Age-adjusted RTL in subjects belonging to fCRC-X and LS families.

<p>The different groups correspond to: cancer-affected fCRC-X cases (median age-adjusted RTL: 0.017); cancer-free individuals from fCRC-X families (median: −0.215); cancer-affected <i>MMR</i> gene mutation carriers (median: −0.131); cancer-free <i>MMR</i> gene mutation carriers (median: −0.079); and cancer-free controls (median: −0.092). Differences in age-adjusted RTL were analyzed using the Wilcoxon rank sum test (Mann-Whitney U). The boxes represent the interquartile range of distributions (25^th and 75^th percentiles); the horizontal lines within the boxes, the medians; and the vertical lines, the 5^th and 95^th percentiles. Data from LS families and controls were published previously <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0086063#pone.0086063-Segui1" target="_blank">[16]</a>.</p

Telomere Length and Genetic Anticipation in Lynch Syndrome

<div><p>Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.</p></div

Genetic and clinical characteristics of the studied groups.

<p>N: number of subjects; SD: standard deviation; M: male; F: female.</p>*<p>Cancer: Individual affected with a LS-associated cancer: CRC and/or cancer of the endometrium, ovary, stomach, small bowel, hepatobiliary tract, pancreas, upper uro-epithelial tract or brain.</p

Differences in average age of onset of cancer (1^st LS-related tumor diagnosed) between parents and children with Lynch syndrome.

<p>N: number of subjects; SD: standard deviation.</p

Age-adjusted relative telomere length.

<p>In subjects belonging to LS families: <i>MMR</i> gene mutation carriers affected with cancer (median: −0.131), <i>MMR</i> gene mutation carriers with no diagnosed cancer (median: −0.079) and cancer-free non-carriers (median: −0.091); and in cancer-free controls (median: −0.097). The boxes represent the interquartile range of distributions (25^th and 75^th percentiles); the horizontal lines within the boxes, the medians; and the vertical lines, the 5^th and 95^th percentiles.</p

Changes in age-adjusted RTL between parents and children.

<p>Box plots representing age-adjusted RTL distributions in cancer-affected parents and children with <i>MMR</i> gene mutations. The boxes represent the interquartile range of distributions (25^th and 75^th percentiles); the horizontal lines within the boxes, the medians; and the vertical lines, the 5^th and 95^th percentiles.</p

Age-adjusted RTL and anticipation in age at cancer diagnosis in parent-child pairs.

<p>MMR: DNA mismatch repair; RTL: relative telomere length; CRC: colorectal cancer; EC: endometrial cancer; UC: urinary tract cancer; M: male; F: female; in surv: cancer diagnosed as a consequence of extensive clinical surveillance of LS families.</p>*<p>Age: Age at cancer diagnosis for cancer-afected carriers, and age at blood draw for cancer-free carriers and non-carriers</p>**<p>Tel_childparent, age-adjusted telomere length is shorter in the child than in the parent. “Yes” indicates that age-adjusted RTL is smaller in the child than in the parent, therefore indicating association with anticipation when cancer-affected carriers are studied.</p>***<p>Cancer-free non-carriers are individuals who belong to Lynch syndrome families but do not carry the pathogenic <i>MMR</i> gene mutation.</p

Anticipation in age of cancer onset in LS families.

<p>Kaplan-Meier curves and associated p-values showing the differences in age of cancer onset between parents and children, all of them cancer-affected <i>MMR</i> gene mutation carriers.</p

Correlation of relative telomere length (RTL) with age at blood draw.

<p>(A) RTL distribution as a function of age for controls (n = 234; white circles) and all <i>MMR</i> gene mutation carriers (n = 244; black circles). (B) RTL distribution as a function of age for cancer-affected <i>MMR</i> gene mutation carriers (n = 144; black circles) and cancer-free <i>MMR</i> gene mutation carriers (n = 100; crossed circles). r: Pearson's correlation coefficient.</p

Distribution of cancer-affected and cancer-free <i>MMR</i> gene mutation cases and controls by quartiles of age-adjusted telomere length.

<p>Distribution of cancer-affected and cancer-free <i>MMR</i> gene mutation cases and controls by quartiles of age-adjusted telomere length.</p