Familial concordance in cancer survival: a Swedish population-based study

doi:10.1016/S1470-2045(07)70282-6

The Lancet Oncology

Volume 8, Issue 11, November 2007, Pages 1001-1006

https://doi.org/10.1016/S1470-2045(07)70282-6 Get rights and content

Summary

Background

Nowadays, the fact that cancers can aggregate in families is generally accepted. The aim of this study was to complete a comprehensive analysis of cancer-survival concordance in parents and their children diagnosed with the same cancer.

Methods

We used a population-based Swedish family database, that included about three million families and data for more than a million individuals with cancer. We analysed survival in children in relation to parental survival by use of the Kaplan-Meier method. We then modelled the risk in children in relation to parental survival by use of two multivariate proportional hazard (Cox) models adjusting for possible confounders of survival.

Findings

In our univariate Kaplan-Meier analysis, children with the same cancer as their parent and whose parent had died within 10 years of diagnosis showed significantly worse survival for breast (log rank p=0·01), colorectal (p=0·04), and prostate cancer (p=0·05) than those whose parents were alive at 10 years from diagnosis. By use of Cox modelling, we noted an increased hazard ratio for death from cancer in children with poor parental survival compared with those with good parental survival for colorectal cancer (hazard ratio [HR] 1·44 [95% CI 1·01–2·01]), lung cancer (1·39 [1·00–1·94]), breast cancer (1·75 [1·13–2·71]), ovarian cancer (2·23 [0·78–6·34]), and prostate cancer (2·07 [1·13–3·79]). All hazard-ratio estimates, except for ovarian cancer, were significant, with significant trends of increasing risk of death in children by degree of worsening survival outcome in parents defined in quartiles of survival (ie, good [best quartile], expected [middle two quartiles], or poor [worst quartile]).

Interpretation

Our findings suggest that cancer-specific survival in parents predicts survival from the same cancer in their children. Consequently, data on survival in a parent might have the potential to guide treatment decisions and genetic counselling. Finally, molecular studies to highlight the genetic determinants of cancer survival are now warranted.

Introduction

Cancer is the second largest cause of disease-related death in the developed world.¹ Lung cancer is the leading cause of cancer death, and in Sweden only one in ten patients with lung cancer survives 5 years after diagnosis.² Prostate cancer is the most common cancer in men, and three of four patients are alive at 5 years after diagnosis.² In breast cancer, 84% of women survive 5 years.² However, the prognosis for ovarian cancer is much worse than that for prostate cancer or breast cancer and ovarian cancer is associated with high mortality, with less than half of patients surviving 5 years after diagnosis.² In colorectal cancer, about six of ten patients survive 5 years.² Cancer survival is determined by many factors, which include the metastatic potential of tumours, treatment, early detection, and behavioural and sociodemographic characteristics.¹

The mechanism by which cells metastasise is surprisingly inefficient in view of the fact that millions of cancer cells try to colonise distant sites on a daily basis. The genetic background of a patient with cancer might be essential for the ability of the tumour to metastasise.3, 4, 5 Allelic variants might modify the likelihood of tumour metastasis occurring through vital secondary events, such as deletions, amplifications, and epigenetic modulations in the metastatic cascade. Furthermore, allelic variation might affect the immune response, because small variations in the ability of an individual to mount an effective cytolytic defence, together with the tumour cell's ability to downregulate specific antigens, might also be important in the metastatic cascade.⁶ Additionally, the response to treatment might be, at least partly, inherited.

Although family history is an established risk factor for incidence of all cancers,7, 8 much less is known about familial correlation in cancer survival. Therefore, we investigated whether survival among parent–child pairs was concordant, by use of a population-based Swedish family database.

Section snippets

Swedish population-based family data

In Sweden, all residents have a unique national registration number, which makes linkage of different records of personal information possible. Our study is based on a record linkage between several population-based registers: the Multi-Generation Register, the Swedish Cancer Register, the Cause of Death Register, and the Migration Register. Additional linkages were also made to the censuses of 1960, 1970, 1980, and 1990, which contain information on individual socioeconomic status. In total,

Results

We noted that less than 1% of data were missing for all the studied variables in the registers. The number of parent–child pairs diagnosed with colorectal, lung, breast, ovarian, and prostate cancer and the number of cancer-specific deaths are shown in table 1. Additionally, the values from the χ² test on the association between the number of parent deaths and the number of child deaths for each cancer site are shown. The number of events for ovarian cancer did not meet the required power on

Discussion

In this Swedish population-based study involving more than 11 million individuals, we have shown, by use of two statistical methods, that cancer-specific survival is concordant among family members for colorectal, lung, breast, and prostate cancer. In the univariate analysis, cancer-specific survival in children in relation to parental cancer-specific death or survival at 10 years after diagnosis was analysed. Children with a history of parental cancer-specific death within 10 years after

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Reply to Kari Hemminki, Jianguang Ji, and Jan Sundquist's Letter to the Editor re: Mark N. Brook, Holly Ní Raghallaigh, Koveela Govindasami, et al. Family History of Prostate Cancer and Survival Outcomes in the UK Genetic Prostate Cancer Study. Eur Urol 2023;83:257–66
2023, European Urology
Re: Mark N. Brook, Holly Ní Raghallaigh, Koveela Govindasami, et al. Family History of Prostate Cancer and Survival Outcomes in the UK Genetic Prostate Cancer Study. Eur Urol 2023;83:257–66
2023, European Urology
Prostate Cancer Predisposition
2021, Urologic Clinics of North America
Genetic Variant Associated With Survival of Patients With Stage II-III Colon Cancer
2020, Clinical Gastroenterology and Hepatology
Many genetic variants have been associated with colorectal cancer risk, although few have been associated with survival times of patients. Identification of genetic variants associated with survival times might improve our understanding of disease progression and aid in outcome prediction. We performed a genome-wide association study to identify variants associated with colon cancer survival time.
We performed a post hoc analysis of data from NCCTG N0147 (Alliance), a randomized phase 3 trial of patients with resected stage III colon cancer, and from NSABP C-08 (NRG), a phase 3 trial that compared therapy regimens for patients with resected stage II or III colon cancer. Genotype analyses were performed on DNA from blood samples from 4974 patients. We used Cox proportional hazards regression to evaluate the association of each single nucleotide polymorphism with times of overall survival and disease-free survival, adjusting for age at diagnosis, sex, treatment group, and principal components of genetic ancestry. We performed the analysis for studies N0147 and C-08 separately, and results were combined in a fixed-effects meta-analysis.
A locus on chromosome 7p15.2 was significantly associated with overall survival time (P ≤ 5x10^–08). The most significant variant at this locus, rs76766811 (P = 1.6x10^–08), is common among African Americans (minor allele frequency, approximately 18%) but rare in European Americans (minor allele frequency <0.1%). Within strata of self-reported ancestry, this variant was associated with times of overall survival and disease-free survival in only African Americans (hazard ratio for overall survival, 2.82; 95% CI, 1.88–4.23; P = 5.0x10^–07 and hazard ratio for disease-free survival, 2.27; 95% CI, 1.62–3.18; P = 1.8x10^–06).
In an analysis of data from 2 trials of patients with stage II or III colon cancer, we identified rs76766811 as a potential prognostic variant in African American patients. This finding should be confirmed in additional study populations. ClinicalTrials.gov Identifiers: NCT00096278 (NSABP C-08) and NCT00079274 (NCCTG N0147).
Current progress and questions in germline genetics of prostate cancer
2019, Asian Journal of Urology
Citation Excerpt :
Epidemiological data provide support for heritability of aggressiveness of PCa. For example, PCa patients are found to be more likely to die of the disease if their father died of PCa [36] . Using a population-based database that includes ∼3 million families to analyze the relationship of survival between sons and their fathers, Lindström et al. [36] found an increased hazard ratio of 2.07 (95% CI:1.13–3.79) for death from PCa in sons with poor father survival compared with those with good father survival, suggesting a genetic susceptibility for lethal PCa.
Dramatic progress has been made in the area of germline genetics of prostate cancer (PCa) in the past decade. Both common and rare genetic variants with effects on risk ranging from barely detectable to outright practice-changing have been identified. For men with high risk PCa, the application of genetic testing for inherited pathogenic mutations is becoming standard of care. A major question exists about which additional populations of men to test, as men at all risk levels can potentially benefit by knowing their unique genetic profile of germline susceptibility variants. This article will provide a brief overview of some current issues in understanding inherited susceptibility for PCa.
Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival
2018, European Urology
Citation Excerpt :
Although radical prostatectomy is widely used to prevent unfavorable PCa outcome, a recent study among men with localized PCa showed that radical prostatectomy or radiation significantly reduced clinical disease progression but did not reduce PCa mortality at 10 yr as compared with surveillance [4]. In families with a PCa history, death from PCa among offspring is related to PCa-specific survival in parents [5,6]. This suggests the existence of genetic factors that influence PCa prognosis.
Most men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging.
To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer.
Blood samples from 11 506 men in Sweden were collected during 1991–1996. Of these, 1053 men were diagnosed with prostate cancer and 245 died from the disease. Stage and grade at diagnosis and outcome information were obtained, and DNA from all cases was genotyped.
A total of 6 126 633 SNPs were tested for association with prostate-cancer-specific survival time using a Cox proportional hazard model, adjusted for age, stage, and grade at diagnosis. A value of 1 × 10⁻⁶ was used as suggestive significance threshold. Positive candidate SNPs were tested for association with gene expression using expression quantitative trait locus analysis.
We found 12 SNPs at seven independent loci associated with prostate-cancer-specific survival time. One of 6 126 633 SNPs tested reached genome-wide significance (p < 5 × 10⁻⁸) and replicated in an independent cohort: rs73055188 (p = 5.27 × 10⁻⁹, per-allele hazard ratio [HR] = 2.27, 95% confidence interval [CI] 1.72–2.98) in the AOX1 gene. A second SNP reached a suggestive level of significance (p < 1 × 10⁻⁶) and replicated in an independent cohort: rs2702185 (p = 7.1 × 10⁻⁷, per-allele HR = 2.55, 95% CI = 1.76–3.69) in the SMG7 gene. The SNP rs73055188 is correlated with AOX1 expression levels, which is associated with biochemical recurrence of prostate cancer in independent cohorts. This association is yet to be validated in other ethnic groups.
The SNP rs73055188 at the AOX1 locus is associated with prostate-cancer-specific survival time, and AOX1 gene expression level is correlated with biochemical recurrence of prostate cancer.
We identify two genetic markers that are associated with prostate-cancer-specific survival time.

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Fast track — ArticlesFamilial concordance in cancer survival: a Swedish population-based study

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Swedish population-based family data

Results

Discussion

Ann Oncol

Cancer Lett

Lancet

Am J Hum Genet

Am J Hum Genet

Toxicol Lett

Gastroenterology

Cancer i siffror

A new member of the growing family of metastasis suppressors identified in prostate cancer

J Natl Cancer Inst

Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression

Int J Cancer

Inflammation and cancer

Nature

Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands

J Natl Cancer Inst

Familial risk of cancer: data for clinical counseling and cancer genetics

Int J Cancer

The Multi-Generation Register 2001

Fast track — Articles
Familial concordance in cancer survival: a Swedish population-based study