Research

14 pages, 711 KiB

Open AccessArticle

Familial Risks for Liver, Gallbladder and Bile Duct Cancers and for Their Risk Factors in Sweden, a Low-Incidence Country

by Kari Hemminki, Kristina Sundquist, Jan Sundquist, Asta Försti, Vaclav Liska, Akseli Hemminki and Xinjun Li

Cancers 2022, 14(8), 1938; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081938 - 12 Apr 2022

Cited by 5 | Viewed by 1820

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Familial Cancer and Germline Genetics)

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17 pages, 2984 KiB

Open AccessArticle

Germline Variants of CYBA and TRPM4 Predispose to Familial Colorectal Cancer

by Lizhen Zhu, Beiping Miao, Dagmara Dymerska, Magdalena Kuswik, Elena Bueno-Martínez, Lara Sanoguera-Miralles, Eladio A. Velasco, Nagarajan Paramasivam, Matthias Schlesner, Abhishek Kumar, Ying Yuan, Jan Lubinski, Obul Reddy Bandapalli, Kari Hemminki and Asta Försti

Cancers 2022, 14(3), 670; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030670 - 28 Jan 2022

Cited by 10 | Viewed by 3117

Abstract

Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole-genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally characterized them. We identified [...] Read more.

Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole-genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally characterized them. We identified a frameshift variant in the CYBA gene (c.246delC) in one family and a splice site variant in the TRPM4 gene (c.25–1 G > T) in another family. While both variants were absent or extremely rare in gene variant databases, we identified four additional Polish familial CRC cases and two healthy elderly individuals with the CYBA variant (odds ratio 2.46, 95% confidence interval 0.48–12.69). Both variants led to a premature stop codon and to a truncated protein. Functional characterization of the variants showed that knockdown of CYBA or TRPM4 depressed generation of reactive oxygen species (ROS) in LS174T and HT-29 cell lines. Knockdown of TRPM4 resulted in decreased MUC2 protein production. CYBA encodes a component in the NADPH oxidase system which generates ROS and controls, e.g., bacterial colonization in the gut. Germline CYBA variants are associated with early onset inflammatory bowel disease, supported with experimental evidence on loss of intestinal mucus barrier function due to ROS deficiency. TRPM4 encodes a calcium-activated ion channel, which, in a human colonic cancer cell line, controls calcium-mediated secretion of MUC2, a major component of intestinal mucus barrier. We suggest that the gene defects in CYBA and TRPM4 mechanistically involve intestinal barrier integrity through ROS and mucus biology, which converges in chronic bowel inflammation. Full article

(This article belongs to the Special Issue Familial Cancer and Germline Genetics)

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13 pages, 949 KiB

Open AccessArticle

Do BARD1 Mutations Confer an Elevated Risk of Prostate Cancer?

by Klaudia Stempa, Dominika Wokołorczyk, Wojciech Kluźniak, Emilia Rogoża-Janiszewska, Karolina Malińska, Helena Rudnicka, Tomasz Huzarski, Jacek Gronwald, Katarzyna Gliniewicz, Tadeusz Dębniak, Anna Jakubowska, Marcin Lener, Joanna Tomiczek-Szwiec, Paweł Domagała, Malwina Suszynska, Piotr Kozlowski, Tomasz Kluz, Mariusz Naczk, Jan Lubiński, Steven A. Narod, Mohammad R. Akbari, Cezary Cybulski and on behalf of the Polish Hereditary Prostate Cancer Consortium Show full author list Hide full author list

Cancers 2021, 13(21), 5464; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215464 - 30 Oct 2021

Cited by 1 | Viewed by 2097

Abstract

The current cancer testing gene panels tend to be comprehensive rather than site-specific. BARD1 is one of the genes commonly included in the multi-cancer testing panels. Mutations in BARD1 confer an increase in the risk for breast cancer, but it is not studied [...] Read more.

The current cancer testing gene panels tend to be comprehensive rather than site-specific. BARD1 is one of the genes commonly included in the multi-cancer testing panels. Mutations in BARD1 confer an increase in the risk for breast cancer, but it is not studied whether or not they predispose to prostate cancer. To establish if BARD1 mutations also predispose to prostate cancer, we screened BARD1 in 390 Polish patients with hereditary prostate cancer. No truncating mutations were identified by sequencing. We also genotyped 5715 men with unselected prostate cancer, and 10,252 controls for three recurrent BARD1 variants, including p.Q564X, p.R658C and p.R659=. Neither variant conferred elevated risk of prostate cancer (ORs between 0.84 and 1.15, p-values between 0.57 and 0.93) nor did they influence prostate cancer characteristics or survival. We conclude that men with a BARD1 mutation are not at elevated prostate cancer risk. It is not justified to inform men about increased prostate cancer risk in case of identification of a BARD1 mutation. However, a female relative of a man with a BARD1 mutation may benefit from this information and be tested for the mutation, because BARD1 is a breast cancer susceptibility gene. Full article

(This article belongs to the Special Issue Familial Cancer and Germline Genetics)

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21 pages, 3313 KiB

Open AccessFeature PaperArticle

Familial Risks and Proportions Describing Population Landscape of Familial Cancer

by Kari Hemminki, Kristina Sundquist, Jan Sundquist, Asta Försti, Akseli Hemminki and Xinjun Li

Cancers 2021, 13(17), 4385; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174385 - 30 Aug 2021

Cited by 18 | Viewed by 2639

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Familial Cancer and Germline Genetics)

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12 pages, 613 KiB

Open AccessArticle

Family History of Head and Neck Cancers

by Xinjun Li, Anni I. Koskinen, Otto Hemminki, Asta Försti, Jan Sundquist, Kristina Sundquist and Kari Hemminki

Cancers 2021, 13(16), 4115; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164115 - 16 Aug 2021

Cited by 3 | Viewed by 2192

Abstract

Background: Head and neck cancers (HNCs) encompass a heterogeneous group of cancers between the mouth and larynx. Familial clustering in HNCs has been described, but how it influences individual sites and to which extent known risk factors, such as human papilloma virus (HPV) [...] Read more.

Background: Head and neck cancers (HNCs) encompass a heterogeneous group of cancers between the mouth and larynx. Familial clustering in HNCs has been described, but how it influences individual sites and to which extent known risk factors, such as human papilloma virus (HPV) infection, may contribute is not well established. Patients/methods: We employed standardized incidence ratios (SIRs) to estimate familial risks for HNC with same (concordant) and different (discordant) cancers among first-degree relatives using data from the Swedish Cancer Registry from 1958 to 2018. Results: Incidence for male and female oropharyngeal cancer increased close to four-fold in the past 39 years. Familial HNC was found in 3.4% of the study population, with an overall familial SIR of 1.78. Patients with concordant nasopharyngeal cancer showed a high risk of 23.97, followed by hypopharyngeal cancer (5.43). The husbands of wives with cervical cancer had an increased risk of oropharyngeal cancer. Discussion/Conclusion: Nasopharyngeal cancers lacked associations with lifestyle or HPV associated cancers, suggesting a role for germline genetics, which was also true for the high-risk families of three HNC patients. In the Swedish population with low smoking levels, HPV is becoming a dominant risk factor, emphasizing the need for sexual hygiene and HPV vaccination. Full article

(This article belongs to the Special Issue Familial Cancer and Germline Genetics)

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12 pages, 1172 KiB

Open AccessArticle

Familial Risk and Heritability of Hematologic Malignancies in the Nordic Twin Study of Cancer

by Signe B. Clemmensen, Jennifer R. Harris, Jonas Mengel-From, Wagner H. Bonat, Henrik Frederiksen, Jaakko Kaprio and Jacob v. B. Hjelmborg

Cancers 2021, 13(12), 3023; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13123023 - 16 Jun 2021

Cited by 3 | Viewed by 3338

Abstract

We aimed to explore the genetic and environmental contributions to variation in the risk of hematologic malignancies and characterize familial dependence within and across hematologic malignancies. The study base included 316,397 individual twins from the Nordic Twin Study of Cancer with a median [...] Read more.

We aimed to explore the genetic and environmental contributions to variation in the risk of hematologic malignancies and characterize familial dependence within and across hematologic malignancies. The study base included 316,397 individual twins from the Nordic Twin Study of Cancer with a median of 41 years of follow-up: 88,618 (28%) of the twins were monozygotic, and 3459 hematologic malignancies were reported. We estimated the cumulative incidence by age, familial risk, and genetic and environmental variance components of hematologic malignancies accounting for competing risk of death. The lifetime risk of any hematologic malignancy was 2.5% (95% CI 2.4–2.6%), as in the background population. This risk was elevated to 4.5% (95% CI 3.1–6.5%) conditional on hematologic malignancy in a dizygotic co-twin and was even greater at 7.6% (95% CI 4.8–11.8%) if a monozygotic co-twin had a hematologic malignancy. Heritability of the liability to develop any hematologic malignancy was 24% (95% CI 14–33%). This estimate decreased across age, from approximately 55% at age 40 to about 20–25% after age 55, when it seems to stabilize. In this largest ever studied twin cohort with the longest follow-up, we found evidence for familial risk of hematologic malignancies. The discovery of decreasing familial predisposition with increasing age underscores the importance of cancer surveillance in families with hematological malignancies. Full article

(This article belongs to the Special Issue Familial Cancer and Germline Genetics)

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12 pages, 814 KiB

Open AccessArticle

Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

by Sally Yepes, Nirav N. Shah, Jiwei Bai, Hela Koka, Chuzhong Li, Songbai Gui, Mary Lou McMaster, Yanzi Xiao, Kristine Jones, Mingyi Wang, Aurelie Vogt, Bin Zhu, Bin Zhu, Amy Hutchinson, Meredith Yeager, Belynda Hicks, Brian Carter, Neal D. Freedman, Laura Beane-Freeman, Stephen J. Chanock, Yazhuo Zhang, Dilys M. Parry, Xiaohong R. Yang and Alisa M. Goldstein Show full author list Hide full author list

Cancers 2021, 13(11), 2704; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112704 - 30 May 2021

Cited by 8 | Viewed by 2952

Abstract

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, [...] Read more.

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies. Full article

(This article belongs to the Special Issue Familial Cancer and Germline Genetics)

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11 pages, 1663 KiB

Open AccessArticle

A Rare Variant in ERF (rs144812092) Predisposes to Prostate and Bladder Cancers in an Extended Pedigree

by Lisa Anne Cannon-Albright, Craig Carl Teerlink, Jeff Stevens, Franklin W. Huang, Csilla Sipeky, Johanna Schleutker, Rolando Hernandez, Julio Facelli, Neeraj Agarwal and Donald L. Trump

Cancers 2021, 13(10), 2399; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102399 - 15 May 2021

Cited by 4 | Viewed by 1815

Abstract

Pairs of related bladder cancer cases who belong to pedigrees with an excess of bladder cancer were sequenced to identify rare, shared variants as candidate predisposition variants. Candidate variants were tested for association with bladder cancer risk. A validated variant was assayed for [...] Read more.

Pairs of related bladder cancer cases who belong to pedigrees with an excess of bladder cancer were sequenced to identify rare, shared variants as candidate predisposition variants. Candidate variants were tested for association with bladder cancer risk. A validated variant was assayed for segregation to other related cancer cases, and the predicted protein structure of this variant was analyzed. This study of affected bladder cancer relative pairs from high-risk pedigrees identified 152 bladder cancer predisposition candidate variants. One variant in ERF (ETS Repressing Factor) was significantly associated with bladder cancer risk in an independent population, was observed to segregate with bladder and prostate cancer in relatives, and showed evidence for altering the function of the associated protein. This finding of a rare variant in ERF that is strongly associated with bladder and prostate cancer risk in an extended pedigree both validates ERF as a cancer predisposition gene and shows the continuing value of analyzing affected members of high-risk pedigrees to identify and validate rare cancer predisposition variants. Full article

(This article belongs to the Special Issue Familial Cancer and Germline Genetics)

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