Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Tfap2a Promotes Specification and Maturation of Neurons in the Inner Ear through Modulation of Bmp, Fgf and Notch Signaling

<div><p>Neurons of the statoacoustic ganglion (SAG) transmit auditory and vestibular information from the inner ear to the hindbrain. SAG neuroblasts originate in the floor of the otic vesicle. New neuroblasts soon delaminate and migrate towards the hindbrain while continuing to proliferate, a phase known as transit amplification. SAG cells eventually come to rest between the ear and hindbrain before terminally differentiating. Regulation of these events is only partially understood. Fgf initiates neuroblast specification within the ear. Subsequently, Fgf secreted by mature SAG neurons exceeds a maximum threshold, serving to terminate specification and delay maturation of transit-amplifying cells. Notch signaling also limits SAG development, but how it is coordinated with Fgf is unknown. Here we show that transcription factor Tfap2a coordinates multiple signaling pathways to promote neurogenesis in the zebrafish inner ear. In both zebrafish and chick, Tfap2a is expressed in a ventrolateral domain of the otic vesicle that includes neurogenic precursors. Functional studies were conducted in zebrafish. Loss of Tfap2a elevated Fgf and Notch signaling, thereby inhibiting SAG specification and slowing maturation of transit-amplifying cells. Conversely, overexpression of Tfap2a inhibited Fgf and Notch signaling, leading to excess and accelerated SAG production. However, most SAG neurons produced by Tfap2a overexpression died soon after maturation. Directly blocking either Fgf or Notch caused less dramatic acceleration of SAG development without neuronal death, whereas blocking both pathways mimicked all observed effects of Tfap2a overexpression, including apoptosis of mature neurons. Analysis of genetic mosaics showed that Tfap2a acts non-autonomously to inhibit Fgf. This led to the discovery that Tfap2a activates expression of Bmp7a, which in turn inhibits both Fgf and Notch signaling. Blocking Bmp signaling reversed the effects of overexpressing Tfap2a. Together, these data support a model in which Tfap2a, acting through Bmp7a, modulates Fgf and Notch signaling to control the duration, amount and speed of SAG neural development.</p></div

Tfap2a regulates the number of transit-amplifying SAG precursors.

<p>(A-I) Cross-sections (medial left, dorsal up) at the level of the utricular macula showing <i>neurod</i> expression in +/+ control, <i>tfap2a</i> mutants and <i>hs</i>:<i>tfap2a</i> embryos. Wild-type and <i>hs</i>:<i>tfap2a</i> embryos were heat shocked at 24 hpf. Disruption of <i>tfap2a</i> leads to accumulation of excess TA cells whereas <i>tfap2a</i> overexpression decreases the number of the TA cells. The outer and inner edges of the otic vesicle are outlined in each image. (J) Mean and standard deviation of the total number of <i>neurod</i> positive SAG precursors for the genotypes and conditions indicated in the color key (counted from serial sections, n = 3–6 ears per time point). Asterisks (*) indicate significant differences from control specimens.</p

Tfap2a regulates maturation of SAG neurons.

<p>(A-L) Images of anti-Isl1 antibody staining in control embryos (A-D), <i>tfap2a</i>^<i>-/-</i> mutants (E-H) and <i>hs</i>:<i>tfap2a</i> embryos (I-L) at 37 hpf. Control and <i>hs</i>:<i>tfap2a</i> embryos were heat shocked at 24 hpf. Whole-mount specimens (A, E, I) show dorsolateral (anterior to the left) and indicate planes of cross-section in (B-D), (F-H) and (J-L). Cross-sections are oriented with dorsal up and medial to the left. The otic vesicle is outlined in each image. White arrows indicate the SAG population to help distinguish it from other Isl1+ populations present in some sections. (M) Total number of Isl1+ neurons in <i>hs</i>:<i>tfap2a</i> embryos at 30 hpf following heat shock at the indicated times (n = 10–15 each). (N-P) Cross-sections of a <i>hs</i>:<i>tfap2a</i> specimen at 37 hpf following heat shock at 29 hpf. Planes of section are similar to those shown in (I). (Q-S) Cross-sections of a <i>hs</i>:<i>tfap2a</i> embryo stained for TUNEL positive SAG neurons at 42 hpf. (T) Mean and standard deviation of the total number of Isl1+ SAG neurons at the indicated times in +/+ embryos, <i>hs</i>:<i>tfap2a</i> embryos, <i>tfap2a</i>^<i>-/-</i> mutants and <i>tfap2a</i> morphants (n = 7–34 embryos per time point). (U) Mean and standard deviation of the total number of TUNEL positive SAG neurons at the indicated times in control embryos and <i>hs</i>:<i>tfap2a</i> embryos (counted from serial sections, n = 3–6 ears per time point). Asterisks (*) indicate statistically significant differences compared to control embryos.</p

Bmp signaling mediates the effects of Tfap2a on SAG development.

<p>(A-L) Cross sections (medial left, dorsal up) through the otic vesicle just posterior to the utricular macula showing expression of <i>her4</i> (A-D) and <i>deltaB</i> (E-H) at 26 hpf and <i>ngn1</i> (I-L) at 28 hpf in control embryos (A, E, I), <i>hs</i>:<i>tfap2a</i> embryos (B, F, J), DM-treated <i>hs</i>:<i>tfap2a</i> embryos (C, G, K) and DM-treated wild-type embryos (D, H, L). All specimens were treated with 1% DMSO and heat-shocked at 24 hpf. (M-P) Mean and standard deviation of the total number of <i>deltaB</i> or <i>her4</i> expressing cells inside the otic vesicle or in the TA pool at 26 hpf under conditions indicated in the color key (counted from serial sections, n = 3–6 ears per time point). (Q-S) Mean and standard deviation of the total number of <i>ngn1</i>+ cells at 28 hpf (Q) and Isl1+ SAG neurons at 30 hpf (R) and 37 hpf (S) under the conditions indicated in the color key. Asterisks (*) indicate statistical differences between the groups indicated in brackets.</p

Reducing Fgf and Notch levels mimics the effects of <i>tfap2a</i> overexpression.

<p>(A-L) Cross-sections (medial left, dorsal up) passing just posterior to the utricular macula and showing expression of <i>ngn1</i> at 28 hpf (A-D), or sections passing through the utricular macula and showing <i>neurod</i> at 37 hpf (E-H) or Isl1 at 37 hpf (I-L) in wild-type control (A, E, I), <i>hs</i>:<i>dnfgfr1</i> embryos (B, F, J), LY411575 inhibitor treated wild-type embryos (C, G, K) and LY411575 inhibitor treated <i>hs</i>:<i>dnfgfr1</i> embryos (D, H, L). All specimens were treated with 0.3% DMSO and heat-shocked at 24 hpf. The otic vesicle is outlined in each image. (M, N) Mean and standard deviation of the total number of <i>ngn1</i> positive cells in the otic epithelium at 28 hpf (M) and total <i>neurod</i> positive SAG precursors at 37 hpf (N) for the genotypes and treatments indicated in the color key (counted from serial sections, n = 3–6 ears per time point). Asterisks (*) indicate significant differences from control embryos and filled squares indicate significant differences relative to <i>hs</i>:<i>dnfgfr1</i> embryos treated with LY411575. (O) Mean and standard deviation of the total number of Isl1 positive SAG neurons at different times for the genotypes and treatments indicated in the color key (n = 6–15 embryos each). In (O) differences between control and experimental specimens were significant at each time point. In addition, LY411575 treated <i>hs</i>:<i>dnfgfr1</i> embryos were significantly different from <i>hs</i>:<i>dnfgfr1</i> alone or LY411575 treatment alone.</p

Tfap2a enhances otic neurogenesis.

<p>(A-L) Cross-sections (medial left, dorsal up) through the otic region just posterior to the utricular macula showing <i>ngn1</i> expression in +/+ control embryos, <i>hs</i>:<i>tfap2a</i> embryos and <i>tfap2a</i>^<i>-/-</i> mutants at the indicated times. Wild-type and <i>hs</i>:<i>tfap2a</i> embryos were heat shocked as indicated in each panel. Overexpression of <i>tfap2a</i> increases the number of neuroblasts in the otic vesicle whereas loss of <i>tfap2a</i> slows down and decreases otic neurogenesis. The outer and inner edges of the otic vesicle are outlined in each image. (M, N) Mean and standard deviation of the total number of <i>ngn1</i> positive cells in the otic epithelium from 24 to 32 hpf for the genotypes indicated in the color key (counted from serial sections, n = 3–7 ears per time point). Asterisks (*) indicate statistically significant differences between groups indicated by brackets (N) or compared to control embryos (M).</p

Tfap2a regulates the level of Fgf and Notch Signaling in the otic vesicle.

<p>(A-V) Whole-mount images (dorsal up, anterior left) showing dorsolateral views of the otic vesicle (outlined). (A-R) Expression of the indicated genes in wild-type embryos, <i>hs</i>:<i>tfap2a</i> embryos and <i>tfap2a</i>^-/- mutants (A-I) or <i>tfap2a</i> morphants (J-R) at 26 hpf (A-L, P-R) and 28 (M-O) hpf. (S, T) Cross-sections (dorsal up, medial left) passing through the utricular macula show <i>spry4</i> expression at 28 hpf in a control embryo and <i>tfap2a</i>^-/- mutant. (U-X) Whole-mounts showing expression of <i>etv5b</i> at 26 hpf. Activation of <i>hs</i>:<i>tfap2a</i> diminishes <i>etv5b</i> expression (U, V), activation of <i>hs</i>:<i>fgf8</i> leads to global upregulation of <i>etv5b</i> (W), and co-activation of <i>hs</i>:<i>fgf8</i> and <i>hs</i>:<i>tfap2a</i> restores <i>etv5b</i> to near normal (X). (Y) Cross-sections (dorsal up, medial left) passing just posterior to the utricular macula showing <i>ngn1</i> at 24 hpf following a 35°C heat shock at 23 hpf. Reduction in the <i>ngn1</i> domain caused by knockdown of <i>tfap2a</i> is rescued by weak activation of <i>hs</i>:<i>dnfgfr1</i>. (Z) Mean and standard deviation of the total number of <i>ngn1</i> positive cells in the otic epithelium at 24 hpf for the genotypes and knockdowns indicated in the color key (counted from serial sections, n = 3–6 ears per time point). Asterisks (*) indicate statistically significant differences between the groups indicated in brackets.</p

Conserved expression of <i>tfap2a</i> during otic neurogenesis.

<p>All images show cross-sections of the otic placode or vesicle in wild type zebrafish embryos (A-J) or chick embryos (L-Q) with a dorsal up and medial to the left. (A, B) At 14 hpf (10 somites) <i>pax2a</i> (red) marks the precursor cells in the emerging otic placode that are co-labeled with <i>tfap2a</i> (blue). (C-H) Cross-sections through the widest part of the neurogenic domain of the otic vesicle, just posterior to the utricular macula. The outer and inner edges of the otic vesicle are outlined. Patterns of <i>ngn1</i> or <i>tfap2a</i> are shown at the indicated times. <i>tfap2a</i> is expressed in the ventrolateral part of the otic vesicle, which partially overlaps the domain of <i>ngn1</i> expression. (I-J) Cross-sections passing through the utricular macula of specimens co-stained for Isl1 (red) and <i>tfap2a</i> (blue) at 48 hpf. Expression of <i>tfap2a</i> is not detected in the floor of the otic vesicle or in the mature SAG neurons at this time. (K) Schematic summary of SAG development in zebrafish, including regional markers. Neuroblasts are specified and delaminate from the otic vesicle (light purple) adjacent to nascent sensory epithelia (green). Recently delaminated neuroblasts migrate towards hindbrain and continue to proliferate, forming the transit-amplifying pool (blue). Neuroblasts then stop dividing and differentiate into mature neurons (red). Relevant genes expressed in each domain are indicated. Expression of <i>tfap2a</i> (dark purple) overlaps the neurogenic domain, as well as the domain of <i>bmp7a</i> expression. Note that all of the tissues indicated express Fgf-target genes (<i>etv5b</i> and <i>spry4</i>) and transducers of Bmp (<i>smad1</i> and <i>smad5</i>), but transit amplifying SAG precursors show specific upregulation of <i>smad1</i> and <i>smad5</i> [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005037#pgen.1005037.ref037" target="_blank">37</a>]. (L-Q) Cross-sections through the otic vesicle of chick embryos at days 3 and 4 (E3 and E4). The sensory region is labeled with Jagged-1 (green). Tfap2a (red) is expressed in the ventrolateral otic domain in chick embryos similar to the pattern observed in zebrafish.</p