Telomere-lengthening germline variants predispose to a syndromic papillary thyroid cancer subtype.

Papillary thyroid cancer (PTC) is the most common endocrine malignancy. 10% to 15% of individuals show familial clustering with three or more affected members, but the factors underlying this risk are unknown. In a group of recently studied individuals with POT1 pathogenic variants and ultra-long telomere length, PTC was the second most common solid tumor. We tested whether variants in POT1 and four other telomere-maintenance genes associated with familial cancer underlie PTC susceptibility. Among 470 individuals, we identified pathogenic or likely pathogenic variants in three genes encoding telomere-binding proteins: POT1, TINF2, and ACD. They were found in 4.5% and 1.5% of familial and unselected cases, respectively. Individuals harboring these variants had ultra-long telomere length, and 15 of 18 (83%) developed other cancers, of which melanoma, lymphoma, and sarcoma were most common. Among individuals with PTC and melanoma, 22% carried a deleterious germline variant, suggesting that a long telomere syndrome might be clinically recognizable. Successive generations had longer telomere length than their parents and, at times, developed more cancers at younger ages. Tumor sequencing identified a single oncogenic driver, BRAF p.Val600Glu, in 10 of 10 tumors studied, but no telomere-maintenance mechanism, including at the TERT promoter. These data identify a syndromic subset of PTCs with locus heterogeneity and telomere lengthening as a convergent mechanism. They suggest these germline variants lower the threshold to cancer by obviating the need for an acquired telomere-maintenance mechanism in addition to sustaining the longevity of oncogenic mutations.

Physiological responses and adjustments of corals to strong seasonal temperature variations (20-28°C).

Temperature is a key driver of metabolic rates. So far, we know little about potential physiological adjustments of subtropical corals to seasonal temperature changes (>8°C) that substantially exceed temperature fluctuation experienced by their counterparts in the tropics. This study investigated the effect of temperature reductions on Montastraea cavernosa and Porites astreoides in Bermuda (32°N; sea surface temperature ∼19-29°C) over 5 weeks, applying the following treatments: (i) constant control temperature at 28°C, and (ii) temperature reduction (0.5°C day-1) followed by constant temperature (20 days; acclimatization period) at 24°C and (iii) at 20°C. Both species decreased photosynthesis and respiration during temperature reduction as expected, which continued to decrease during the acclimatization period, indicating adjustment to a low energy turnover rather than thermal compensation. Trajectories of physiological adjustments and level of thermal compensation, however, differed between species. Montastraea cavernosa zooxanthellae metrics showed a strong initial response to temperature reduction, followed by a return to close to control values during the acclimatization period, reflecting a high physiological flexibility and low thermal compensation. Porites astreoides zooxanthellae, in contrast, showed no initial response, but an increase in pigment concentration per zooxanthellae and similar photosynthesis rates at 24°C and 20°C at the end of the experiment, indicating low acute thermal sensitivity and the ability for thermal compensation at the lowest temperature. Respiration decreased more strongly than photosynthesis, leading to significant build-up of biomass in both species (energy reserves). Results are important in the light of potential poleward migration of corals and of potential latitudinal and species-specific differences in coral thermal tolerance.