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

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.

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Cancer Risks For Mismatch Repair Gene Mutation Carriers: A Population-Based Early Onset Case-Family Study

Clinical Gastroenterology and Hepatology ◽

10.1016/j.cgh.2006.01.002 ◽

2006 ◽

Vol 4 (4) ◽

pp. 489-498 ◽

Cited By ~ 110

Author(s):

M JENKINS ◽

L BAGLIETTO ◽

J DOWTY ◽

C VANVLIET ◽

L SMITH ◽

...

Keyword(s):

Mismatch Repair ◽

Gene Mutation ◽

Early Onset ◽

Family Study ◽

Population Based ◽

Mismatch Repair Gene ◽

Cancer Risks ◽

Repair Gene ◽

Mutation Carriers ◽

Early Onset Case

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Room for improvement: One third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-021-00171-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Sophie Walton Bernstedt ◽

Jan Björk ◽

Kaisa Fritzell ◽

Allan D. Spigelman ◽

Erik Björck ◽

...

Keyword(s):

Lynch Syndrome ◽

Mismatch Repair ◽

Gene Mutation ◽

Clinical Care ◽

Predictive Testing ◽

Study Data ◽

University Hospital ◽

Mismatch Repair Gene ◽

Repair Gene ◽

Risk Of Cancer

Abstract Background Lynch syndrome is caused by germline mutations in the mismatch repair genes and is characterised by a familial accumulation of colorectal and other cancers. Earlier identification of Lynch syndrome patients enables surveillance and might reduce the risk of cancer. It is important to explore whether today’s clinical care discovers patients with Lynch syndrome suitable for surveillance in time. This study aimed to describe what led to a diagnosis of Lynch syndrome in the cohort referred to the Hereditary Gastrointestinal Cancer Unit, Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance. Methods This was a descriptive study. Data from 1975 to 2018 were collected and compiled as a database. Age at diagnosis was calculated from the date when a pathogenic MMR gene mutation was confirmed, from the period June 1994–September 2018. Data were collected from patient protocols prospectively during patient consultations and medical records retrospectively. Criteria for inclusion were registration at the outpatient clinic and a confirmed mismatch repair gene mutation. Results A total of 305 patients were eligible for inclusion. Three major reasons for diagnosis were identified: 1. Predictive testing of a previously known mutation in the family (62%, mean age 37), 2. A family history of Lynch associated tumours (9%, mean age 37), 3. A diagnosis of cancer (29%, mean age 51). The proportion diagnosed due to cancer has not changed over time. Conclusion A high proportion of patients (29%) were identified with Lynch syndrome after they had been diagnosed with an associated cancer, which suggests that there is significant room for improvement in the diagnosis of patients with Lynch syndrome before cancer develops.

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