Cancer in the familyA cancer cell or tumor is not inherited, but the susceptibility of developing cancer can be inherited. It is estimated that only about five percent of cancers are associated with inherited genetic predisposition. Key points Cancer found in a parent doubles the risk of a child developing the same type of cancer, but there are big differences between the various types of cancers. Both environmental and genetic factors affect the increased risk. The heritability of cancers is estimated to be about 30%. This means the proportion of variation in susceptibility that can be attributed to genetic factors based on the degree of kinship. Also the genetic contribution varies greatly according to the type of cancer. Several hereditary cancer subtypes are known, but they make up only a small proportion of all cancers. Many Finns have cancer patients in their family members, and this may raise concerns regarding their own or their other family members’ risk of developing cancer. Information about cancers in the family, as well as data regarding which age the cancer was diagnosed at, have been utilized in scientific studies. The aim is to estimate individual cancer risk on the basis of cancer cases amongst relatives. When assessing this information, it is important to know the age of the person with cancer at the moment the disease was diagnosed as well as the age at which healthy members of the family were last known to have been alive without cancer. Cancers develop when a change in genes or in their function occurs. These changes are rarely hereditary. Changes in the activity of genes can lead to the cell beginning to operate in an abnormal way. Abnormal operation may result in, among other things, uncontrolled cell division, so that the tissue mass increases. Such changes occur in cells throughout our lifetime, and they are called somatic changes. Sometimes changes occur in the germ cells, which can be inherited by the offspring. Such events are called hereditary cancer or hereditary susceptibility to cancer. A tumor is not inherited, but the susceptibility of developing cancer can be inherited. Environmental and genetic factors can control changes in gene function, eventually leading to tumor. Since cancer is more likely to occur after middle age, this may cause people to believe that cancer occurs in their family more than usual. However, many cancers in the family do not necessarily indicate an inherited predisposition to cancer. It is estimated that only a small fraction, i.e., approximately 5% of all cancers are linked to a genetic predisposition. Familial aggregation of cancers means the excess aggregation of cancer in families more often than would be expected if the family members were independent of each other. The excess aggregation may be caused by an environmental or genetic-related factor that the family members have in common. The excess aggregation of cancers can be assessed by comparing the cancer risk in relatives to that of the entire population. This way, the excess risk of family members relative to target population average can be found out. Heritability is the proportion of the variation in the susceptibility to cancer, which correlates to the degree of kinship of family members divided by total variation in cancer susceptibility. This summary measure is sensitive to various environmental factors, and therefore it is difficult to generalize. According to a recent longitudinal study on twins, heritability is largest in aggregation, prostate cancer, melanoma, breast cancer and ovarian and uterine cancers.  Figure 1: Overall life time risk for most common cancers and life time risk when family member has been diagnosed with cancer. Breast cancer heritability A woman’s risk of being diagnosed with breast cancer during her life is approximately 12.5% (Figure 1). If she has one sibling with a history of breast cancer, the risk increases approximately to 20%. The risk becomes higher the more relatives she has with cancer. [2, 3] It must be remembered, however, that only about one out of ten women with breast cancer have a parent or sibling who also has breast cancer. Whereas 90% of breast cancer patients are not in this situation. It is estimated that genetics explain about 30% of the variation in susceptibility in breast cancer and the remaining 70% is explained by factors related to the environment (Figure 2).  In breast cancer, genetic studies have identified genes in chromosome 17 (BRCA1 and BRCA2), which increases the risk of breast cancer, particularly in young women who carry this gene variant. However, this variant appears to be rare (1.8%) in breast cancer patients , so it only explains a small part of all breast cancers. Its impact on the general population is therefore very low. If a genetic defect can be found in the BRCA1 or BRCA2 genes of a woman, she has a 60-80% risk of developing breast cancer during her lifetime.  Figure 2: Proportions of genetic and environmental factors in variation of cancer incidence for most common cancers. In recent years, a total of over one hundred gene or gene regions possibly related to breast cancer has been found, but these gene candidates explain only up to half of genetic susceptibility in breast cancer. A substantial proportion of the genetic variation is therefore still unknown or associated with the cooperative action of environmental and genetic causes. Genetic studies of breast cancer are oriented towards the very rare, previously unknown genetic forms, which are hoped to explain at least part of the now unknown genetic variations in the risk of breast cancer.  Colorectal cancer heritability Hereditary forms of bowel cancer can be divided into two main types. The most common type of hereditary bowel cancer is Lynch syndrome (HNPCC, hereditary nonpolyposis colorectal cancer). It occurs in 0.1% of Finns, and its proportion of all bowel cancers is 2-5%. According to various estimates, 20-70% of people with this gene defect will develop bowel cancer during their lifetime. They often fall ill at a younger age than usual, on average, from 40 to 45 years of age. Finns have an approximately 10% risk of developing bowel cancer in their lifetime. The risk doubles if there is a sibling suffering from bowel cancer in the family. The genetic defect associated with Lynch syndrome increases the susceptibility of stomach, urinary tract, biliary tract, endometrial, or ovarian cancer. Colorectal cancer is the most common cancer in families with at least one HNPCC patient.  Familial adenomatous polyposis (FAP), is a predominantly hereditary polyposis syndrome caused by a mutation in the APC gene. About 1% of all bowel cancers are due to mutations in the APC gene. Plenty of adenomatous polyps, which later develop into cancers, are formed in the intestine of a young adult with the FAP syndrome. Removal of polyps before clinical diagnosis may be considered as a preventive measure. Combined with effective monitoring and treatment it significantly reduces the FAP patients’ risk of falling ill with and dying from bowel cancer.  Also, the risk of patients with ulcerative colitis developing intestinal cancer has increased, therefore they will be monitored through regular endoscopy. As a whole, about 29% of bowel cancer susceptibility variation can be explained by genetic factors (Figure 2). The importance of environmental factors is therefore significant (71%) also in bowel cancer.  Prostate cancer heritability The risk of a Finnish male getting prostate cancer during his lifetime is estimated at 15%. Prostate cancer found in the father or brother doubles or triples the risk. As much as 57% of variation in susceptibility in prostate cancer is estimated to be inherited.  This is also supported by findings showing that about 15-20% of prostate cancers occur in families. However, only about 2-5% of cancers are, most likely, related to inherited susceptibility, so the vast majority of familial aggregation in prostate cancers can thus probably be explained by common environmental factors.  At least three first-degree relatives or two under 55-year-old first-degree relatives with prostate cancer indicate strong inherited susceptibility of prostate cancer. Prostate cancer diagnosed at a young age thus indicates a stronger hereditary possibility.  So far, a number of genes and genetic mutations associated with inherited susceptibility for prostate cancer have been identified. Researches include the HPCX-region genes and the BRCA2 gene, which significantly increases the risk of breast cancer in women. According to one study, the BRCA2 gene mutation was linked to up to 5% of hereditary prostate cancers. The possible role of BRCA2 in familial prostate cancer is, however, still unclear. [9, 10] Lung cancer heritability Smoking is the most important risk factor in lung cancer associated with approximately 85-90% of lung cancers. The individual risk of lung cancer also increases if the family has history of other lung cancers. The risk of getting lung cancer is about 6% for Finnish men and 3% for women during their lifetime. The risk of getting lung cancer increases in men up to 15% if they have a sibling with the same cancer. The risk in women increases to 8%, accordingly. Lung cancer in a parent impacts the child’s or grandchild’s lung cancer risk less than a sibling with a lung cancer. Lung cancer diagnosed before the age of 50 suggests that the susceptibility of other members of the family developing lung cancer is higher than usual. In particular, a sibling having suffered from lung cancer at young age increases the risk of illness of a family member up to six-fold. It is estimated that about 7-8% of lung cancers are associated with inherited susceptibility. Hereditary susceptibility appears to be specifically connected to certain types of lung cancers, such as adenocarcinoma and large cell carcinoma.  According to a recent research, inheritance explains approximately 18% of lung cancer susceptibility variation.  Smoking, however, is clearly the most important risk factor for lung cancer. Individual cancer risk In the assessment of individual cancer risk, statistical models can be utilized to take into account the potential family burden and other well-known environmental and lifestyle-related risk factors of cancer. Risk assessment, constructed with the help of such models can be utilized when designing monitoring and the need for treatment. However, these models and the risk assessments created with them are not complete and valid in all situations. If the doctor feels that the individual’s concern about increased genetic risk of cancer is justified, the patient will be re-directed to a genetic counselling policlinic for further examinations and possible genetic testing. The amount of data which is measurable from the human genome is still growing rapidly, and the utilization of it in cancer treatments is increasing. It will be interesting to see to what extent this new information can also be utilized in the prevention of familial cancers. Literature Mucci LA, Hjelmborg JB, Harris JR et al. Familial risk and heritability of cancer among twins in Nordic countries. JAMA 2016; 315(1): 68–76. Moller S, Mucci LA, Harris JR et al. The heritability of breast cancer among women in the Nordic Twin Study of Cancer. Cancer Epidemiol Biomarkers Prev 2016; 25(1): 145–50. Bevier M, Sundquist K, Hemminki K. Risk of breast cancer in families of multiple affected women and men. Breast Cancer Res Treat 2012; 132(2): 723–8. Syrjäkoski K, Vahteristo P, Eerola H et al. Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients. J Natl Cancer Inst 2000; 92(18): 1529–31. Oivanen T, Holli K. Periytyvä rintasyöpäalttius – voidaanko riskiryhmien ennustetta parantaa? Suom Lääkäril 2005; 60: 2997–3001. Aarnio M, Sankila R, Pukkala E et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999; 81(2): 214–8. Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis 2009; 4(1): 22. Eturauhassyöpä. Current Care Guidleines. The Finnish Medical Society Duodecim and the Finnish Urologist Associations working group. Helsinki: The Finnish Medical Society Duodecim 2014 [updated 27.5.2014]. www.kaypahoito.fi Pakkanen S, Baffoe-Bonnie AB, Matikainen MP et al. Segregation analysis of 1,546 prostate cancer families in Finland shows recessive inheritance. Hum Genet 2007; 121(2): 257–67. Gayther SA, de Foy KA, Harrington P et al. The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res 2000; 60(16): 4513–8. Li X, Hemminki K. Inherited predisposition to early onset lung cancer according to histological type. Int J Cancer 2004; 112(3): 451–7.