: 411e4. 4 Malkin D, Li FP, Strong LC, et al. Germline TP53 mutations in cancer families. Science 1990; 250: 1233e8. 5 Stebbing J, Ellis P, Tutt A. PARP inhibitors in BRCA1-/BRCA2associated and triple-negative breast cancers. Future Oncol 2010; 6: 485e6.

Colorectal cancer The other main tumour site where high-risk dominant genes play an important role is the large bowel. Approximately 2e3% of colorectal cancer is caused by inherited mutations in one of four DNA mismatch repair genes that cause Lynch’s syndrome. Mismatch repair genes are important in about 13% of colorectal cancer, and inheriting a pathogenic variant confers a 30e80% lifetime risk. However, mutations also enhance risks of endometrial, ovarian, gastric and upper urinary tract cancers. Identifying high-risk individuals can save lives because bowel cancer can be prevented by regular colonoscopy.

FURTHER READING Eeles R, Ponder B, Easton D, Eng C, Horwich A. Genetic predisposition to cancer. 2nd edn. London: Chapman & Hall, 2004. Hodgson S, Foulkes WD, eds. Inherited susceptibility to cancer. Cambridge: Cambridge University Press, 1998. Lalloo F, Kerr B, Friedman J, Evans DGR, eds. Risk assessment and management in cancer genetics. Oxford: Oxford University Press, 2005. McIntosh A, Shaw C, Evans G, et al. Clinical guidelines and evidence review for the classification and care of women at risk of familial breast cancer. NICE guideline CG014. London: National Collaborating Centre for Primary Care/University of Sheffield, 2004. Updated 2006, 2013.

Where are the remaining genes? The great majority of high-risk predisposition has been elucidated, but only about 50% of the remaining polygenic element has been identified. ‘Generic’ genetic tests for cancer, which test

TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. Question 1 A 30-year-old man presented with a 1-month history of rectal bleeding. He had no family history of cancer or polyps but had a 10-year old daughter.

Question 2 A 35-year-old woman presented with a concern about her cancer risks. She herself was well. Her mother, aged 60 years, was undergoing treatment for advanced high-grade serous ovarian cancer, and her maternal aunt had developed a grade 3 triplenegative breast cancer aged 42 years. The patient’s maternal grandmother, now deceased, was reported as having had breast cancer in her 40s.

Investigation  Colonoscopy showed >100 adenomatous polyps in the large bowel What are the implications for his daughter? A. There is a 50% risk for the child B. The risk is very small C. There is no risk to the daughter D. There could be a 50% risk or virtually no risk for the daughter E. There is a 25% risk in his daughter

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What genetic testing should be carried out and on whom? A. The family history is certain to be due to an underlying pathogenic variant in BRCA1 or BRCA2 and testing can be offered to the woman with complete reassurance if negative. B. Genetic testing for a large panel of cancer genes should be offered straight away to the woman attending clinic as other genes may be involved C. Discussions should be had with the woman that testing of her mother initially for BRCA1 and BRCA2 should be undertaken initially as this would provide a definitive answer and potential treatment options for the mother D. No testing should be offered as the likelihood of an actionable pathogenic variant is below the NICE threshold. E. Testing can only be offered to the woman if she comes from a population with a strong founder effect such as the Jewish population.

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Question 3 A 25-year-old woman had been found to have a medullary thyroid cancer. She had no family history of cancer. She had two children, aged 5 and 7 years. Which of the following is correct? A. The absence of a family history of cancer means that genetic testing is unlikely to be helpful B. If genetic testing were offered, it would require full analysis of a set of high-risk familial cancer genes C. If an underling pathogenic variant were identified, her children would not require any specific management until they were aged 18 years D. Molecular analysis of her tumour is likely not to show complex molecular and cytological changes E. The patient is at increased risk of developing neuroendocrine tumours of the gastrointestinal tract


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