Graphical Abstract Highlights d Biallelic germline NTHL1 mutations predispose to a multitumor syndrome d Biallelic germline NTHL1 mutation carriers are at risk for breast cancer d Tumors from NTHL1-deficient patients reveal a cross-cancer NTHL1-associated signature d Mutational signature analyses can assist to identify germline DNA repair defects

Germline variants affecting the exonuclease domains of POLE and POLD1 predispose to multiple colorectal adenomas and/or colorectal cancer (CRC). The aim of this study was to estimate the prevalence of previously described heterozygous germline variants POLE c.1270C4G, p.(Leu424Val) and POLD1 c.1433G4A, p.(Ser478Asn) in a Dutch series of unexplained familial, early onset CRC and polyposis index cases. We examined 1188 familial CRC and polyposis index patients for POLE p.(Leu424Val) and POLD1 p.(Ser478Asn) variants using competitive allele-specific PCR. In addition, protein expression of the POLE and DNA mismatch repair genes was studied by immunohistochemistry in tumours from POLE carriers. Somatic mutations were screened using semiconductor sequencing. We detected three index patients (0.25%) with a POLE p.(Leu424Val) variant. In one patient, the variant was found to be de-novo. Tumours from three patients from two families were microsatellite instable, and immunohistochemistry showed MSH6/MSH2 deficiency suggestive of Lynch syndrome. Somatic mutations but no germline MSH6 and MSH2 variants were subsequently found, and one tumour displayed a hypermutator phenotype. None of the 1188 patients carried the POLD1 p.(Ser478Asn) variant. POLE germline variant carriers are also associated with a microsatellite instable CRC. POLE DNA analysis now seems warranted in microsatellite instable CRC, especially in the absence of a causative DNA mismatch repair gene germline variant. INTRODUCTIONFaithful DNA replication and the repair of errors are both essential for the maintenance of genomic stability and suppression of carcinogenesis. 1 Duplication of genomes with high accuracy is achieved through three mechanisms: the high selectivity of DNA polymerases; exonucleolytic proofreading; and post replication mismatch repair. 2 The DNA polymerases ε (POLε) and δ (POLδ) are required for the efficient genome replication in the eukaryotic replication fork. 3 Their major component proteins, encoded by POLE and POLD1, respectively, possess an intrinsic 3′-5′ proofreading domain that removes incorrectly inserted nucleotides during DNA synthesis. [4][5][6][7][8][9] Studies in the yeast have shown that mutations in the proofreading domains of POLε or POLδ increase spontaneous mutation rates. 8,9 In addition, somatic mutations in the proofreading domains of POLD1 and POLE have been identified in microsatellite instable (MSI) and hypermutated subgroups of colorectal cancers (CRCs). [10][11][12] Recently, Palles et al reported that heterozygous germline variants in the proofreading domain of the DNA polymerases POLE and POLD1 predispose, with a high penetrance, to multiple colorectal adenomas, early onset CRC (OMIM #114500) and endometrial cancer (OMIM #608089). These variants were found by whole-genome sequencing and linkage analysis in three large families with a dominant pattern of CRC and multiple adenomas. 13 Subsequent screening of 3805 CRC patients revealed that these variants are relatively rare: POLE

Daylength insensitivity is an advantageous trait for spring wheat (Triticura aestivum L.) since it allows both a better seed increase from the nurseries in southern latitudes and wider potential use in breeding programs around the world. The ‘Chris’ source of daylength insensitivity was evaluated in the upper Midwest to determine if this trait had adverse effects on agronomic performance. Sixty random daylength insensitive (I) and 60 random daylength sensitive (S) lines from crosses of ‘Era’ with two daylength insensitive lines were evaluated from 1975 through 1977 to select 10 elite lines for yield from each class, S and I. These elite lines were tested in three environments in 1979. Ten near‐isogenic line pairs for I and S were tested in six environments in a paired plot design. These 10 pairs of nearisogenic lines had also been tested from 1975 through 1977 in the random line test. The I lines headed earlier than the S lines in all tests. Grain yield differences between the elite I and S lines and near‐isogenic I and S pairs depended upon the sites tested and their dates of seeding. In general, the S lines tended to be higher yielding at the more northerly location. At the more southerly location, and under delayed seeding conditions, the I lines were similar to or higher yielding than their respective S lines. In general, the Chris source of daylength insensitivity did not appear to seriously affect agronomic performance. However, high yielding I lines may be more difficult to obtain than high yielding S lines for the northern areas. This may be due to either insensitivity or the effect of earlier heading on performance, since the insensitive lines were almost all earlier heading.

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Background:A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders.Methods:Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level.Results:Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2–42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues.Conclusions:Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.