ASCO abstract: Association of Lynch syndrome and risk of invasive cervical cancer.

Abstract:
Background: Lynch syndrome, a hereditary cancer syndrome characterized by germline mutations in mismatch repair (MMR) genes, is associated with an elevated lifetime risk of cancer development, predominantly endometrial, colorectal and ovarian. To date, no increased risk of cervical cancer for mutation carriers has been reported. 
Methods: Families with an identified pathologic mutation in one of the MMR genes MLH1, MSH2, MSH6 or PMS2 were obtained from Colon Cancer Family Registry (Australasia, USA and Canada). Families were ascertained via a population- based colorectal cancer case or via family cancer clinics. Attempts were made to obtain pathology reports for cases of cervical cancer. Modified segregation analyses incorporating rigorous corrections for ascertainment were used to estimate relative and cumulative risks of cervical cancer for mutation carriers. Binomial tests and t-tests and were used to compare observed histology and ages of diagnosis to population norms.  
Results: A total of 66 cases of cervical cancer were reported among 369 families (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) containing 7,119 females and 7,812 males, 2,033 of whom were genotyped (1,073 carriers and 960 non-carriers). The incidence of cervical cancer was estimated to be higher for carriers than non-carriers by a factor of 5.4 (95% CI 2.2-13.5; p = 0.002). The corresponding estimated cumulative risk to age 80 years for women from the USA sites was 4.4% (95% CI 1.8-11.0 %) for MMR mutation carriers compared with 0.8% for non-carriers. Mean age of cervical cancer diagnoses in carriers was 42.9 years (range 18-70), younger than the corresponding mean age of 47 years in the general population (p = 0.01, 95% CI 39.8-46.0) (seer.cancer.gov/csr/1973_1999/cervix.pdf). Pathology reports were available for 12 cases with 8 (67%) reported as either adenocarcinoma or mixed histology with a predominance of adenocarcinoma, significantly more (p = 0.003) than the expected proportion of 25% based on SEER data.  
Conclusions: These novel findings suggest that cervical cancer is associated with Lynch syndrome and that the histology of cervical cancers in MMR mutation carriers may vary from expected population standards.