| 1. |
- Hemminki, Kari, et al.
(author)
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Are population level familial risks and germline genetics meeting each other?
- 2023
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In: Hereditary Cancer in Clinical Practice. - : Springer Science and Business Media LLC. - 1731-2302 .- 1897-4287. ; 21:1
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Research review (peer-reviewed)abstract
- Large amounts of germline sequencing data have recently become available and we sought to compare these results with population-based family history data. Family studies are able to describe aggregation of any defined cancers in families. The Swedish Family-Cancer Database is the largest of its kind in the world, covering the Swedish families through nearly a century with all cancers in family members since the start of national cancer registration in 1958. The database allows estimation of familial risks, ages of cancer onset and the proportion of familial cancer in different family constellations. Here, we review the proportion of familial cancer for all common cancers and specify them based on the number of affected individuals. With the exception of a few cancers, age of onset of familial cancer is not different from all cancers combined. The highest proportions of familial cancer were found for prostate (26.4%), breast (17.5%) and colorectal (15.7%) cancers, but the proportions of high-risk families with multiple affected individuals were only 2.8%, 1% and 0.9%, respectively. A large sequencing study on female breast cancer found that BRCA1 and BRCA2 mutations could account for 2% of the cases (subtracting the proportions in healthy individuals) and that all germline mutations accounted for 5.6% of the cases. Early age of onset was a distinct feature of only BRCA mutations. In heritable colorectal cancer, Lynch syndrome genes dominate. Large studies on penetrance in Lynch syndrome have shown an approximately linear increase in risk from 40–50 years up to age 80 years. Interesting novel data revealed a strong modification of familial risk by unknown factors. High-risk germline genetics of prostate cancer is characterized by BRCA and other DNA repair genes. HOXB13 encodes a transcription factor which contributes to germline risk of prostate cancer. A strong interaction was shown with a polymorphism in the CIP2A gene. The emerging germline landscape of common cancers can be reasonably accommodated by family data on these cancers as to high-risk proportions and age of onset.
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| 2. |
- Hemminki, Kari, et al.
(author)
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Autoimmune diseases as comorbidities for liver, gallbladder, and biliary duct cancers in Sweden
- 2023
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In: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 129:8, s. 1227-1236
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Journal article (peer-reviewed)abstract
- Background: Autoimmune diseases are associated with many cancers but there is a lack of population-based studies with different autoimmune diseases that have a long follow-up. This is also true of hepatobiliary cancers, which include hepatocellular cancer (HCC) and rarer entities of gallbladder cancer (GBC), intra- and extrahepatic cholangiocarcinoma (iCCA and eCCA), and ampullary cancer. Methods: Diagnostic data on 43 autoimmune diseases were collected from the Swedish Inpatient Register from 1987 to 2018, and cancer data were derived from the national cancer registry from 1997 onward. Relative risks were expressed as standardized incidence ratios (SIRs). Results: In a population of 13.6 million, 1.1 million autoimmune diseases were diagnosed and subsequent hepatobiliary cancer was diagnosed in 3191 patients (17.2% of cancers). SIRs for HCC were 2.73 (men) and 2.86 (women), 3.74/1.96 for iCCA, 2.65/1.37 for GBC, 2.38/1.64 for eCCA, and 1.80/1.85 for ampullary cancer. Significant associations between autoimmune disease and HCC were observed for 13 autoimmune diseases, with the highest risks being for autoimmune hepatitis (48.92/73.53, men/women) and primary biliary cirrhosis (38.03/54.48). GBC was increased after six autoimmune diseases, with high SIRs for ulcerative colitis (12.22/3.24) and men with Crohn disease (9.16). These autoimmune diseases were also associated with a high risk of iCCA, which had seven other associations, and eCCA, which had five other associations. Ampullary cancer occurrence was increased after four autoimmune diseases. Conclusion: An autoimmune disease is a common precursor condition for hepatobiliary cancers. This calls for careful control of autoimmune disease symptoms in each patient and encouragement to practice a healthy lifestyle.
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| 3. |
- Hemminki, Kari, et al.
(author)
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Cancer of unknown primary is associated with diabetes.
- 2016
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In: European Journal of Cancer Prevention. - 1473-5709. ; 25:3, s. 246-251
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Journal article (peer-reviewed)abstract
- The incidences of both type 1 diabetes (T1D) and T2D are increasing worldwide. T2D is associated with many cancers. However, no data are available on cancer of unknown primary (CUP), a relatively common, fatal cancer for which tobacco smoking is the only known risk factor. At diagnosis, CUP metastases are found in various organs, which has implications for prognosis. We carried out a nationwide study on the association of CUP with T1D and T2D. 32 600 T1D patients and 178 000 T2D patients were identified from the national healthcare registers and these were linked to the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for CUP from 1997 through 2010 using anyone without diabetes as a reference. The SIR of CUP in 421 diabetic patients was 1.71, highest for CUP with liver (2.17) and respiratory system (1.95) metastases. The SIR was 2.91 for T1D, but with a small number of patients, 1.38 for T2D with insulin treatment, and 1.78 for the main group of T2D. CUP with liver and respiratory system metastases increased for each diabetic type; however, for T2D, CUP with gastrointestinal and bone metastases also increased. The results provide the first demonstration that CUP is one of the cancers associated with diabetes, with definite evidence on T2D. CUP has a poor prognosis, which may be even worse when diabetes is the underlying comorbidity. A mechanistic question for future work is to determine whether diabetes promotes primaries that escape detection or their metastatic spread.
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| 4. |
- Hemminki, Kari, et al.
(author)
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Cancer risk in amyloidosis patients in Sweden with novel findings on non-Hodgkin lymphoma and skin cancer
- 2014
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In: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 25:2, s. 511-518
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Journal article (peer-reviewed)abstract
- Background: Systemic amyloidosis (SSA) is a common form of amyloidosis but it remains often unnoticed because of the slow progression in old patients. The cause for SSA is the accumulation of wild-type transthyretin amyloids in critical tissues. We provide here data showing that SSA may be associated with old-age non-Hodgkin lymphoma.Systemic amyloidoses include immunoglobulin light chain (AL) amyloidosis, serum amyloid (AA)-related amyloidosis and senile systemic amyloidosis (SSA). AL amyloidosis is associated with myeloma, and we showed recently that transthyretin-related hereditary amyloidosis was related to non-Hodgkin lymphoma (NHL). In SSA, amyloids constitute wild-type transthyretin. We wanted to analyze cancer risks in amyloidosis, particularly in SSA. Nonhereditary amyloidosis patients were identified from the Swedish Hospital Discharge and Outpatients Registers from years 1997 through 2010. Their cancer risk was assessed based on the Swedish Cancer Registry using standardized incidence ratio (SIR) between amyloidosis patients and the remaining population. To gain information about amyloidosis subtypes, we used the Swedish Prescribed Drug Register from years 2005 through 2010 to find out the specific medication prescribed. Among 1400 identified amyloidosis patients, cancer risk was increased for myeloma, NHL and squamous cell skin cancer. Myeloma and skin cancers were diagnosed 7-8 years earlier than in the population, whereas NHL was diagnosed in elderly patients. The SIR was 204 for myeloma in patients who received AL amyloidosis medication, and it was 17.22 in patients receiving rheumatoid arthritis medication, suggesting AA amyloidosis. In remaining patients, including SSA, NHL risk was 14.78, including lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia (51.41) and diffuse large B-cell lymphoma (18.69). In these patients, endometrial cancer (7.04) and cancer of unknown primary site (6.56) were also increased. SSA is likely to be a main cause of NHL in the elderly population. The present findings suggest a novel mechanism for amyloidosis-related cancer, highlighting the role of chronic stimulation by amyloid.
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| 5. |
- Hemminki, Kari, et al.
(author)
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Familial risks and proportions describing population landscape of familial cancer
- 2021
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In: Cancers. - : MDPI AG. - 2072-6694. ; 13:17
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Journal article (peer-reviewed)abstract
- Background: Familial cancer can be defined through the occurrence of the same cancer in two or more family members. We describe a nationwide landscape of familial cancer, including its frequency and the risk that it conveys, by using the largest family database in the world with complete family structures and medically confirmed cancers. Patients/methods: We employed standardized incidence ratios (SIRs) to estimate familial risks for concordant cancer among first-degree relatives using the Swedish Cancer Registry from years 1958 through 2016. Results: Cancer risks in a 20–84 year old population conferred by affected parents or siblings were about two-fold compared to the risk for individuals with unaffected relatives. For small intestinal, testicular, thyroid and bone cancers and Hodgkin disease, risks were higher, five-to-eight-fold. Novel familial associations included adult bone, lip, pharyngeal, and connective tissue cancers. Familial cancers were found in 13.2% of families with cancer; for prostate cancer, the proportion was 26.4%. High-risk families accounted for 6.6% of all cancer families. Discussion/Conclusion: High-risk family history should be exceedingly considered for management, including targeted genetic testing. For the major proportion of familial clustering, where genetic testing may not be feasible, medical and behavioral intervention should be indicated for the patient and their family members, including screening recommendations and avoidance of carcinogenic exposure.
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| 6. |
- Hemminki, Kari, et al.
(author)
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Familial Risks between Urolithiasis and Cancer
- 2018
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Journal article (peer-reviewed)abstract
- © 2018 The Author(s). Urolithiasis (UL, urinary tract stone disease) has been reported to increase subsequent cancers in the urinary tract. Recently, we showed data that surveillance bias may be an important confounder in the reported associations. In the present approach we want to address the question of possible cancer risk posed by UL mechanistically. Both UL and cancer have strong genetic components and we hypothesize that familial association between UL and cancer may be plausible. We thus assess familial risks between UL and cancer, hoping to find an explanation why UL may pose a risk of cancer. UL patients were identified from hospital inpatient and outpatient records and they were organized in families based on the Multigeneration Register into which also national cancer data were linked. Standardized incidence ratios were calculated for cancer in the offspring generation when parents were diagnosed with UL, and conversely for UL when parents were diagnosed with cancer. Familial risks between UL and cancer were generally small and inconsistent providing no convincing support of genetic sharing between UL and cancer. However, bladder UL was associated weakly with prostate cancer, and ureter and bladder UL were associated with salivary gland cancer. Potential mechanisms for these findings are proposed.
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| 7. |
- Hemminki, Kari, et al.
(author)
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Familial risks for gallstones in the population of Sweden
- 2017
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In: BMJ open gastroenterology. - : BMJ. - 2054-4774. ; 4:1
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Journal article (peer-reviewed)abstract
- Objectives: Gallstone disease (cholelithiasis) has a familial component, but detailed data on the modification of familial risk are lacking. Using nationwide hospital and population records, we aimed to determine detailed familial risks for medically diagnosed gallstone disease.Design: Subjects were obtained from the Multigeneration Register, which contains family data on the Swedish population, and patients with gallstone disease were identified from the Hospital Discharge Register (1964-2015) and the Outpatient Register (2001-2015). Standardised incidence ratios (SIRs) were calculated as the ratio of observed to expected number of cases.Results: Gallstone disease was diagnosed in 660 732 patients, with an overall incidence of 131 per 100 000 person-years. Familial cases accounted for 36.0% of all patients with gallstone disease. Of these, 50.9% had a parental family history (SIR 1.62), 35.1% had a sibling history (SIR 1.75) and 14.0% had a parental+sibling history (SIR 2.58). Among a total of 54 630 affected siblings, 84.4% were sibling pairs (SIR 1.55). However, the remaining 15.6% of the affected siblings constituted the high-risk group of multiple affected siblings and an SIR >10; these persons accounted for 7.7% of all familial cases. The spousal risk was only slightly increased to 1.18.Conclusions: Overall, the results point to the underlying genetic causes for the observed familial clustering, which may involve polygenic gene-environmental interactions for most familial cases but high-risk genes in close to 10% of cases. Family histories should be taken into account in the medical setting and used for counselling of at-risk individuals.
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| 8. |
- Hemminki, Kari, et al.
(author)
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Familial Risks for Liver, Gallbladder and Bile Duct Cancers and for Their Risk Factors in Sweden, a Low-Incidence Country
- 2022
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In: Cancers. - : MDPI AG. - 2072-6694. ; 14:8
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Journal article (peer-reviewed)abstract
- We used the Swedish Cancer Registry data to address familial risks for concordant (same) and discordant (different) hepatobiliary cancers, including their associations with any other cancers and with known risk factors. Risks were also assessed between spouses. The analysis covered Swedish families and their cancers between years 1958 and 2018. Adjusted familial risks were expressed as standardized incidence ratios (SIRs). Familial SIRs for concordant hepatocellular carcinoma (HCC) were 2.60, and for gallbladder cancer they were at the same level (2.76). Familial risk was also found for intrahepatic bile duct cancer and for female extrahepatic bile duct cancer. HCC was associated with lung and cervical cancers; extrahepatic bile duct and ampullary cancers were associated with colon and pancreatic cancers, suggesting Lynch syndrome. Among spouses, hepatobiliary cancer was associated with HCC, stomach, pancreatic, cervical and upper aerodigestive tract cancers. Among risk factors, family members diagnosed with alcohol-related disease showed association with HCC. The observed familial risks for hepatobiliary cancers were relatively high, and considering the poor prognosis of these cancers, prevention is of the utmost importance and should focus on moderation of alcohol consumption, vaccination/treatment of hepatitis viral infections and avoidance of overweight and other risk factors of type 2 diabetes.
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| 9. |
- Hemminki, Kari, et al.
(author)
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Familial risks in and between stone diseases : Sialolithiasis, urolithiasis and cholelithiasis in the population of Sweden
- 2018
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In: BMC Nephrology. - : Springer Science and Business Media LLC. - 1471-2369. ; 19:1
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Journal article (peer-reviewed)abstract
- Background: According to the literature the three stone diseases, sialolithiasis (SL), urolithiasis (UL) and cholelithiasis (CL) share comorbidities. We assess familial and spouse risks between these stone disease and compare them to familial risks for concordant (same) stone disease. Methods: Study population including familiar relationships was obtained from the Swedish Multigeneration Register and stone disease patients were identified from nation-wide medical records. Standardized incidence ratios (SIRs) were calculated for 0-83 year old offspring when their first-degree relatives were diagnosed with stone disease and the rates were compared to individuals without a family history of stone disease. Numbers of offspring with SL were 7906, for UL they were 170,757 and for CL they were 204,369. Results: SIRs for concordant familial risks were 2.06 for SL, 1.94 for UL and 1.82 for CL. SIRs for SL and UL were slightly higher for women than for men. Familial risks between stone diseases were modest. The highest risk of 1.17 was for UL when family members were diagnosed with CL, or vice versa. The SIR for UL was 1.15 when family members were diagnosed with SL. Familial risks among spouses were increased only for UL-CL pairs (1.10). Conclusions: Familial risks for concordant SL were 2.06 and marginally lower for the other diseases. Familial risks between stone diseases were low but higher than risks between spouses. The data show that familial clustering is unique to each individual stone disease which would imply distinct disease mechanisms. The results cast doubt on the reported comorbidities between these diseases.
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| 10. |
- Hemminki, Kari, et al.
(author)
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Familial risks in urolithiasis in the population of Sweden
- 2018
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In: BJU International. - : Wiley. - 1464-4096. ; 121:3, s. 479-485
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Journal article (peer-reviewed)abstract
- Objective: To assess detailed familial risks for medically diagnosed urolithiasis (UL, urinary tract stone disease) based on nationwide hospital and population records. Patients/Subjects and Methods: Subjects were identified from the Swedish Multigeneration Register in which there were 211 718 patients with UL. Standardised incidence ratios (SIRs) were calculated by comparison to individuals without a family history of UL. Results: The highest familial SIRs were invariably found for the same (concordant) type of UL: 2.18 for kidney, 2.20 for ureter, and 1.93 for bladder. SIRs increased from 1.84, when one parent was affected, to 3.54 when both parents were affected, which was a multiplicative interaction. The SIR was 1.79 when one sibling was affected but it increased to 24.91 when two siblings were affected. Such excessive risks (5.2% of familial cases) are probably explained by high-penetrant genes. A low SIR of 1.29 between spouses suggested a minor contribution by shared environmental factors on the familial risk. Conclusions: The results point to underlying genetic causes for the observed familial clustering and establish the genetic landscape of UL. Family histories should be taken in UL diagnostics and prevention could follow guidelines recommended for recurrent UL.
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