Hereditary cancers: diagnosed patients are only the tip of the iceberg

Although knowledge on pathogenic germline variants has improved over the years, researchers are hunting for new genetic causes of cancer to better identify families at higher risk to develop the disease 

DNA cancer

Prof. Nicoline Hoogerbrugge

In recent years, evolution of next-generation sequencing (NGS) technology on large series of genes has allowed to measure the population burden of hereditary predisposition to cancer. Overall, 5-10% of colorectal cancers, ovarian cancers or breast cancers develop in persons who have pathogenic variants in cancer susceptibility genes, but incidence highly varies among genes (J Clin Oncol. 2017 Apr 1;35(10):1086-1095; Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7). Despite growth in molecular oncology and improvements in tumour testing, says Prof. Nicoline Hoogerbrugge, Radboud University Medical Centre, Nijmegen, The Netherlands, only a minority of people at high risk of hereditary cancers are being identified, thus decreasing the chances for oncologists to engage them in tailored genetic counselling and prevention programmes.

A genetic tumour risk syndrome (genturis) is a genetic disorder in which inherited (germline DNA) genetic mutations in one or more genes strongly predispose the individuals to the development of benign or malignant tumours, sometimes with childhood onset.

How can a hereditary cancer be recognised among common cancers?

This is one of the biggest challenges in the field as we are talking of common cancers with a rare, hereditary cause. Many individuals with a genturis show some hallmarks such as having a cancer diagnosis at young age and having multiple primary tumours, multiple relatives with the same type of cancer, a specific phenotype – e.g., polyposis or developmental aberrations –, or specific tumour characteristics like microsatellite instability (MSI). However, there is a degree of variability, for instance in hereditary breast cancers young age is an important aspect that leads to suspect a diagnosis, while in ovarian cancer the most common hereditary forms can also occur in women who are over 70.

Genetic testing then reveals if a hereditary tumour has been found but it is necessary to look for specific mutations when they are known. For instance, the younger the age of colorectal cancer (CRC) diagnosis the higher the chance that it is Lynch syndrome. It is very effective to perform MSI analysis (or IHC analysis of the mismatch repair proteins) in every patient with colorectal or endometrial cancer below age 70, as almost all MSI CRCs found above age 70 are caused by methylation of the MLH1 promotor rather than by Lynch syndrome (Int J Cancer. 2020 Oct 15;147(8):2150-2158). However, absence of MLH1 promoter methylation in a tumour is not sufficient for a Lynch syndrome diagnosis as also bi-allelic somatic mutations of a mismatch repair gene may lead to microsatellite instability. The definitive diagnosis of Lynch syndrome can only be made by the detection of a pathogenic germline variant in a mismatch repair gene (Gastroenterology. 2021 Mar;160(4):1414-1416.e3).

From a clinical perspective, sometimes you are taken by surprise, you may find a hereditary cancer although you have no other signals, no family history or multiple cancers. Currently, we know 40 genturis, all related to various forms of hereditary cancers, but it is likely that others exist and we simply have not yet identified them all.

A sizeable proportion of the pathogenic variants in cancer-related genes that are observed on tumour-only analysis are of germline origin, and ESMO released some recommendations in 2019 for the management of this piece of information (Annals of Oncology 30: 1221–1231, 2019). What is the informative value of tumour-only analysis to assess the risk of hereditary cancer?

The a priori chance of finding a pathogenic germline variant varies per tumour type and patient characteristics. For instance, pathogenic TP53 mutations will mostly be somatic while pathogenic mutations in BRCA1 or BRCA2 are quite frequently of germline origin. Most tumour-based analyses are performed to characterise the tumour and its genetic drivers to optimise the treatment of a patient, but they are not designed to detect all types of germline variants and therefore they often cannot be used to exclude a genturis. If results of a tumour test point towards a putative hereditary cause, it is good practice to discuss them in a Molecular Tumour Board in the presence of a clinical geneticist.

On the other hand, also patients with early stages of cancer that normally do not undergo a comprehensive tumour DNA analysis may benefit from the identification of a germline variant and thus should be eligible for clinical counselling and germline testing. Currently, we are using tumour-DNA from every new patient with epithelial ovarian carcinoma to do a pre-screen for germline analysis. Not every patient with a BRCA mutation in the tumour DNA has a germline mutation, but the tumour test may be designed such that it can preselect patients with a high chance of having a pathogenic germline variant (J Natl Cancer Inst. 2020 Feb 1;112(2):161-169).

What are the major challenges in treating hereditary cancers?

Patients with a hereditary cancer are often treated as if they rather have a common form of the disease. Personalising treatment does not only depend on molecular profiling a tumour and the identification of actionable variant mutations, but also from the availability of targeted agents that can interfere with the genetic cause of the disease. One of the exceptions now is the PARP inhibition in patients with ovarian, breast, prostate and pancreatic cancer and a pathogenic BRCA1/2 variant, with some agents already approved in the advanced/metastatic settings in Europe. Currently, there are only a few treatments based on the genetic causes of cancer and finding new options of care is of great importance.

Overall, 5-10% of colorectal cancers, ovarian cancers or breast cancers develop in persons who have pathogenic variants in cancer susceptibility genes. However, despite growth in molecular oncology and improvements in tumour testing, only a minority of people at high risk of hereditary cancers are being identified today. Prof. Nicoline Hoogerbrugge, Radboud University Medical Centre, Nijmegen, The Netherlands, describes how hereditary cancers can be detected and current challenges in their management.

Due to their nature, hereditary cancers are a ‘family business’ implying a search for specific genetic variants in a patient’s relatives. How is the risk of developing a tumour managed in those carrying cancer genes mutated in the germline?

Although our knowledge has improved over the years, there are still a lot of uncertainties on the cancer risk and management of a person diagnosed with a germline mutation in a known cancer gene who does not come from a family that is prone to the disease. In contrast, we also see families that are fully loaded with cancer but still there is not a gene detected which is causative for that tumour type.

We are hunting for new genetic causes of cancer because once you have found one person with a hereditary cancer you can save an entire family from the diagnosis of cancer and from death

Prof. Nicoline Hoogerbrugge

Therefore, we are hunting for new genetic causes of cancer because once you have found one person with a hereditary cancer you can save an entire family from the diagnosis of cancer and from death.

There are several options for early detection and for even cancer prevention, but not for all genturis. For instance, when you have a family history of BRCA1 or BRCA2 that comes with an increased risk of breast and ovarian cancer, evidence shows that by involving women at-risk in surveillance programmes which offer MRI every year - at a certain age combined with a mammography every other year - we can early detect breast cancer and really improve prognosis.  Female patients can also be given another choice, to reduce the risk for breast cancer by prophylactic surgery. Additionally, salpingo-oophorectomy is advised - around age 35-45, depending on the affected gene - to reduce the risk for ovarian cancer. In Lynch syndrome, patients undergoing every other year a colonoscopy and removal of adenomas from age of 25 years may reduce not only their risk of cancer occurrence but also morbidity and mortality from cancer.

So, there are various options to reduce the risk of hereditary cancers, provided that the right diagnosis is made. There is also a lot of research going on now on lifestyle that may help to reduce the risk of cancer, for instance physical activity most likely has a positive impact on the risk of common colorectal cancer (J Clin Oncol. 2015 Jan 10;33(2):180-8;PLoS One 2015; 26:e0120706), but it is still not clear to what extend preventive behaviours play a role in the hereditary forms of the disease.

Early detection and diagnosis of a hereditary cancer requires a deep knowledge of the genetic of cancer, which is rapidly evolving. Do you think that medical oncologists are sufficiently trained in assessing the genetic causes of cancer?

Genetics is literally booming, we all are aware of that, and I do think that more training may help medical oncologists to keep pace with advances in the field. Knowledge from 2-3 years ago may not be adequate to the current time, so we need to offer education opportunities on a regular basis where medical oncologists and clinical geneticists can share knowledge and learn from each other like we do with the annual ESMO Preceptorship on Hereditary Cancer Genetics and with the European Reference Network in Genetic Tumour Risk Syndrome providing web lectures every other week on different aspects and types of a genturis. We also need more tools that provide guidance on how to recognise, diagnose, treat and provide prevention recommendations to patients with a germline genetic susceptibility, and to this purpose a dedicated website has been launched recently. In Europe, the implementation of guidelines is good, however there is still room for improvement, we need to join forces to be able to detect every person who is at risk of hereditary cancer and run prevention programmes.

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