It is estimated that there is hereditary susceptibility behind 5-10% of cancers. The percentage varies depending on the type of cancer.
Hereditary susceptibility may be suggested by diagnosis of the same type of cancer in several near relatives and/or development of the disease at an exceptionally young age, or by a certain type of tumour, such as retinoblastoma or triple-negative medullary breast cancer in a young woman.
Identifying hereditary susceptibility to cancer is significant
for planning the follow-up of the person diagnosed with cancer
sometimes also for planning the cancer treatment, such as the choice of surgical technique.
In addition, identifying hereditary susceptibility facilitates predictive genetic testing of family members.
Family members with significantly increased risk of disease can then be directed for intensified surveillance and, on the other hand, family members not carrying the gene defect can be spared such surveillance.
Predictive genetic testing is mainly not performed before the person has reached adult age, unless the established gene defect is associated with an increased risk of developing the disease and its surveillance already in childhood or adolescence.
Each cancer susceptibility syndrome has a typical spectrum of diseases. Different types of cancer in several near relatives do not necessarily suggest hereditary susceptibility to cancer unless the cancers belong to the spectrum of a certain cancer susceptibility syndrome or the individuals developed the disease at an exceptionally young age.
Referral to a clinical geneticist
A primary health care physician should identify which of those patients worried about their family cancer risk would benefit from more detailed assessment and investigations in a clinical genetics unit. This includes patients who developed the disease at a young age and those with the same type of cancer occurring in several generations.
The referral should include data on the patient's cancer and the most accurate information possible on which near relatives have had cancer, what type of cancer, and at what age.
As patients in most cases have no documented information about their relatives, referral can be made based on the history.
You can consult the specialized clinical genetics unit in your area about the indications for referral.
Referral for assessment by a clinical geneticist should primarily be made for any family member who has had cancer, because diagnostic gene testing to see whether there is a gene defect causing susceptibility to cancer running in the family is normally made for a person with cancer.
However, if family members who have had cancer have died, referral can be made for a healthy family member.
Diagnostic gene testing may possibly also be done with biopsy samples.
Investigations into hereditary susceptibility to cancer are always voluntary.
Investigations at a clinical genetics unit
The clinical genetics unit will assess whether the patient or the family fulfil the criteria for diagnostic gene testing for the cancer susceptibility syndrome in question. A more detailed family history is often recorded on a separate family history form, and cancer diagnoses of family members are, with their consent, confirmed from patient records and pathological records.
A gene panel test based on a new generation sequencing method and covering the genes considered in the differential diagnosis is normally used.
Diagnostic gene testing is performed at a clinical genetics unit or in cooperation with clinical oncologists and clinical geneticists. The choice of test and interpretation of results require special knowledge.
Most gene defects associated with hereditary cancer are dominantly inherited but with incomplete penetrance, meaning that not all carriers of the gene defect develop cancer.
After the gene defect associated with the susceptibility has been identified in a person with cancer, predictive genetic testing can be done in any healthy family member at risk. Predictive genetic testing should always be carried out at a clinical genetics unit after genetic counselling and, as necessary, after a reconsideration period, and only if the person him/herself wishes to be examined.
Predictive genetic testing is performed, mainly, when the person has reached adulthood (over 18 years and often even later) at which point the adult person may themselves decide whether they wish to have the genetic testing done. An exception to this are such cancer susceptibility syndromes that entail an increased risk of developing the disease already in childhood or adolescence and in which surveillance or interventions are recommended before reaching adulthood. A clinical geneticist should provide in the genetic counselling given to the index person and in his/her medical record guidance on when predictive genetic testing of relatives can be considered.
Gene defect carriers should be provided with recommendations for surveillance depending on the risks of cancer associated with the detected gene defect and according to international recommendations.
Surveillance is often carried out in specialized care but can in some cases be done in primary health care according to recommendations given by a clinical genetics unit.
The most common forms of hereditary susceptibility to cancer
Hereditary susceptibility to breast and/or ovarian cancer
General criteria for referral (if the patient so wishes)
At least three cases of breast and/or ovarian cancer in near relatives, with one before the age of 50 years
Two cases of breast cancer in near relatives, both before the age of 50 years
Breast cancer before the age of 40 years
Medullary or triple-negative breast cancer before the age of 60 years
Bilateral breast cancer before the age of 50 years
Breast and ovarian cancer in the same woman
Male breast cancer
At least two cases of ovarian cancer in near relatives
Other cancers in addition to breast and ovarian cancer in near relatives at a young age, raising suspicion of some known cancer susceptibility syndrome
Hereditary susceptibility to bowel cancer
The most common hereditary susceptibility to bowel cancer is included in Lynch syndrome which is associated with increased risk of bowel cancer and cancer of the uterine corpus, and to a lesser degree of some other cancers Lynch Syndrome.
It is recommended to screen for Lynch syndrome in all patients with colon or rectal cancer with immunohistochemical or microsatellite instability testing of tumour sample. An abnormal result is not always due to Lynch syndrome, but helps in identifying the right persons for genetic counselling and diagnostic genetic testing.
Also hereditary polyposes are associated with increased risk of bowel cancer. The most common of these is familial adenomatous polyposis (FAP) and more rare ones include, for example, MUTYH polyposis, juvenile polyposis and Peutz-Jeghers syndrome.
Defects of some other genes, such as POLE and POLD1 also seem to be associated with increased risk of bowel cancer. A significant share of familial aggregation of bowel cancer is explained by multifactorial susceptibility.
If no tests have been done before, the possibility of hereditary susceptibility should be suspected at least in the following cases:
bowel cancer diagnosed before the age of 50 years
bowel cancer or cancer of the uterine corpus in three or more near relatives or several such cancers in a single relative
diagnosed polyposis.
Susceptibility to endocrine cancer
The MEN1 (multiple endocrine neoplasia type 1) syndrome should be suspected in any person with either two or more expressed diseases compatible with the syndrome or just one such disease and a relative diagnosed with MEN1.
Hyperparathyroidism and hypercalcaemia
Pituitary adenoma
Neuroendocrine tumour of the pancreas, stomach or small intestine
The disease may be associated with adrenal tumours, lipomas, angiofibromas or collagenomas.
MEN2 syndrome due to a RET gene defect should be suspected in any patient with medullary thyroid cancer. In some patients, the syndrome may involve phaeochromocytoma and hyperparathyroidism.
The possibility of hereditary susceptibility should be assessed in any patient with phaeochromocytoma or paraganglioma. There may be an underlying syndrome:
Hereditary susceptibility is involved in only a small percentage of cases. This is mainly due to cancer susceptibility syndromes involving other risk of disease and the risk of a specific histological type of renal cancer.
Hereditary susceptibility may be suggested by
young age at developing the cancer
bilateral or multifocal renal cancer
clear cell renal cancer in two family members that are first-degree relatives to each other
papillary type 1 histology
other findings suggestive of a cancer susceptibility syndrome, such as
retinal or CNS haemangioblastomas in von Hippel-Linday syndrome
renal and pancreatic cysts in von Hippel-Linday syndrome
phaeochromocytoma or neuroendocrine pancreatic tumour in patients with von Hippel-Lindau syndrome
cutaneous leiomyomas in patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome
pulmonary cysts and spontaneous pneumothorax or cutaneous fibrofolliculomas or other benign skin lesions in patients with Birt-Hogg-Dube syndrome
cancer history suggestive of Lynch syndrome in the immediate family.
Pancreatic cancer
Certain cancer susceptibility syndromes, such as the melanoma-pancreatic cancer syndrome due to a CDKN2A gene defect, susceptibility to breast cancer and ovarian cancer due to a BRCA2 gene defect, or Lynch or Peutz-Jeghers syndrome may involve a risk of pancreatic cancer. Occurrence of cancers within the spectrum of such cancer susceptibility syndromes in the immediate family of a patient with pancreatic cancer may suggest hereditary susceptibility.
If two or more family members who are first-degree relatives to each other are diagnosed with pancreatic adenocarcinoma, there may be hereditary susceptibility to pancreatic cancer.
The genes involved are, however, poorly known, and some cases may be explained by multifactorial susceptibility or by coincidence.
Also, there is little evidence of any usefulness of MRI or endoscopic ultrasound surveillance of healthy relatives or carriers of susceptibility gene defects.
Gastric cancer
Diffuse gastric cancer before the age of 50 years, or even at a later age in any patient whose near relative has had gastric cancer or lobular breast cancer, may suggest hereditary diffuse gastric cancer (HDGC) syndrome due to a CDH1 gene defect.
Intestinal gastric cancer often involves other than hereditary risk factors, such as a Helicobacter infection. An increased risk of disease may be associated with Lynch syndrome. The background of increased family incidence of pure intestinal gastric cancer is unknown.
Increased family incidence of prostatic cancer
Single susceptibility gene defects are poorly known, and in most cases an increased family incidence appears to be explained by multifactorial susceptibility.
BRCA2 and possibly also BRCA1 gene defects may involve an increased risk of metastasizing prostatic cancer. At least men with prostatic cancer who have near relatives with breast and/or ovarian cancer suggesting BRCA1/2 gene defects should be referred for assessment by a clinical geneticist.
Other cancer susceptibility syndromes
Some rare cancer susceptibility syndromes are associated with an increased risk of several cancer types. Multidisciplinary surveillance is planned within a clinical genetics unit in cooperation with specialties performing the surveillance.
The cancer susceptibility syndrome caused by the TP53 gene defect (Li-Fraumeni syndrome), for example, is associated with increased risk of many cancer types (breast cancer at young age in women, soft tissue sarcoma and osteosarcoma, adrenal cortex tumour, brain tumour; to a lesser extent many other cancer types, leukaemia, melanoma and bowel cancer, for example)
Risk of cancer may be increased and surveillance beneficial already in childhood age.
Regular imaging and clinical surveillance may be carried out in carriers of the gene defect; there is preliminary evidence of its benefits.
To the extent possible, x-ray examinations causing radiation exposure should be avoided, and the same applies to smoking and UV radiation exposure.
Some hereditary diseases are, in addition to other morbidity, also associated with increased risk of cancer.
Neurofibromatosis 1 (NF1), for example, involves an increased risk of cancer (e.g. optic glioma of childhood, brain tumours, breast cancer at the age below 50 and malignant peripheral nerve sheath tumor MPNST).
If new symptoms or changes appear, the possibility of cancer should be kept in mind and the patient referred for further investigations.
Breast MRI surveillance is recommended in women at the age of 30-50 years. If a woman who has NF1 syndrome is not within such surveillance, specialized care should be consulted.
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