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Thread: Lynch Syndrome Linked to Breast, Pancreatic Cancers

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    Distinguished Community Member gpawelski's Avatar
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    Default Lynch Syndrome Linked to Breast, Pancreatic Cancers

    A prospective study has confirmed that Lynch syndrome, an inherited disorder that predisposes to many types of cancer, significantly raises the risk of both breast cancer and pancreatic cancer.

    The trial is the first to "find a strong association between breast cancer and Lynch syndrome," said senior author and genetic epidemiologist Mark A. Jenkins, Ph.D., of the centre for molecular, environmental, genetic, and analytic epidemiology at the University of Melbourne.

    Risk of breast cancer was fourfold higher for the Lynch syndrome patients, compared with the general population. The syndrome is known to increase the risk for a wide variety of other cancers, including colon cancer. Patients are typically advised to begin colonoscopies at an earlier age and repeat them more often than does the general population.

    The new findings suggest that women with the syndrome might also benefit from enhanced breast cancer screening, but "further clarification of the risk of breast cancer for women at various ages is needed to determine the recommended age for mammography ... and to determine whether additional tests such as MRI are warranted," Dr. Jenkins said.

    The researchers also found an 11-fold increase in pancreatic cancers among the Lynch syndrome patients. Although elevated risk of this cancer has long been suspected, the evidence from previous studies has been inconsistent. The results were published online Feb. 13 in the Journal of Clinical Oncology.

    The autosomal dominant disorder, detected with a blood test, is caused by a mutation in one of four DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. The estimated carrier frequency in the population ranges from 1 in 360 to 1 in 3,010 individuals, depending on whether all four specific mutations, or fewer than four, are included in the calculations.

    Family members without the mutation, however, do not have a greater risk for cancer, and do not need more intensive screening than does the general population – something that has been unclear until now.

    The investigators followed 446 mutation carriers and 1,029 noncarrier relatives recruited from the Colon Cancer Family Registry in 1997-2010. Almost all study subjects (96%) were white, and slightly more than half were female. At recruitment, mean age ranged from 40 to 50 years for the different subgroups. The registry includes subjects from the United States, Canada, Australia, and New Zealand.

    After a median follow-up of 5 years, mutation carriers had a 20-fold greater risk of colorectal cancer, a 31-fold greater risk of endometrial cancer, a 19-fold higher risk of ovarian cancer, an 11-fold greater risk of renal cancer, and a 10-fold greater risk of stomach and bladder cancers, compared with the general population. The increase in risk for breast and pancreatic cancer was 4-fold and 11-fold, respectively.

    For each cancer type, the increased rate in mutation carriers was highly significant, with P values ranging from .009 to less than .001. In addition, the Lynch syndrome patients’ cancer diagnoses typically came at an earlier age than it did in the general population. (J. Clin. Oncol. 2012 Feb. 13 [doi:10.1200/JCO.2011.39.5590]).

    "Estimates of site-specific cancer risks for MMR gene mutation carriers inform optimal clinical management," the researchers noted. "Screening colonoscopy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy have the potential to decrease the risk of colorectal cancer, endometrial cancer, and ovarian cancer, respectively."

    "Eventually, we expect that the management of cancer risk, including the choice and timing of screening, will be able to be tailored to the specific underlying gene mutation in a person with Lynch syndrome." However, there are no data demonstrating that screening for cancers other than colorectal "is beneficial, in part due to the absence of effective screening tests," Dr. Jenkins and colleagues wrote.

    The authors said that they have no relevant conflicts of interest. The study was funded by the National Cancer Institute.

    The Oncology Report
    Gregory D. Pawelski

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    Default Lynch Syndrome Linked to Breast, Pancreatic Cancers

    Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study

    Aung Ko Win, Joanne P. Young, Noralane M. Lindor, Katherine M. Tucker, Dennis J. Ahnen, Graeme P. Young, Daniel D. Buchanan, Mark Clendenning, Graham G. Giles, Ingrid Winship, Finlay A. Macrae, Jack Goldblatt, Melissa C. Southey, Julie Arnold, Stephen N. Thibodeau, Shanaka R. Gunawardena, Bharati Bapat, John A. Baron, Graham Casey, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Robert W. Haile, John L. Hopper and Mark A. Jenkins

    Abstract

    Purpose:

    To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population.

    Patients and Methods:

    We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.

    Results:

    Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97).

    Conclusion:

    We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.

    J. Clin. Oncol. 2012 Feb. 13 [doi:10.1200/JCO.2011.39.5590]
    Gregory D. Pawelski

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    Default New Analysis Provides Clearer Picture of Cancer Risks Associated With Lynch Syndrome

    Lynch syndrome is an inherited condition of cancer predisposition caused by mutations in certain genes involved in repairing DNA damage, called “mismatch repair” genes. A new study published in the Journal of Clinical Oncology provides a new, clearer picture of the cancer risks that carriers of these mutations face, which could ultimately help guide future screening efforts to detect these cancers at an early stage.

    In the study, researchers at The University of Melbourne in Australia confirmed the increased risk of cancers already recognized to be associated with Lynch syndrome, including those of the colon, uterus, ovary, kidney, stomach, and bladder. They also reported that mutation carriers face a significantly increased risk of breast and pancreatic cancers.

    The researchers followed a group of more than 400 individuals with a mutation in one of the four "mismatch repair" genes associated with Lynch syndrome, and more than 1,000 of their relatives who were not carriers of these mutations. Study participants were evaluated every five years at recruitment centers affiliated with the Colon Cancer Family Registry in Australia, New Zealand, Canada, and the United States.

    After a median follow-up of five years, they found that compared to the general population, individuals with Lynch syndrome had a 20-fold greater risk of colorectal cancer; a 30-fold greater risk of endometrial (uterine) cancer; a 19-fold higher risk of ovarian cancer; an 11-fold greater risk of kidney cancer; a 10-fold greater risk of pancreatic, stomach, and bladder cancers; and a four-fold greater risk of breast cancer.

    Those with Lynch syndrome also tended to be diagnosed with these cancers at an earlier age than cancer patients in the general population. The study found no evidence showing that family members without mutations associated with Lynch syndrome faced an increased risk of cancer compared to the general population; as a result, they do not need more intense cancer screenings than the general population.

    The researchers said their findings regarding breast cancer were unexpected. They suggest that further studies to clarify breast cancer risk are needed to determine the optimal age for mammography for each patient, and to determine if other tests, such as MRI, should be recommended in women with Lynch syndrome. Currently, individuals with Lynch syndrome typically undergo colonoscopy at an earlier age than the general population, but no other special screening regimens have been agreed upon.

    About Lynch Syndrome

    DNA errors are a common occurrence within cells and under normal circumstances, a set of genes called “mismatch repair genes" correct a specific type of DNA errors called mismatches. Patients with Lynch syndrome, however, have a mutation in one of four of specific “mismatch repair genes.” This means that sometimes their cells are not able to repair certain DNA errors, which can result in additional gene mutations and cancer development.

    According to the National Cancer Institute, one to three percent of the population may have Lynch syndrome, and the disease is particularly associated with high risk of colon cancer. In fact, researchers estimate that three to five of every 100 colon cancers are caused by Lynch syndrome. Individuals with Lynch syndrome also tend to be diagnosed with cancer at a younger age than people in the general population, and are at greater risk of developing multiple cancers during their lifetime.

    What this Means for Patients

    This study adds to growing body of evidence linking specific inherited genetic mutations to certain cancers. Over time, as improved screening methods become available, the findings may help doctors refine screening guidelines for breast, uterus, colon, and other cancers among patients with Lynch Syndrome. In the meantime, patients with Lynch syndrome are advised to work with their doctors to determine which screening tests are appropriate, so cancers can be detected and treated as early as possible.

    Cancer.Net
    Gregory D. Pawelski

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