Clinical aspects of Lynch syndrome

Colorectal cancer is the second most common cancer in women and the third most common cancer in men worldwide, with 1.8 million new cases and almost 861000 deaths in 2018. Approximately 5–10% of the annual CRC burden can be attributed to inherited high risk germline mutations. The most common inherited colon cancer syndrome is Lynch syndrome, which accounts for up to 5% of all CRCs. Lynch syndrome displays both genotypic and phenotypic heterogeneity and can be suspected on the basis of a strong family history of colorectal- or endometrial cancer, but also of other tumors. Genetic counselling is recommended for families with Lynch syndrome, to provide the patient and family members with information about cancers risk and options for surveillance and management. In paper I we compared disease associated haplotypes in families from Sweden, Germany and France, all carrying the MLH1 mutation c.2059C>T, in order to elucidate if this is a founder mutation. When analyzing the haplotype in the families with Swedish descent, a shared region of approximately 0.9–2.8 Mb was identified. The MLH1 c.2059C>T mutation thus act as a founder in the Swedish population, but is also found in Europe, Asia and Australia, indicating that this is a recurring mutation globally albeit with a very low allele frequency. In paper II and III we investigated if genetic anticipation was part of the clinical picture in a Swedish cohort of Lynch syndrome families, as well as in a larger European cohort of PMS2 mutation carriers. In paper II, a total 1003 proven mutation carriers from 239 families with Lynch syndrome were included. An anticipation effect of 2,55 years and hazard rate of 1.33 between generations was seen in families with MSH2 mutation. In addition, an anticipation effect of 7.33 years and a hazard ration of 1.86 per generation was shown in families with PMS2 mutation. In paper III, 637 individuals from 123 families with PMS2 mutation were recruited from Netherlands, Norway, Germany, Denmark, Spain, including the Swedish PMS2 patients in paper II. Participants were assigned mutation probabilities in cases of unknown carrier status. As opposed to the result in paper II, an anticipation effect initially shown in a crude analysis was no longer statistically significant when corrections were made for gender and birth cohort. In paper IV we characterized the tumor spectrum, excluding colorectal- and endometrial cancers, in a nationwide cohort of 235 Swedish Lynch syndrome families. Data was stratified for gender, primary cancer, age, and mutated gene. Relative proportions of specific cancer types were compared to corresponding proportions in the reference population from the national Swedish Cancer Registry. Individuals of both sexes in our cohort had a higher proportion of gastric cancer, small bowel cancer and urinary tract cancer compared to the general population. In female mutation carriers, the proportion of ovarian cancer and non-melanoma skin cancer was increased compared to the general population

Sequence features of HLA-DRB1 locus define putative basis for gene conversion and point mutations

<p>Abstract</p> <p>Background</p> <p>HLA/MHC class II molecules show high degree of polymorphism in the human population. The individual polymorphic motifs have been suggested to be propagated and mixed by transfer of genetic material (recombination, gene conversion) between alleles, but no clear molecular basis for this has been identified as yet. A large number of MHC class II allele sequences is publicly available and could be used to analyze the sequence features behind the recombination, revealing possible basis for such recombination processes both in HLA class II genes and other genes, which recombination acts upon.</p> <p>Results</p> <p>In this study we analyzed the vast dataset of human allelic variants (49 full coding sequences, 374 full exon 2 sequences) of the most polymorphic MHC class II locus, <it>HLA-DRB1</it>, and identified many previously unknown sequence features possibly contributing to the recombination. The CpG-dinucleotide content of exon 2 (containing the antigen-binding sites and subsequently a high degree of polymorphism) was much elevated as compared to the other exons despite similar overall G+C content. Furthermore, the CpG pattern was highly conserved. We also identified more complex, highly conserved sequence motifs in exon 2. Some of these can be identified as putative recombination motifs previously found in other genes, but most are previously unidentified.</p> <p>Conclusion</p> <p>The identified sequence features could putatively act in recombination allowing either less (CpG dinucleotides) or more specific DNA cleavage (complex sequences) or homologous recombination (complex sequences).</p

The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect

BACKGROUND: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. METHODS: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. RESULTS: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. CONCLUSIONS: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. IMPACT: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition

G C content in exons 1–6, based on the dataset including the entire coding region (49 sequences)

The dotted line indicates the overall average G+C. Mean ± sem is shown.<p><b>Copyright information:</b></p><p>Taken from "Sequence features of locus define putative basis for gene conversion and point mutations"</p><p>http://www.biomedcentral.com/1471-2164/9/228</p><p>BMC Genomics 2008;9():228-228.</p><p>Published online 19 May 2008</p><p>PMCID:PMC2408603.</p><p></p

CpG distribution in -e2, based on the dataset including the 374 complete -e2 sequences

A, each individual sequence lined under each other in the consensus numbering order starting from *010101. Black boxes indicate CpG dinucleotides and gray boxes other dinucleotides. B, CpG frequency for each nucleotide position. The dotted line indicates 100%.<p><b>Copyright information:</b></p><p>Taken from "Sequence features of locus define putative basis for gene conversion and point mutations"</p><p>http://www.biomedcentral.com/1471-2164/9/228</p><p>BMC Genomics 2008;9():228-228.</p><p>Published online 19 May 2008</p><p>PMCID:PMC2408603.</p><p></p

Transitions and transversions in , based on the dataset including the entire coding region (49 sequences)

Mean ± sem is shown.<p><b>Copyright information:</b></p><p>Taken from "Sequence features of locus define putative basis for gene conversion and point mutations"</p><p>http://www.biomedcentral.com/1471-2164/9/228</p><p>BMC Genomics 2008;9():228-228.</p><p>Published online 19 May 2008</p><p>PMCID:PMC2408603.</p><p></p

CpG-dinucleotide content in exons 1–6, based on the dataset including the entire coding region (49 sequences)

A, the observed CpG-dinucleotide content. B, the observed CpG level (as in A) divided by the mathematically estimated CpG content (based on the total G+C level). Mean ± sem is shown. The ratios were separately calculated for each allele and then averaged.<p><b>Copyright information:</b></p><p>Taken from "Sequence features of locus define putative basis for gene conversion and point mutations"</p><p>http://www.biomedcentral.com/1471-2164/9/228</p><p>BMC Genomics 2008;9():228-228.</p><p>Published online 19 May 2008</p><p>PMCID:PMC2408603.</p><p></p

Sliding window analysis of nucleotide diversity in exon 2, displaying stretches of totally conserved bases in the 374 -e2 sequences (of the length ≥ 3 bp; thick grey lines below the abscissa)

Also indicated are the previously identified ARS-coding codons (thick black lines above the diversity graph).<p><b>Copyright information:</b></p><p>Taken from "Sequence features of locus define putative basis for gene conversion and point mutations"</p><p>http://www.biomedcentral.com/1471-2164/9/228</p><p>BMC Genomics 2008;9():228-228.</p><p>Published online 19 May 2008</p><p>PMCID:PMC2408603.</p><p></p