Genetic variants on chr 11q and 6q as markers for prostate and colorectal cancer predisposition

a gene variant and marker technology, applied in the field of gene variants on chr 11q and 6q as markers for prostate and colorectal cancer, can solve the problems of low cure rate, uncontrolled growth, and low cure rate of prostate cancer, and achieve the effects of increasing susceptibility, reducing susceptibility, and reducing susceptibility

Inactive Publication Date: 2014-09-04
DECODE GENETICS EHF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach allows for more accurate assessment of cancer susceptibility and potential treatment responses, helping to avoid invasive procedures for low-risk individuals and identifying genetic variants contributing to a substantial fraction of cancer cases.

Problems solved by technology

Cancer, the uncontrolled growth of malignant cells, is a major health problem of the modern medical era and is one of the leading causes of death in developed countries.
However, if diagnosed after spread and metastasis from the prostate, prostate cancer is typically a fatal disease with low cure rates.
While prostate-specific antigen (PSA)-based screening has aided early diagnosis of prostate cancer, it is neither highly sensitive nor specific (Punglia et. al., N Engl J Med.
This means that a high percentage of false negative and false positive diagnoses are associated with the test.
The consequences are both many instances of missed cancers and unnecessary follow-up biopsies for those without cancer.
In addition to the sensitivity problem outlined above, PSA testing also has difficulty with specificity and predicting prognosis.
PSA levels can be abnormal in those without prostate cancer.
Subsequent confirmation of prostate cancer using needle biopsy in patients with positive PSA levels is difficult if the tumor is too small to see by ultrasound.
Multiple random samples are typically taken but diagnosis of prostate cancer may be missed because of the sampling of only small amounts of tissue.
Although genetic factors are among the strongest epidemiological risk factors for prostate cancer, the search for genetic determinants involved in the disease has been challenging.
Studies have revealed that linking candidate genetic markers to prostate cancer has been more difficult than identifying susceptibility genes for other cancers, such as breast, ovary and colorectal cancer.
Several reasons have been proposed for this increased difficulty including: the fact that prostate cancer is often diagnosed at a late age thereby often making it difficult to obtain DNA samples from living affected individuals for more than one generation; the presence within high-risk pedigrees of phenocopies that are associated with a lack of distinguishing features between hereditary and sporadic forms; and the genetic heterogeneity of prostate cancer and the accompanying difficulty of developing appropriate statistical transmission models for this complex disease (Simard, J. et al., Endocrinology 143(6):2029-40 (2002)).
As described above, identification of particular genes involved in prostate cancer has been challenging.
In contrast to these positive reports, however, some studies have failed to detect any association between RNASEL alleles with inactivating mutations and prostate cancer (Wang, L. et al., Am. J. Hum. Genet.
Three additional missense changes: Ser217Leu; Ala541Thr; and Arg781His, were also found to associate with an increased risk of prostate cancer.
Furthermore, none of the published prostate cancer genes have been reported to predict a greater risk for aggressive prostate cancer than for less aggressive prostate cancer.
Each such variant would be expected to carry a small increase in risk; however, if the variant is common, it may contribute significantly to the population attributable risk (PAR).

Method used

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  • Genetic variants on chr 11q and 6q as markers for prostate and colorectal cancer predisposition
  • Genetic variants on chr 11q and 6q as markers for prostate and colorectal cancer predisposition

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example 1

Identification of Markers and LD Block Regions Associated with Prostate Cancer

[0305]Patients Involved in the Genetics Study

[0306]A population based list of all prostate and colorectal cancer patients that were diagnosed in Iceland from 1955 to 2005 form the basis for this study. Patients have been invited to join the study since 2001 on an ongoing basis. As of June 2007, blood samples from 1,850 prostate cancer and 1,169 colorectal cancer patients have been recruited. Genomic DNA from those samples, as well as samples from over 27,000 control individuals was extracted and genotyped.

[0307]Genotyping

[0308]A genome-wide scan of 1,645 Icelandic individuals diagnosed with Prostate Cancer, 1,010 colorectal cancer patients and 27,049 population controls was performed using Infinium HumanHap300 SNP chips from Illumina for assaying approximately 317,000 single nucleotide polymorphisms (SNPs) on a single chip (Illumina, San Diego, Calif., USA). SNP genotyping for replication in other case-con...

example 2

[0316]Further analysis of marker rs11228565, which is located within LD Block C11 and in LD with rs10896450 (D′=1, r2=0.25), was performed, with results as shown in Table 7.

[0317]Highly significant association of the A allele of rs11228565 to prostate cancer was revealed, with combined P-value for all cohorts genome-wide significant (P=6.7×10−12). The odds ratio (OR) for rs11228565 after adjusting for rs10896450 was determined to be 1.16 (P value=4.9 E-04) when using results for all populations except Finland (i.e. where we have results for both markers rs11228565 and rs10896450 in: Iceland, Chicago, Netherlands, Nashville and Spain cohorts.

TABLE 7Association of rs11228565 with prostate cancer.StudyCaseControlsControlpopulationMarkerAlleleP valueORCases (n)Freq.(n)Freq.Icelandrs11228565A7.72E−031.2317840.2097710.176Thers11228565A2.15E−021.179920.22917810.202NetherlandsSpainrs11228565A3.42E−011.093940.24013990.224Finlandrs11228565A3.22E−061.3026430.21016890.169Chicago,rs11228565A8.00...

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Abstract

It has been discovered that certain polymorphic markers on chromosome 6 and chromosome 11 are indicative of a susceptibility to prostate cancer and colon cancer. The invention describes diagnostic applications for determining a susceptibility to cancer using such markers, as well as kits for use in such applications.

Description

RELATED APPLICATION[0001]This application claims priority under 35 U.S.C. §119 or 365 to Iceland, Application No. 8696, filed Nov. 30, 2007. The entire teachings of the above application are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Cancer, the uncontrolled growth of malignant cells, is a major health problem of the modern medical era and is one of the leading causes of death in developed countries. In the United States, one in four deaths is caused by cancer (Jemal, A. et al., CA Cancer J. Clin. 52:23-47 (2002)).[0003]The incidence of prostate cancer has dramatically increased over the last decades and prostate cancer is now a leading cause of death in the United States and Western Europe (Peschel, R. E. and J. W. Colberg, Lancet 4:233-41 (2003); Nelson, W. G. et al., N Engl. J. Med. 349(4):366-81 (2003)). Prostate cancer is the most frequently diagnosed noncutaneous malignancy among men in industrialized countries, and in the United States, 1 in 8 men will ...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): C12Q1/68G06F19/18G06F19/00G16B20/10G16B20/20G16B20/40G16H10/40G16H50/30G16H70/60
CPCC12Q1/68G06F19/18G06F19/34C12Q2600/106C12Q2600/118C12Q2600/136C12Q2600/172G16H50/70C12Q1/6886Y10T436/143333G16B20/00G16H70/60G16H50/30G16H10/40Y02A90/10G16B20/20G16B20/40G16B20/10C12Q2600/156
InventorTHORLACIUS, STEINUNNSULEM, PATRICKGUDMUNDSSON, JULIUS
OwnerDECODE GENETICS EHF