This document discusses familial associations with cancer risk and the possibility of genetic linkages. It notes that some cancers cluster in families due to genetic, epigenetic, or shared environmental factors. Large studies are needed to identify and characterize familial components. Some examples of familial associations provided include an increased risk of breast cancer for women with BRCA gene mutations and elevated cancer risks seen in Nordic studies of relatives of those diagnosed with nervous system tumors. The challenges of intergenerational cancer registry studies are also outlined.

1. Familial associations and disease
risk.
Linkage possibilities
By
Steinar Tretli, PhD, Professor
The Cancer Registry of Norway

2. Cancer are closely connected to both genetic
conditions and environmental exposures.

3. • We observed for several types of cancer a familial
association /clustering.
• This may be caused by genetic, epigenetic or
environmental (incl lifestyle) effects.
• Relatives to a cancer case are usually concerned about
their own/family cancer risk.

4. Familial associations?
• For several familial associations, we know the genetic
condition behind.
This is the case for breast cancer among women with a
AT-mutation («Ataxia telengiasia»)
or
• elevated risk of breast cancer risk in carriers of BRCA1
mutation (indirectly detected by breast cancer in early
age)
• We usually need large studies to locate and characterize
the familiar component

5. • Familial associations in disease incidence may
give important indications of the cause of the
disease.
• Familial associations are relevant in the
discussion of genetic effects and may be a basis
for genetic councelling.
• Familial associations may be relevant in the
discussion of environmental effects and a basis
for envirionmental intervention.

6. Environmental and heritable causes of cancer among 9.6 million individuals in
the Swedish family‐cancer database.
International Journal of Cancer
Volume 99, Issue 2, pages 260-266, 8 MAR 2002 DOI: 10.1002/ijc.10332
http://onlinelibrary.wiley.com/doi/10.1002/ijc.10332/full#fig1
Familiality = genetic factors + shared environmental factors
+ childhood shared environmental factors

7. Environmental and heritable causes of cancer among 9.6 million individuals in
the Swedish family‐cancer database.
International Journal of Cancer
Volume 99, Issue 2, pages 260-266, 8 MAR 2002 DOI: 10.1002/ijc.10332
http://onlinelibrary.wiley.com/doi/10.1002/ijc.10332/full#fig1
Familiality = genetic factors + shared environmental factors + childhood
environmental factors

8. Environmental and heritable causes of cancer among 9.6 million individuals in
the Swedish family‐cancer database.
International Journal of Cancer
Volume 99, Issue 2, pages 260-266, 8 MAR 2002 DOI: 10.1002/ijc.10332
http://onlinelibrary.wiley.com/doi/10.1002/ijc.10332/full#fig1
Familiality = genetic factors + shared environmental factors + childhood
environmental factors

9. Int J Cancer 99,260-266 (2002)
Relation n, both Correlation (95% CI) n, both Correlation (95% CI) n, both Correlation (95% CI)
affected affected affected
Stomach Colon Rectum
Mother-father 203 0.15 (0.13–0.17) 422 0.12 (0.11–0.14) 122 0.09 (0.07–0.11)
Daughter-daughter 1 0.29 (0.21–0.45) 4 0.22 (0.14–0.31) 0
Son-son 4 0.41 (0.37–0.52) 5 0.28 (0.16–0.39) 2 0.30 (0.09–0.43)
Daughter-son 0 9 0.25 (0.18–0.33) 1 0.17 (0.07–0.29)
Mother-daughter 5 0.12 (0.04–0.15) 73 0.20 (0.19–0.23) 12 0.15 (0.10–0.21)
Mother-son 7 0.14 (0.04–0.21) 60 0.20 (0.17–0.24) 15 0.17 (0.11–0.22)
Father-daughter 13 0.16 (0.09–0.21) 58 0.17 (0.13–0.20) 20 0.17 (0.12–0.22)
Father-son 16 0.16 (0.10–0.22) 50 0.17 (0.13–0.21) 14 0.12 (0.06–0.18)
Half sibs 0 2 0.18 (0.11–0.31) 0
Adoptives 0 3 0.09 (-0.05–0.21) 0
Kamila CZENE, Paul LICHTENSTEIN and Kari HEMMINKI:
ENVIRONMENTAL AND HERITABLE CAUSES OF CANCER AMONG 9.6 MILLION INDIVIDUALS IN THE SWEDISH
FAMILY-CANCER DATABASE

10. This means that we need large populations to
locate and caracterize the effect.

11. Example
Nordic study of nervous system tumours (CNS).
Among 63307 CNS cases 32 347 belonged to the offspring generation
Brain (Concordant family history):
SIR= 1.7 (1.5,1.8) in offspring of affected patients (n=353)
SIR= 2.0 (1.7,2.3) in siblings (n=201)
SIR= 9.4 (5.5,15.1) parent and sibling affected (n= 17)
Spine (Concordant family history):
SIR= 4.4 (1.1,11.3) in offspring of affected patients (n=4)
SIR= 7.1 (1.8,18.4) in siblings (n=4)
Peripheral nerves (Concordant family history):
SIR= 16.3 (9.3,26.6) in offspring of affected patients (n=16)
SIR= 27.7 (16.1,44.4) in siblings (n= 17)
SIR= 943.9 ( 245.5, 2440.6) parent and sibling affected (n=4)

12. Challenges in cancer studies:
Old enough registries: Parents- children (most types of cancer
occur in old ages.)
Few offspring per family: Difficult to study genetic factors and
shared environmental factors

13. The personal identification nummer (PIN) given to all
Norwegian citizen ( and the same in the other nordic
countries), has made it possible to build up a generation
register. The PIN for every child is linked to the mother’s PIN
and also father’s PIN (Father defind by information from the
mother). Maternity and patternity histories are created by
Statistics Norway (SSB) from 1935 and onwards and the
registry is own by Skattedirektoratet. From 1967 the same
information can be find in the Norwegian birth registry.

14. Several outcome registries in Norway may be linked to
the Norwegian population registry
(own by Skattedirektoratet):
• The Cancer Registry (1953-)
• The Medical Birth Registry (1967-)
• The Patient Registry (2008-)
• The Description Registry ( 2004-)
• The Cause of Death Registry (1951-)

15. Affected family
member(s)
Number of families
• No affected family
members
• Father only
First son only
• Second son only
Third son only
• Fourt son only
• Fifth son only
• Father & first son
• Father & sec. sons
• Father & First &
second sons
• First & second sons
• First & third sons
• First & fourth sons
• First & fifth sons
• Second & third sons
• Second & fourth sons
• Second & fifth sons
• Affected
family members
1,127,796
2,268
3,487
1,272
328
65
18
19
10
2
33
7
1
1
4
3
1
7,524
Familial testicular germ-cell tumors in Norway
The Relative risk given:
• affected father 4.03 (95% CI: 3.12, 5.19)
• One affected brother 5.88 (95% CI: 4.70,7,36)
• Two affected brothers 21.71 (95% CI: 8.93, 52.76)
Example 2. (Valberg et al, Am J Epidemiol, 2014)

16. Example 3
Association study on birth defects and
cancer incidence.
Result: Birth defects are associated to
increased cancer risk.
The cancer risk is not elevated in
sisters, brothers or parents of children
with birth defects. (Show table)

17. Thank you for your attention!
Steinar.Tretli@kreftregisteret.no